MINISTRY OF HEALTH OF REPUBLIC OF MOLDOVA THE STATE UNIVERSITY OF MEDICINE AND PHARMACY "N.

TESTEMITANU"

MEDICAL PATHOPHYSIOLOGY I volume GENERAL NOSOLOGY TYPICAL PATHOLOGICAL PROCESSES

Theoretical course Edited by professor V.Lutan

Chisinau 2002 CONTENT GENERAL NOSOLOGY 1. General characteristic of pathophysiology .. 7 1.1. The definition of pathophysiology as a science and didactic discipline.7 1.2. The structure and component parts of path physiology..8 1.3. The task of pathophysiology.......9 1.4. The object and methods of study. The method of pathophysiological experiment..10 1.5. The importance and place of path physiology in the process of medical stuff instruction.11 2. General etiology 2.1. The characteristics of the disease causes. 2.2. The characteristics of the disease appearance conditions

3. General pathogenesis 3.1. The role of etiological factor in the appearance and progression of the disease. The lesion - as a disease substrate 3.2. The role of pathogenic factor in the disease evolution. The cause and effect relationship. The main link of pathogeneses. The vicious circle. 3.3. The role of reactivity of organism in the disease development 4. General nosology 4.1. The notion of health and disease .. 4.2. The classification of diseases . 4.3. The periods of development of disease .. 4.4. The structure of the disease

5. The general sanogenesis

TYPICAL PATHOLOGICAL PROCESSES The cellular pathological typical processes

6. Cell injury 6.1 The cellular membrane lesions 6.2 Cell nucleus lesions.. 6.3 The endoplasmic reticulum lesions.. 6.4 Mitochondrial lesions 6.5 The lysosomes lesions 6.6 The consequences and general manifestations of cell injury.
6.6.1 6.6.2 6.6.3 6.6.4 6.6.5 Enzyme- emia.. Hyperpotassemia. Acute phase reaction Fever Stress

7. Cell dystrophy.. 8. Apoptosis 9. Necrosis

The typical pathological processes in the tissues

10. The cellular dedifferentiation. 11. The impairment of regenerative processes ... 12. Hyperplasia. Hypertrophy.. 13. Atrophy 14. Sclerosis.
The typical pathological processes in the organs

15. Inflammation ... 15.1 General characteristic... 15.2 The etiology of inflammation . 15.3 The pathogenesis of inflammation ..
15.3.1 The alteration in site of inflammation. The primary and secondary alteration . 15.3.2 The mediators of inflammation .. 15.3.3 The vascular reaction in site of inflammation 15.3.4 The exudation in site of inflammation 15.3.5 The leucocytes emigration in site of inflammation. Phagocytosis. The proliferation and regeneration in site of inflammation The relationship between the inflammation and reactivity of organism . The general changes in the organism during the inflammation. The biological importance of inflammatory reaction .

15.4 15.5 15.6

16. The allergic pathological processes ... 16.1 General characteristics of allergic reactions ....... 16.2 The etiology of allergy. The characteristics of allergen . 16.3 The pathogenesis of allergic reactions
16.3.1 The allergic reaction type I . 16.3.2 The allergic reaction type II 16.3.3 The allergic reaction type III .. 16.3.4 The allergic reaction type IV .... 16.3.5 The allergic reaction type V .. Nonspecific hyper-sensibility Auto allergic reactions

16.4 16.5

17. Regional blood circulation disorders 17.1 Arterial hyperemia .. 17.2 Venous hyperemia .. 17.3 Ischemia... 17.4 Embolism. 17.5 Blood stasis.. 17.6 Disorders of blood rheology.... 18. The disorders of capillary interstitial exchange. The disorders of lymph genesis and
lymph dynamics ... 18.1. The control of capillary-interstitial exchange...... 18.2 The control of lymph genesis and lymph dynamics. 18.3 The disorders of capillary-interstitial exchange 18.3.1 Edema.... 18.4 The disorders of lymph dynamics.... The integrated pathological typical processes

19. Metabolic imbalance 19.1 The carbohydrates dyshomeostasis.

19.1.1 Hypoglycemia. 19.1.2 Hyperglycemia 19.1.3 Hyperketonemia.

19.1.4 Galactosemia...... 19.1.5 The consequences of carbohydrates dyshomeostasis..... 19.2 Lipids dyshomeostasis. 19.2.1 The general etiology of lipids dyshomeostasis...... 19.2.2 Hyperlipidemia.. 19.2.3 Hypercholesterolemia 19.2.4 Lipid metabolism disorders in organs 19.3 Protein dyshomeostasis.... 19.3.1 The general etiology of protein dyshomeostasis.... 19.3.2 The protein dyshomeostasis 19.4 Starvation..

20. The electrolyte dyshomeostasis.. 20.1 Sodium dyshomeostasis.. 20.2 Potassium dyshomeostasis.. 20.3 Calcium dyshomeostasis. 20.4 Magnesium dyshomeostasis 20.5 Magnesium dyshomeostasis. 20.6 Phosphates dyshomeostasis. 20.7 Chlorine dyshomeostasis.
21. Fluids dyshomeostasis. 21.1 Intracellular and extracellular fluid volume changes.. 21.2 Hyperhydration 21.2 Dehydration. 22. Acid-base imbalance.... 22.1 Acidosis 22.2 Alcalosis 23. General dysoxia.................................................................................................................... 23.1 General hypoxia....................................................................................................... 23.2 General hyperoxya................................................................................................... 24. Thermic dyshomeostasis...................................................................................................... 24.1 Terminal states......................................................................................................... 24.2 Biological death....................................................................................................... 24.3 Pathogenetic principles of resuscitation.................................................................. 25. The death..............................................................................................................................

PREFACE

The course meets the theoretical concept of Pathophysiology Department Staff, State University of Medicine and Pharmacy N. Testemitanu from Moldova, about the concept of teaching pathophysiology to students of Faculty of General Medicine, Dentistry and Pharmacy. Simultaneously with the development and improvement of methodology of physician training have developed methods for teaching of preclinical subjects, including pathophysiology. Pathophysiology can be seen from two aspects: the teaching aspect and the aspect of medical practice science. Natural role of pathophysiology as preclinical teaching discipline follows from the definition of them - studying the general laws of origin, occurrence, development and resolution of pathological processes. Specific pathological process located at different levels of organization of body - molecular, cellular, tissue, in organ and whole body - is the focus of pathophysiology. Following this purpose pathophysiology endows medical students with knowledge about all the basic pathological processes, whose combination forms the disease - nosologic entities. Medical pathophysiology as fundamental science, studies etiology and pathogenesis of disease, elaborates the principles of pathogenic and etiotropic prevention and therapy of disease. However, its task as a teaching discipline consists in equipping students with modern knowledge about the basic pathological processes of disease with constituent parts that will be studied in the practical disciplines. Unlike the fundamental pathophysiology, the current theoretical course is called Medical Pathophysiology, what is emphasizing teaching and applied nature of the material. The volume of presented information correspond to the informational level of student the third year and knowledge necessary for of medical practice activity. Current volume contains only theoretical pathophysiology (etiology, pathogenesis, nosology and general sanogenesis) and general pathophysiology (typical pathological processes). Exposure data on all the typical pathological processes follow their natural logic, the evolution of the cell to the whole body. During this course of pathophysiology were included only confirmed information and viable concepts. The authors hope that this book will be useful primarily for medical school students, and will raise the interest of physicians. General Nosology 1. The general characteristics of pathophysiology 1.1. 1.2. 1.3. 1.4. 1.5. The definition of pathophysiology as a science and didactic discipline The structure and the component parts of pathophysiology The tasks of pathophysiology The object and methods of study. The method of pathophysiological experiment The importance and place of pathophysiology in the process of medical stuff instruction 1.1 The definition of pathophysiology as a science and didactic discipline The pathologic physiology (pathophysiology) it is a fundamental medical science and preclinical discipline studied during the physicians instruction. Pathophysiology derives from a much general science pathology. Pathology (from Greek: pathos-suffering; logos-science) it is the science which studies the general laws of origin, evolution and the ending of morbid processes, and the complex of biochemical, morphological and functional changes at the molecular, cellular, organ, system and organism levels.

Pathology is an integrative science, which combine more concrete discipline: pathological biochemistry, morph-pathology, physiopathology, genetics, microbiology, clinic discipline. Pathology consists from the following compartments: theoretic pathology general pathology special pathology clinic pathology Theoretic pathology a part of pathology which studies the general laws of the origin, appearance, evolution and the ending of the disease and establish its essence. Theoretic pathology studies the disease as a philosophic, biologic and social category. General pathology a part of pathology which studies the general laws of origin, appearance, evolution and ending of the typical pathologic processes indifferently of the cause, the peculiarities of species and individuality of the organism (gender, age, build etc.), and placement in the organs. The general pathology studies also the complex of biochemical, morphologic and functional changes as part of typical pathological processes. Conventional the general pathology can be divided in general pathological biochemistry, general morphological pathology and general pathophysiology. Special pathology a part of pathology which studies general laws of the origin, appearance, evolution and ending of typical pathological processes placed in each system of the organism and biochemical, morphological and functional specific changes for this processes. Conventional the special pathology can be divided in special pathological biochemistry, special morphologic pathology and special pathophysiology. Clinical pathology a part of pathology which studies a complex of pathological processes from organs and characteristically system for each disease (nosologic entity) and complex of different clinical manifestation of different diseases. The name of pathologic physiology discipline studies so physiology as pathology. Physiology is a theoretic discipline, which studies vital activity of the healthy organism cells function, tissues, organs, systems and of the whole healthy body. Pathologic physiology (pathophysiology) or functional pathology studies vital activity of the sick organism the function of the cells, tissues, organs, systems and the whole organism. Together with all the disciplines named above, pathophysiology is a component part of pathology, which studies the pathologic processes and diseases from the functional aspect. 1.2. The structure and component parts of pathophysiology As a component of general pathology, pathophysiology repeats its structure. The structure and component parts of pathophysiology symmetrically corresponds to the structure of pathology. Thus pathophysiology contains: - theoretical pathophysiology or general nosology, - general pathophysiology or the typical pathologic processes, - special pathophysiology or the pathophysiology of the sick organisms systems - clinical pathophysiology or the pathophysiology of the sick organism

General Nosology (Greek: nosos suffering; logos - science) studies the general laws of the disease origin (general etiology), disease evolution (general pathogenesis), the ending of the disease (sanogenesis, tanatogenesis), and disease structure (the proper nosology). General pathophysiology studies the general laws of etiology, appearance, evolution and ending of the typical pathologic processes, which have common properties regardless of the provoked cause, biologic species, and the localizations of the process. General pathophysiology studies also the functional changes at the subcellular, cellular and tissue levels. According the level of localization we distinguish: - cellular typical pathological processes, - typical pathological processes of the tissue, - typical pathological processes of the organs, - integrated typical pathologic processes. The typical pathologic processes represent the alphabet of pathology, but their combination and their peculiarities according the cause, biologic specific properties and individual properties of the organism, localization in different organs determine the unique character of each disease. The typical cellular pathologic processes can evaluate in cellular lesion, cellular dystrophy and cellular necroses. The development of the cellular pathologic processes leads to tissue pathologic processes dedifferentiation, atrophy, hypertrophy and hyperplasia. The deregulations of regional blood circulation, inflammation, allergic processes and deregulations of capillary-interstitial exchange are parts of pathological processes in the organs. The integral pathological processes manifest themselves through dyshomeostasis (metabolic, hydro, electrolytic, acid-basic), dyzoxia, vital organs insufficiency, death of the organism. Take in consideration that typical pathological processes are explored by pathophysiology in cooperation with other medical-biological disciplines pathological morphology, pathological biochemistry, microbiology etc. Special pathophysiology studies the peculiarities of appearance, evolution and ending of typical pathological processes with a concrete placement in different organs, systems of the organism and functional manifestations at the sub cellular, cellular, tissue levels, organ and systems. This compartment studies typical pathological processes in the CNS, endocrine, cardiovascular, respiratory, digestive, excretory, reproductive in cooperation with pathologic morphology and biochemistry. Clinical pathophysiology studies functional changes at the following levels: subcellular, cellular, tissue, organ and system in different nosologic entities (diseases). The integral picture of the diseases consist from integration of functional, morphological and biochemical changes. 1.3 The tasks of pathophysiology The tasks of pathophysiology are: 1. studying of the general laws of origin, appearance, evolution and resolution of the disease as a philosophical category (general nosology); 2. studying of general laws of origin, appearance, evolution and resolution of typical pathological processes (general path physiology); 3. studying of the appearance, evolution , functional manifestations peculiarities and the ending of typical pathological processes with a concrete placement in different organs and system of the organism (special path physiology); 4. studying of functional changes at the different levels: subcellular, cellular, tissue, organ, system and the whole organism during a certain disease (clinical path physiology).

1.4 The object and methods of study. The method of pathophysiological experiment The general object of study of all disciplines that form pathology, inclusive pathophysiology is the sick organism. Chronologically, at the moment of forming as an experimental discipline, the primordial object of study of pathophysiology was the laboratory animals. The done studies on the laboratory animals gave essential information about the pathological processes and experimental diseases, which being extrapolated and adjusted to the human organism constitute the theoretical base of experimental pathology and therapy. Actually, simultaneously with implementation in practice of noninvasive methods of investigation, more frequent in the center of the research is the patient. So the object of study of modern pathophysiology is the laboratory animal submits to experimental reproduced pathological processes as well as the patient in the same time. So, most important method of research of pathophysiology is the method of pathophysiological experiment. The essence of pathophysiological experiment consists of reproduction and modeling of the human disease on the laboratory animals. Currently, pathophysiological experiments are effectuated also on the isolated organs (heart, stomach and muscles), cellular cultures, isolated cells (nervous, muscular and endocrine cells), and cellular organelles (mitochondria, lysosomes). Made in acute or chronic conditions, accompanied by the supplementary methods (biochemical, physiological, histological, microbiological, hematological, immunological and clinical), the pathophysiological experiment allows to obtain a complex of information about pathological changes beginning at the molecular level and end with whole organism. Pathophysiological experiment has several stages. The first stage is the preliminary one during which the explorer defines the suggested experiment, stipulates the goals and tasks of the experiment, formulates the questions; he is going to get answers. The second stage includes the selection of the adequate model of pathologic process or disease which is maximally corresponding to natural process find in humans. At the same stage takes place the selection of research methods according to the goal and tasks of the experiment. On the third stage it is formulated the experiment algorithm, it is determined the succession of the interventions on the object, functional signs, which are going to be recorded. On the fourth stage takes place the processing of obtained information during the experiment analyzing and decipher of all the dates and their transformation in accepted units, biometry, which allows the observation of the veracity of all recorded changes, correlational analyses which reveals the dynamism of process, the interpretation of obtained result, formulation of the conclusion. This stage ends the pathophysiological experiment. Then will be realize the most important task of the experiment - the extrapolation of obtained from the laboratory animals dates on the patients with a natural spontaneous disease. This extrapolation needs the evidence of the biological peculiarities of the human and the laboratory animal used in the experiment, coherence of the disease model with its natural prototype, truthfulness of studied units etc. Only a very detailed and long research can confirm or contest identity of the natural pathologic process and the artificial one, this will determine the results value obtained in the experiment. Providing clinical medicine with non-invasive methods allowing the deep study of life processes at different levels of organization of the human ill body is a strong arsenal in studying pathological processes directly in humans and accelerates the validation of experimental data in medical practice. 1.5 The importance and place of pathophysiology in the process of medical stuff instruction The pathophysiology as a discipline in the preclinical medical training is in close relations with other disciplines. Some of them precede pathophysiology preparing the theoretical premises for studying of pathological processes and diseases (histology, biochemistry, genetics, physiology, microbiology etc.). Other disciplines are studied in the same time with pathophysiology (pathological morphology). The third categories are those clinical disciplines, studying pathophysiology.

Thus pathophysiology is a preclinical discipline develops the scientific vision of future physicians concerning the essence of the disease, defines the typical pathological processes which constitute the basics of the disease (the medical pathologies alphabet) shapes the elements of clinical thinking and prepares to assimilate clinical disciplines. Concluding study pathophysiology, the student must know general information about the essence of disease as philosophical, biological and social category, this being the general philosophic concept of the a physician: : to know the general laws of origin, appearance, evolution, ending and functional manifestation of the most spread typical pathologic processes (alphabet of the clinical pathology); to know the most important pathogenetic and sanogenetical mechanisms and functional changes at the cellular level, organ, systemic and the whole organism in the most spread diseases (clinical path physiology). Pathophysiology forms the dialectic way of clinical thinking and supply the student with some practical skills. At the end of studying of pathophysiology the student must know how to make a pathophysiological experiment, to interpret analytically and synthetically the results of the laboratory investigations (haemograms, urine analyses, gastric and duodenal juice, electrocardiograms, spirometry etc.). These tasks are going to help the student to assimilate easily the future clinical discipline and will form the professional-scientific concept of the physician.

2. General Etiology 2.1. The characteristics of the disease causes 2.2. The characteristics of the disease appearance conditions Etiology ( from greek aitia cause; logos - science) it translates as science about the cause of the disease. At present etiology is defined as the science and compartment of path physiology, which studies the causes and conditions of disease appearance. Etiology answers the question: What have caused the disease? Etiology consists of two notions: general etiology and special etiology. General etiology is defined as science and a compartment of theoretical path physiology (of nosology), which studies the general laws of disease origin, interrelation and interaction of the cause, the exogenous and endogen conditions in the disease origin. Or, general etiology studies only that laws that are common for all the disease origin. The contras, the special etiology investigates the origin laws, the causes and appearance condition of each concrete disease and is a prerogative to all clinical disciplines. The disease in the etiologic context is defined as an interaction result between the cause and living body in specific conditions. 2.1. The characteristics of the disease causes The disease cause can be any substance, energy or information, interacting with the human body (a complex of substances, energy and information) and causes structural and functional changes. The cause, as the effect, are two abstract categories, manifesting themselves in a concrete way in different conditions. Any substance, energy or information becomes a cause only in that moment when it interacts with another substance, energy or information from the human body causes an effect. The etiologic factor is the cause and conditions complexity in the moment when it interacts with the organism and provokes the disease (need to mention that at the moment the notion of cause and etiologic factor are equivalents). Theoretically any substance, energy or information interact with the body causes disease, but in reality this probability varies from 0 till 100%. The knowledge of this probability by doctor is a way of prognosis of the morbidity. The diversity of material factors (substance, energy and information), that evolve as causes of different diseases requires a systematization of their.

The classification of the factors that can serve as a factor for disease development is done according different criterias: A. Classification according to origin: a) Exogenous cause are outside of the body, environment; it is represented the most of disease causes; b) Endogen causes are inside of the body, represented by specific defects or peculiarities of structure and body function. The knowledge of the origin of the disease cause is important for the prophylaxis and therapeutic strategy. So, the diseases caused by exogenous factors can be prevented by environment amelioration, while the diseases caused by endogen factors (eg: hereditary diseases) needs a special prophylaxes. B. Classification according to the nature of the causal factors : a) Mechanical factors act through the potential mechanical energy (compression) or kinetic (positive or negative acceleration, composition of forces); the action result are the structural changes of the body mechanical traumas. b) Physical factors act through the physical energy of the atoms movement (thermal energy), of the elementary particles (electrons, protons, neutrons), of the electromagnetic waves (light, ionized ray), of the fields (electric, magnetic, gravitational); the result of physical factors action are the physical traumas actinic disease, free radical formation etc. c) Chemical factors acts through the initiation of chemical factors with the body substances which character depends on the chemical substance nature and can be reaction of oxidation, reduction, neutralization, dissemination; the result of the chemical factors action is biochemical homeostasis deregulation of the body; d) Informational factors the factors which have significantly biologic information for the body and act on the information receptor system of the body (mediators, hormones, antigens); e) Biologic factors different living beings (viruses, bacteria, fungi, protozoa) that act on the human body in a complex way through the mechanical, physical energy or information (antigens, active biologic substances); f) Psychogenic factors a particular class of informational factors that acts through the conscience (linguistic signals); psychogenic factors dont have direct harmful effects, but act on the body through the psychic psycho-somatic action; g) Social factors interrelation between people, which determine the hierarchical position of the person in the society; the loss of the hierarchic position by a person in the society represents a very strong pathogen factor (stressing) capable to provoke a myocardial infarction, gastric ulcer, arterial hypertension, hyperthyroidism. C. Classification according to the pathogen potential: a) Indifferent factors for the organism; these factors dont cause any kind of changes or reaction in the body (eg: the inert gases from the atmosphere) and the possibility of disease appearance due to indifferent factors is zero. In case of repeated action in the same time with another pathogen factor these can trigger the disease through the conditioned reflex mechanism; b) Physiological factors acting on the body cause reasonable reactions, physiological qualitative and quantitative, they do not disturb the homeostasis and as a result the body adapts; they may become pathogenic only when exceed the physiologic diapason of intensity and duration of action, acts on sensible body (eg. in allergy) or trigger the disease through the conditioned reflex mechanism. c) Conventional pathogenic factors the factors, which become harmful only in an environment with specific conditions, or these conditions amplify the cause action or diminish the body resistance, so, produce a disequilibrium of peaceful coexistence of the organism with the conventional pathogen factor (eg. the saprophytic micro flora of the digestive tract). It is easy to observe that the probability of getting ill under the action of conventional pathologic factors varies a lot. d) Pathogen factors the factors that provoke disease in every condition with a 100% probability. D. Classification according to the topographic action on the body:

10

a) The General action is orientated in the same time to the whole body, when possible all structures of the body are exposed to the pathogen action of the harmful factor (cosmic factors, gravitation). In the same time the general factors have an isotrope action with equal intensity and uniform lesions of all structures situated in the action zone and anisotrop action or trope action with selective direction on certain structures (eg. Hepatotrope, cardiotrope, nephrotrope, neurotrope, psychotropic action of chemical substances in general toxemia). b) Local action, it is limited by a specific structure organ, anatomic region. A common property for all causes of disease (pathogen factors, harmful factors) is the capacity to change the biochemical, structural, functional, informational, psychic and social homeostasis of the man. The roll of cause in the disease origin is decisive. The cause determines the possibility of disease appearance and the specific character of the disease. If the cause is absent then the disease appearance is impossible, but in the same time if the cause is present doesnt mean that the disease appearance is inevitable. The relation between cause and disease may be formulated in the following way: in the cause absence the disease does not appear; under the action of a cause the disease can occur. The probability of disease appearance under the cause action depends on the conditions. The knowledge of the disease cause is the theoretical base for the specific prophylaxis, which helps to avoid the cause action on the body. The knowledge about the cause is also the base for specific therapy which tries to remove the cause from the body after the disease appeared already. 2.2. The conditions characteristic of disease appearance The condition is the substance, energy or information, which direct doesnt cause the disease, but accompanies the cause action and may encourage or can prevent its action. According to the anthropocentric principle accepted in medicine (the man is located in center), the conditions, which prevent the cause action and disease appearance are called positive (for man), but those, which facilitate the cause action and contribute the disease appearance- unfavorable(for man). According to the origin and their localization, the conditions can be divided in exogenous and endogenous. The exogenous conditions are a part of the environment atmosphere, hydrosphere, technosphere, sochisphere, cosmic action, life conditions, professional condition, alimentation . The endogenous conditions are a part of the body itself hereditary, constitution, reactivity, components of internal environment, metabolism, and morph functional peculiarities of all the organ systems. The internal conditions as the external conditions can be mechanical, physical, chemical, informational and biological. The conditions as a dialectic category have a concrete character: the same factor (substance, energy, information) in specific conditions can develop as a cause and as a condition for disease appearance. The role of conditions is to create possibilities (or impossibilities) for achieve of cause action and disease appearance. The knowledge of conditions is the theoretical base for nonspecific prophylaxes and nonspecific therapy. The nonspecific prophylaxes, which is efficient for the majority of diseases, consists of exogenous and endogenous favorable conditions, which would stop the cause action on the body before the disease starts. From this kind of conditions there are : the physical rest, microclimate optimal condition, qualitative alimentation, vitamin consumptions, microelements . The same factors can be used in nonspecific therapy after the disease onset already for specific therapeutic effect amplification. 3. General Pathogeneses 3.1. The role of etiological factor in appearance of the disease. The lesion as a material substrate for the disease. 3.2. The role of pathogenic factors in disease evolution. The cause and effect interrelation. The main link of pathogeneses . The vicious circle. 3.3. The role of body in the disease development.

11

Pathogeneses (from Greek pathos suffering; logos - science) is a science and a compartment of theoretical path physiology, which studies the appearance mechanisms, development and disease resolution. Pathogeneses answers to the question: How it appears, develops and ends the disease? We distinguish two types of pathogeneses notions: general pathogeneses and specific pathogeneses. General Pathogeneses is a compartment of theoretical path physiology, which studies the general appearance mechanisms of disease, development and end of the typical pathological processes of the disease. These lows are common for the majority of the disease and have an abstract aspect, theoretical and philosophical. Special Pathogeneses studies the lows of appearance, development and end of each concrete disease, taking in consideration the etiologic factor, organ where takes place the process and the individual properties of the body. Special Pathogeneses studies these diseases ( internal diseases, surgical diseases, infectious diseases). From the all general laws common for the pathologic processes and diseases indifferently whatever cause, biologic species, pathologic process localization there are: a) The laws of interaction between the cause and the body in the process of disease appearance and evolution; the etiologic factor role in the onset process and disease development; b) The laws of interaction between the pathogenic factors; the role of pathogenic factors in disease evolution; c) The role of body reaction in the disease appearance and development. 3.1. The role of etiological factor in the disease appearance. The lesion as a material substrate of the disease. The primary effects of the cause action on the body and the start point of the disease are the lesions. The lesion is any persistent and irreversible deregulation of the body homeostasis biochemical, structural, functional and psychic. The dyshomeostasis manifests through structure disintegration and structure deregulation. (the cause is also called the pathogen factor (pathos disease + genesis to give birth), harmful factor, injuries factor. In this way, the pathogenesis of cause is determined by its capacity to provoke an injury of the body, but the injury represents the effect of the disease cause action and in the same time the pathogenic factor, absolutely indispensable for the complete disease development (Pathogenic factor its a part of pathogeneses, maintains the disease development). The lesion is the material substrate of each disease. The specific of lesion depends on the cause properties, but the disease specific on the lesion specific. The lesion classification is according to different criteria. A. According to properties of harmful factors and lesion character : a) mechanical lesions caused by mechanical factors (destruction, structural disintegration of the body cellular organelles, cells, tissue, organs .); b) physical lesions caused by physical factors (thermal distortion of the organic substances, molecular ionization, free radical formation and peroxidation own substances, cell polarization etc.); c) chemical lesions caused by chemical substances (disintegration or transformation of chemical substances of the body); d) complex lesions: mechanic, physical, chemical, informational and antigenic caused by biological factors; e) mental disorders caused by psychogenic factors, but later and somatic factors caused by psycho-somatic mechanism; There is a need to mention that effects of the pathogenic factor action have a specific character of the factor. B. According to the lesion localization on the different hierarchic levels of the body organization: a) atomic lesions the modification of elementary structure modification of the atoms from the body under the action of high energy. Under the action of ionized rays and different particles occurs the atom ionization with loss or capture of electrons and formation of positive and negative ion pairs;

12

under the action of neutrons occurs their absorption by the stable atoms with transformation in unstable elements, radioactive. These primary modifications of the atoms structure can lead to secondary modification, for example molecular lesion. b) molecular lesion modifications in the primary structure, secondary, tertiary or quaternary of molecules, in special those complex like proteins, lipo- and glycoproteins, DNA, RNA, enzymes, hemoglobin, immunoglobulin, receptors etc. All diseases, that have as a base the molecular lesions, meet molecular pathology with such compartments as: hereditary diseases, genetic mutations, hemoglobinopathies, enzymes pathology, receptor pathology, membrane pathology, immune pathology. c) sub cell lesions the damage of cellular organelles in selective way or nonspecific by different pathogen factors: cytoplasm membranes which are the first targets of the pathogen factor action and are injured by the most of them leading to secondary lesions of the other cellular organelles, nucleus and genetic apparatus under the action of mutagens action in different hereditary diseases, lysosomes with releasing their enzymes and later cellular autolysis , the mitochondria with disorders of oxidative phosphorylation processes , energy generation or conservation, Golgi apparatus. Because the cell is a complex structure, the injury of any organelle may lead to the cell disintegration as a biological system. d) cellular lesions are the direct consequence of the irreversible injury of sub cellular structures; all of cellular lesions is the cell pathology (eg: cellular dystrophies, necroses etc.). e) tissue lesions or systemic concomitant selective cells affectation with unique origin, indifferently of their localization: bone pathology (osteoporoses, osteodystrophies ); muscle pathology (striate muscle affectation in myasthenia), vascular system affectation (absolute primary erytrocytosis, lympholeucosis, myeloleucosis); connective tissue (collagenosis); epithelium (A avitaminosis) etc. f) lesions at the level of the hole body (integral lesions) concomitant affectation of the all structures of the (hypoxia, intoxication, shock etc.). The disease may begin with action of pathogen factor at any organization level of the body, but any would be injured hierarchical level by direct action of cause in consequence appear ascending scale effects until integral disorders, in this way this leads to new disorders or lesions in descending direction until to cellular level. The disease is all pathological processes present on the all levels of organization of the body.

C. According to the succession of the lesion appearance: a) primary lesions appear as an effect of pathogen factor ; b) secondary lesions appear as a result of the action of the primary lesions. These cause other lesions, so that they cause another lesions etc. All further lesions caused by effects of the harmful factor action are the secondary lesions. The disease never do not limited on the primary lesions, but includes also secondary lesions. The material substratum of all diseases are different lesions caused by harmful factor and later by the action of its effects. Between the primary and secondary lesions there is a dialectic interrelation of cause and effect with transformation of the effect in a new cause which leads to auto amplification, expansive in progression of the lesions. The importance of primary and secondary lesions and the relation between them is the possibility to lay the therapeutic procedures, which will remove the primary lesions, caused by the harmful factor, as the secondary processes with a negative significance for the body. For example in the inflammatory processes are applied the antimicrobial therapy as oppression the secondary lesions, as hyperemia and exaggerated exudation. D. According to the affected filed: a) local lesions, regional affects a limited anatomic structure (a part of an organ, organ, anatomic region); b) general lesions affects in the same time more regions or even the hole body. Between the local and general lesions are specific dialectic correlations. During the disease development indifferently of the lesion level (molecular, sub cellular or cellular), the beginning of the disease ( with generalized or localized lesions) occurs a combination

13

between local and general lesions through generalization of local changes and localization of general changes. The disease represents all local and general modifications. The local action of the harmful factor initial leads to the damage of local structures, but later appear lesions situated out of the first affected zone. This kind of process is called the generalization of local process. The ways and mechanisms of generalization pathologic process are: a) Neurogenic mechanism: local primary lesions through the nervous system (receptors, afferent ways, nervous centers, efferent ways) initiates different animal and vegetative reflexes with reactions from the effectors organs that werent affected by the pathogen factor; another neurogenic way is the neuronal axonal transport of the toxins (tetanus) or infection (rabies) to the CNS with generalization of pathologic effects; b) hematogen mechanism toxin and pathogen germs dissemination with the blood flow from the primary affected zone to the distal organs and their implication in the pathologic processes, which becomes general (eg: toxemia, septicemia etc.); c) lymphogenic mechanism circulation by the lymphatic system of: toxins and pathogen germs, cancer cells from primary local site to distance organs which leads to multiple secondary foci (metastasis of septic processes, malignant tumors). d) generalization through continuity spreading of pathologic process from the primary foci to the neighboring structures through a direct contact (purulent inflammatory process localized in the liver can affect through a direct contact the diaphragm and later the lung); e) functional mechanism the functional abolish of affected organ can induce disorders in other organs that depends on this function (oxygen deficiency from lung disease induces hypoxic changes in all organs that consume oxygen). In case of large action of the pathogen factor not all structures of the body are affected in the same degree: some organs are affected more then others. The preferential damage of some structures by the generalized action of the harmful factor is called localization of pathologic process. The localization ways and mechanisms are: a) localization as a result of different sensibility of the body structures by the action of pathogen factor (different vulnerability). In this way, the ionized rays action on the hole body the most vulnerable and injured are the tissue with the highest mitotic activity (eg. hematopoietic organs, intestinal epithelium, germinative epithelium), as here are localized the radiation diseases; through the general action of atmospheric hypoxia the most vulnerable are cortical neurons that cause their death before other cells; b) localization through the excretion by specific organs of exogenous toxins and their accumulation until the harmful quantities in this way occur predominant damage of the kidney in general intoxication with quicksilver, of the digestive tract in the lead intoxication; c) localization through tropism mechanism a specific affinity of the pathogen factor to the different structure, mediated by the presence of specific receptors of the pathogen factors (CNS sensibility and of innervated organs to respective mediators action, target organs sensibility to hormones action ), of the antigens (sensibility of antibody storing cells to the action of antigens in the anaphylaxis etc.), through favorable micro ecology (ex: the bile represents a selective nutritive medium for the salmonella). The disease represents an inseparable combination of local and general lesions. The disease is a general process but with a predominant localization in one structure or another. The pragmatic importance between local and general processes helps in the therapeutic strategy formulation. In every disease the doctor applies so topic therapeutic procedure orientated to liquidation of local phenomenon, so general therapy orientated to liquidation of general pathologic phenomena from the body. E. According to the predominant character of the lesion: a) structural changes; b) functional disorders; The interrelations between structural changes and functional disorders have a dialectic character. The structure and function are two dialectic categories derived from the shape and content. The incorrect interpretation of these two categories leads to conceptual collisions initiated by the wrong

14

question: What is the primordial thing in a disease the structural lesions or the functional changes? The rapport between the structural lesions and functional disorders ? The report between the structural lesions and functional disorders observed in different diseases are not always equal what has allowed to underline some organic diseases, in which prevails functional diseases, while the structural lesion are absent. In the dialectics vision the disease is an inseparable combination of structural lesions functional disorders. Ordinarily, in most of diseases degree of the functional disorders complies with degree of the structural lesions (ex. the intensity of the functional disorders in bleeding is proportional to the loss blood mass). In some cases this rapport may be unbalanced. In this way, in some diseases structural lesions do not comply with the vast functional disorders, what may be explained by the excessive work of some structures (ex: lack of kidney is not characterized by functional disorders). There are pathologies, in which very limited structural lesions lead to severe functional disorders even to death what depend on the vital importance of these organs (ex: respiratory center). In every disease may be detected in the same time structural changes and functional disorders although the rapport between these is not always proportional. From this postulate follows the therapeutic tactic, which will be in apply of the combined therapy orientated to reparation of structural defects and perturbed functions. The trigger moment of disease is the harmful action of the pathogen factor, which causes lesions structural changes and functional disorders. In this way, the harmful factor is absolutely essential and decisive in the trigger of disease. In the later disease evolution the etiologic factor plays a different role. In some cases the etiologic factor has a determining role during all the disease, but the development mechanism of the disease is from the beginning until the end, supported by the etiologic factor. In this way, all the disease manifestation are conditioned by the presence and action of harmful action; respectively its remove leads to disease manifestations, so the disease is interrupted (ex. acute infection, acute intoxication); In the second category of diseases the etiologic factor has a variable role from decisive in the beginning and in relapses of the chronic disease and until the indifferent in the clinic remission period (ex. in specific chronic infection as tuberculoses, the causal factor mycobacterium, has a decisive role in the disease beginning, but is present in the body and after convalescences without apparent activity, becoming recessive in tuberculoses). There is a third category of diseases, in which the causal factor plays the impulse role being necessary just in the initial phase of the primary lesions. For example in mechanical, thermal traumas the cause actions for a very short period, while the disease develops in the absence of the initial cause. These mechanisms are present in all the disease but in cases discussed here they are more evident. The knowledge about the concrete role of the etiologic factor in the disease development allows the correct apply of the specific therapy in cases when the etiologic factors play a decisive role and in cancellation of the specific therapy with accent on the pathogenetic therapy then, when decrease the role of the etiologic factor. 3.2. The role of pathogenic factors in disease evolution. The cause and effect interrelation in disease evolution. The main link of pathogeneses.The vicious circle . The effects caused by the pathogen factor action and the all secondary effects are called pathogenic factors , that maintain the disease evolution. The main mechanisms, that maintain the disease development are the pathogenethic factors. Between the pathogenic factors there is a dialectic relation of cause and effect through successive and repeated transformation of phenomena from effect in cause. Challenging cause (first cause, cause of I degree), acting on the body, causes effects as lesions, which may be called as pathogenic factors of I degree. The pathogenic factors of I degree become cause of II degree, causing new consequences - pathogenic factors of II degree; the latter becomes the causes of III degree , resulting effects of III degree etc. In this way, it forms a long and branched chain of pathologic factors (links of chain), bound by cause and effect relation, which is the motor force of disease development.

15

PF

Pf1

Pf2

Pf3

The primary effect caused by the cause of disease represents primary lesions, while the latter effects represent secondary lesions. In most of the cases the volume of secondary lesions is bigger then the volume of primary lesions. So, the pathogenesis of each disease represents a pathogenic chain, formed from many pathogenic processes (links), up from couple pathogenic processes, from what one is cause and another is effect, for as latter that one that was the effect will transform in the cause etc. For example in bleeding one from many pathologic chains of cause and effect is: anemia hypoxemia myocardial hypoxia diminishing of contractibility cardiac debit decreasing organs hyper perfusion cellular lesions organs insufficiency. In disease pathogenesis and development not all the links of cause and effect chain play an equivalent role. The analyses of the most of disease was found that in each disease there is a couple of pathogenic processes called the main link, from what depends maintaining the all link and after its removal disintegrates all chain, but disease evolution is interrupted. The importance of this postulate is that to stop the disease progression not is necessary to remove all pathogenic phenomena, but is necessary to annihilate the main link, as all pathogenic chain to disintegrated. For example in bleeding the main link, that initiates a lot of other pathologic processes (brain hypoxia with coma, myocardial hypoxia with cardiac failure, kidney hypoxia with renal failure) is blood loss anemia, but the annihilation of the main link through transfusion of blood removes pathologic processes from all organs. During the clinic evolution of most chronic diseases, with a long evolution more main links are replacing each other in a successive way, that has a dominant role in different periods of disease development. These processes are called the dominant link of pathogeneses. The doctors role is to follow the succession of dominant links and to find at the time the passage of the disease period in another, for adequate pathogenic therapy application orientated to liquidate the dominant link. During the burning disease development we can distinguish periods as toxemias, bacteraemia , that have different pathogenic links and requires specific pathogenic therapy. The etiotrope therapy is based on the causal factor and harmful conditions while the pathogenic therapy is based on liquidation of pathogenic factor. The development and branching of the pathogenic chain may lead to some phenomena, that have similar effects as the first cause action in this case the pathogenic chain is close, forming a circle. The peculiarity of this circle consists of that fact that the last effect from the chain amplifies the lesion caused by the first cause. One important thing is that the body by itself can not interrupt the evolution of this pathologic phenomena, this kind of circle is called a vicious circle. The vicious circle is closed pathogenic chain of causes and effects, in which the last effect has similar action as the first cause. For example during vary low temperature occur the decrease catabolic processes and consecutively decrease the thermo geneses ; the decreasing of catabolic processes have the same effect as the fist cause decrease of body temperature. This kind of vicious circles are meet in every disease and the doctor responsibility is to find and interrupt this processes through therapeutic interventions.

3.3. The role of organism reactivity in the disease development. The material described above represents the main mechanisms of appearance and development of disease pathological phenomena of lesions characterized by structural changes and functional disorders. But the disease has not only pathological phenomena and the body is not a non - reactive dead body. The living material has a capacity of reactivity that permits to respond to any action from the internal or external world, including to different lesions caused by harmful factors action, through structural and functional changes according to excitant action. Or, to the harmful factor action the body replies with different reactions, predominantly with a good biologic character. The organism reactivity is manifested through reactions elementary acts of the body aroused by pathogen factors

16

action and as well as to those physiological. The disease is not only the result of the harmful factor but is a result of harmful factor interaction with the reactive living body, that contains so destructive pathological processes and as well as physiological orientated to restoration of disturbed homeostasis. The importance of this postulate is that the doctor will apply a therapeutic strategy based on the lesion action limitation of the pathogen factor and concomitant the amplification of physiologic reactions of homeostasis restoration. The reactivity differs according to the biologic species (s pecies reactivity), according to the race peculiarities and ethnicity (group or race reactivity), according to the individual peculiarities (sex, age peculiarities etc.). These criteria of classification have a big practical importance because the doctor will take in consideration the normal parameters of the individual reactivity of a concrete patient (the race, sex, age, hereditary etc.). The faculty to reaction have not only whole body, but also molecules, cellular organelles, cells, tissue, and organs. This fact allows to talk about of reactivity in a large plan of biologically hierarchy on the different levels of the body organization. For the medical use the reactivity term is used in the sense of the reactivity as a dialectic totality of the reactivity of all hierarchic compounds of the body cells, tissue, organs and systems. The general biologic essence of the reactivity is biochemical, structural and functional conservation and psychic specific for the biologic species and person in variable condition of the environment. The organism corrects the changes produced by different factors and in this way keeps the integrity and its structural and functional homeostasis, internal medium homeostasis. So, the reactivity is translated through species and individual resistance the capacity to resists to the environment pressure and to preserve the biologic identity. The resistance is the major biologic purpose while the reactivity is the way of achieving this purpose. As we mentioned above the capacity to react to medium changes is a characteristic for all the body structures at any organizational level. In this way some complex molecules change their properties according to the environment conditions. For example hemoglobin affinity to oxygen changes according to the oxygen and carbon dioxide concentration, pH, temperature. In the same way digestive enzyme activity depends on medium action. The cellular organelles respond to different stimuli through DNA replication in the nucleus, protein syntheses, intensification in the ribosomes, the rapport change between the oxidative and mitochondrial phosphorilation processes, the atomic oxygen generation by lysosoms, induction synthesis or activation of different enzymes. An example of cellular reactivity can be elementary cellular reaction as multiplication, excitation, secretion, excretion, contraction, phagocytosis, and apoptosis, speed change of tissue regeneration, cellular breathing etc. The tissue reactivity is manifested by complex reaction at tissue level: hypo- hyperplasia, hypohypertrophy. At the organ level the reactivity is manifested through specific function changes like: trophicity, metabolism, circulation etc. The system reactivity is raised by intrinsic parameter modification or by extrinsic stimuli, from another system or environment. The vector of systemic reaction is controlled for system and body homeostasis maintaining. For example the homeostasis of the arterial pressure is maintained through vessels and heart reactions. Another reactive system is the immune system that reacts at the contact with any antigenic substance through specific immune reactions. The whole body reactivity depends on the reactivity of all organism levels. The body reactivity is expressed through physiological (locomotive acts, reproduction, self-preservation) and pathological (stress, shock and disease) complex reaction. The reactivity devices are several structures with different functions: the reception device of excitants action and perception device of homeostasis parameters modification, the comparative device, that compare the present parameters value with the normal one which is kept in the genetic memory, the apparatus that elaborates the commend for answer and the apparatus that make the answer. According to the reaction's significance and intensity reactivity has physiological or pathological character. Physiological reactivity of the body is proper to quality and intensity of the excitant and homeostasis preserving speed. In case in which the reaction does not correspond to qualitative and

17

quantitative criteria of the excitant (it is excessive or insufficient in comparison with excitant intensity, dont have an adaptive character) we talk about of pathologic reactivity. The pathologic reaction is characterized by: qualitative, quantitative and individual inadequacy. The qualitative coherence of the reaction and excitant consists of the fact that the reaction aroused by the excitant is orientated to anti homeostatic consequences liquidation came out after its action. The quantitative coherence corresponds to body reaction intensity and dyshomeostasis volume produced by the excitant. That kind of reactivity or intensity to which corresponds dis homeostasis volume and that have an adaptive character is called normoergic. The normoergic reactivity parameters are stabilized through population studies taking in consideration the race, sex, age, constitution and after that is declared the norm for the most of the population. The reactivity is equivalent to organism resistance with the capacity of homeostasis preserving. In case the reactivity whether above the normal limits is called hyperergy, in case is under norms limits hypoergy. Ordinarily the reactivity level corresponds to the resistances level in this way the normoergia corresponds to optimal resistance while the increase or decrease of reactivity is fallowed by increase or decrease of resistance. For example immune response intensity measured through antibodies titre represents in the same time the resistance measure. There are exceptions like cases when hyperegia is accompanied by decrease of resistance becoming itself the cause of body injury (ex: allergic ractions with an exaggerated reactivity and zero resistance), but hypoergia is manifestation of the body increased resistance (in immunized people is absent the reaction of infectious factor inoculation), but the resistance is maxim. The doctor will adjust the reactivity until normal intensity exaggerated reactivity will be attenuated , but insufficient reactivity will be stimulate. In our days the practical medicine has a lot of opportunities like immune stimulant or immune suppressor remedies, pro inflammatory or anti inflammatory factors and antipyretic remedies etc. The physiological reactivity manifests through physiological reactions qualitative and quantitative adequate reaction of the excitant orientated to homeostasis maintaining or restoration that unbalanced by the harmful factors. The physiological reactions are triggered under the action of physiologic excitants as under the harmful factors action. The main criteria of physiological reactions being tendency to reestablish the homeostasis . All the physiological reactions triggered by harmful factor action may be classified according to their biologic essence: A. Adaptive reactions, due to these reactions the healthy body adapts to new conditions, different from the previous. They serve for body homeostasis maintaining. The duration and intensification tuning fork of factors action, in which the body maintains the homeostasis represents the adaptation capacity body adaptability. The adaptability is a function of biologic character, species, individual sex, age, constitution etc. B. Protective reactions, through which the body protects itself from the pathogen factors action. This reactions are effectuated through: a) barriers, which serves as an obstacle for harmful factor action and prevents it entrance in the internal medium (mechanical barriers skin, mucosa; chemical barriers skin secretions, digestive glands; local immune barriers lysosoms, antibodies etc.); b) the attenuation of pathogen factor action already present in the internal medium (tampon systems, immune organs, liver detoxication etc.) ; c) the elimination of the pathogen factor present in the body (excretory organs, lung exhalation, couth, vomit, diarrhea etc.); d) de novo barrier formation that limits the body contact with the pathogen factor (encapsulation, granulation, inflammatory foci petrification). B. Compensatory reactions, due to them the body compensates the structural defects and functional disorders of some organs through function (structural) excess of other synergist organs that havent been injured. The compensatory reactions may occur: a) on the sub-cellular level (the mitochondria injuries lead to amplification of other organelles function); on the tissue level (the decrease of cells number leads to function amplification of the intact cells);

18

b) on the organ level (the affectation of a paired organ leads to hyper function of the intact one), on the system level (cardiac failure leads to peripheral arterioles spasm); c) on the organism level (erythrocytes deficiency in hemorrhage leads to the activation of pulmonary ventilation). The biologic essence of compensatory reactions on every level is keeping functional and structural homeostasis of the body. D. Reparative reactions, due which the body restores the structural and functional deficit. The reparative reaction depends on the injured level and can occur on the molecular level (auto reparation of injured DNA molecules), sub cellular (cells organelles repair), on the tissue and organ level. The reparative reaction essence is keeping functional and structural homeostasis of the body. Or, all reactions reactions of the body (adaptive, protective, compensator and reparative) are orientated to keeping body homeostasis through prevention of pathogen factor action or through keeping functional and structural homeostasis of the injured body. The pathologic reaction is an elementary act of the body induced by the pathogen factor action or the physiologic one but which is not qualitative (dose not correspond to excitant quality and dose not posses a homeostatic character) and quantitative (does not correspond to excitant intensity being weaker or stronger) adequate to the excitant. The pathologic reactions represent a destructive element of the disease. The physiologic reactions may also include some homeostatic disorders (for example: excessive sweating during hyperthermia or vomiting in case of alimentary intoxication that may lead to dehydration; pulmonary hyperventilation in hypoxia leads to respiratory alkalosis). Later this physiologic alteration will need medical correction. The body reactions have a concrete character in each disease: the same reaction in different diseases may have protective physiologic character in one case and pathologic in another one (diarrhea in alimentary intoxication has a protective character while the same diarrhea in cholera is absolutely pathologic). The doctor will differentiate the reaction character in both cases because the therapeutic tactics will be opposite in each case diarrhea stimulation in case of intoxication and its stop in case of cholera. In some cases the same reaction may have an adaptive character or compensator (for ex: pulmonary hyperventilation in a healthy person at the mountain altitude have an adaptive character and dose not necessary need the doctor intervention but the same hyperventilation in a patient with cardiac disease at the see level has a compensator character and needs the doctors intervention). The disease represents an inseparable combination between injury, orientated to body disintegration and body reaction, orientated to integrity maintaining . The disease appearance will depend on the rapport between the disease appearance or non- appearance, its evolution to convalescence or death will depend on the rapport between the character and volume of the injuries and the character and intensity of the body reaction. This rapport is not an absolute account but a relative one: the lesions consequences are determined not only by its volume but also by the body intensity reactions. The importance of this postulate is that if the doctor wants to direct the disease development to convalescence is necessary to increase the body reactions. This may be by diminishing destructive action of the pathogen factor and also by stimulation of physiological reactions as adaptive, protective, compensatory and reparative. For example in gastric ulcer the medical interventions try to attenuate the ulceration action (gastric acidity reduction), as the stimulation of stomach mucosa regeneration. In the heat of the factors moment of disease evolution is the confrontation of two antipodes, oriented to body destruction a homeostatic reactions, orientated to keeping body homeostasis. The disease development vector is a twice negation: the healthy body the ill body recovered body or in other case the healthy body the ill body the dead material. In bough cases disease resolution represents a twice negation the recovered body negates the body before the disease but the dead body negates the alive body. 4. General Nosology 4.1. The notion of health and disease

19

4.2. The diseases classification 4.3. The periods of disease development 4.4. The structure of disease 4.1. The notion of health and disease The notion of health and disease are two dialectic categories and may be studied only together through comparison. World Health Organization defines the health as: a state of a physical, spiritual and social comfort and not only the disease absence or physical defects. But this definition has not practical approval. Much more useful is to define the health through a notion as norm. In its medical practice the doctor is unable to determine degree of physical, psychic and social comfort of the patient. The collects the subjective and objective information about the patient (the subjective sensations and information communicated by the patient, biochemical, structural, functional and psychical homeostatic parameters) and compare this information with a standard etalon and then find out if the patient parameters differs form the norm values. This permits to find out if the parson is healthy or not. In this way appears a new category named norm. The norm is a concrete category, specific for a certain group of people, according the race, sex, age, constitution etc. Or, the norm is the medium statistic value of morphologic, functional, biochemical and psychic parameters of the human body of a special race, sex, age and constitution in special existence conditions. For example if in one person there is not register any changes in morphologic homeostasis (through radiological, endoscope, computerized tomography methods etc.), biochemical homeostasis changes (biochemical blood investigation or urine and gastric and duodenal juice etc.), functional homeostasis disorders (ECG, EEG, Spiro gram, electromyography etc.), psychic homeostasis changes (physic effort, glucose overdose etc.), then for sure we take the decision that the person is absolutely healthy. The norm can not be characterized by a fix number. All human body parameters (biochemical, morphological and physiological) depend on the genotype, phenotype, and functional state and existence conditions. The body also has a capacity to change its parameters according to life conditions for maintaining of vital functions adaptability is the name of this quality. Or, the health is not only a state characterized by normal body parameters in optimal conditions as physical and psychical rest but also the capacity to maintain the body homeostasis during external conditions oscillations. Because of this is not enough to determine the body parameters value in optimal conditions but also during their changes. And only if the body can respond to supra solicitation through adequate parameters changing which determines the grade of adaptability just in this case the health state may be established. Health is characterized through normative values of morphological, functional and biochemical parameters of the body in optimal conditions of physical and psychical rest and also through normative deviations of the same parameters during existence condition changes. The definition of health may be : health is the body capacity to maintain structural, functional, biochemical and psychic homeostasis in variable existence conditions. The disease may be defined as a new qualitative state of the body that can appear under the action of harmful factors and is characterized through a homeostatic disequilibrium (morphological, functional, biochemical and psychic), inadaptability, social disequilibrium, loss of work capacity and social economic values for a certain period of time.

4.2. The diseases classification The disease classification is divided into classes according to different principles: A. The classification according to causal principle (etiologic): a) infectious diseases; b) non infectious diseases; c) professional diseases;

20

d) hereditary diseases; e) weatherpaties; B. The anatomic topographic classification (according to injury classification): a) cardiovascular disorders; b) respiratory disorders ; c) gastrointestinal disorders; d) renal disorders ; e) nervous system disorders etc. C. Classification according to the sex and age: a) gynecological disorders; b) andrology disorders ; c) pediatric disorders; d) geriatric disorders; D. Classification according to way of spreading: a) infectious diseases ; b) endemic diseases; 4.3. The periods of disease development The nosology is a science about disease. General nosology describes common stages of development for all diseases, indifferently of the etiology or character of the diseases, while special nosology describes the development of a concrete disease. Each disease represents a complex process that develops and get for special stages common for all diseases. These stages characterized the most general laws of triggering , culmination and resolution of the disease. In evolution of every disease we can distinguish four periods: latent, prodromal, complete manifestation and resolution or end of the disease. A. Latent period (for infectious diseases period of incubation) begins with the action of pathogen factor and ends with first diseases clinical manifestations appearance. From a chronologic point it can occur from several seconds (electric current action) to several years (ex: AIDS). Although in latent period disease manifestations are absent (evident lesions, homeostatic changes, adaptability loss, physic, psychic and social discomfort) is only apparent and depends on diagnostic methods. The absence of clinical manifestations does not exclude changes on molecular, sub cellular and cellular level inaccessible for our methods of investigation. That what can not be found through clinical methods (lesions on molecular and sub cellular level, biochemical substances, results of some microorganisms activity, forging antigens, xenogeny hereditary material) may be determined through performing biochemical, immunologic methods, through DNA multiplication reactions, electronic microscopy etc. The diagnostic methods development grows shorter the latent period and someday is going to be excluded forever. During of this period occur a lot of important events for farther disease development. For example in case of infectious diseases occur the multiplication and storage of pathogen germs in the body in necessary quantities to provoke considerable lesions (critic mass of pathogen factor), lesion accumulation until critic level (critic mass of lesions) necessary for transformation of the injured structure in a new quality (healthy cell affected cell (ill), healthy organ affected organ (ill), healthy body ill body). This critic level is expressed by the number of injured molecules that make impossible the cell function; it is also expressed by the number of injured cells that make impossible organ function etc. This ascendant succession of events will take place till the injury will reach organs, systems or whole organism and the hide clinical manifestation will came out. During structural injuries and functional deregulation accumulation begins the release of organism reactions (adaptive, protective, compensator and reparative). Even at the beginning the disease represents an interaction of the pathogen factor with the organism, a combination between injuries and organism reactions. In case organism reactions predominance the disease will be interrupted

21

even in the latent period; in case of distractive processes predominance evaluate to the second period. The pragmatic importance of the latent period (incubation period of infectious diseases) is the doctor possibility to prevent the further disease development. B. Prodromal period (the period of disease anticipation) it lasts from the appearance of first clinical manifestations till the complete disease development. This period is characterized by the presence of general symptoms without a concrete topographic localization (weakness, physical, psychical and gastrointestinal discomfort, unlocalized vague pain, fevers etc.). In the same time they have a nonspecific character, seen in different diseases. That is why during this period is difficult to identify the disease. In the organism during this period take place injuries accumulation and organism reactions unfolding. The result of these processes also depends on the rapport between distraction and conservation and may lead to recovery or disease evolution to the next period. The pragmatic importance of this period is that the doctor even if doesnt know the disease may consolidate organism forces and attenuate distractive processes and the favorable disease evolution will follow. During this period some nonspecific therapy may by applied (qualitative alimentation, vitamins, microelements etc.). C. The period of complete disease manifestation . It lasts between all clinical manifestation appearances inclusive the specific one and till the disease resolution. During this period injuries and organism reactions reach the highest point. The nonspecific and specific therapy application is possible: a therapy based on pathogen factor action and unfavorable conditions removal, the pathogenic therapy that is orientated to pathogen factor liquidation that represents the dominant link, the symptomatic therapy orientated to symptom liquidation which is dangerous at the moment. D. The period of disease resolution. The disease end is influenced by injuries volume and character, organism reaction intensity and therapeutic approaches. The disease can finish with complete recovery, incomplete recovery, pathologic state or organism death. Complete recovery is the injured structures, deregulated functions, homeostasis, and organism adaptability restoration of the person. Complete recovery is not the organism return to the state before the disease: the recovered organism represents a new quality different then that before the disease (for ex: get the immunity to the won infection). Incomplete recovery is a more frequent variant in medical practice. At the end or the disease are present some residual phenomenon (structure deficiency), but latter are compensated. One variant of disease resolution is transforming in pathologic state a stagnant process without evident dynamic or total absence of dynamics present for a long period of time, maxim for life and can not be completely compensated. The organism death is the result of absolute organism reaction insufficiency necessary for homeostasis maintenance. 4.4. The structure of disease The disease has a similar structure that contains several stereotype elements. These elements are lesions (biochemical, structural and functional disturbances) and organism reactions (adaptive, protective, compensator, reparative and pathologic). In clinics they are known as symptoms. In every disease these elements associates forming typical complex for a certain disease or certain periods of the disease pathologic processes. The clinic equivalent of pathologic processes is syndromes. Pathologic processes represent a combination between elementary structures (lesions and organism reactions) that derivates from a general cause. The pathologic process is a totality of successive events derived from the cause factor action and includes a complex of structural lesions and functional deregulation plus organism reactions to these injuries (adaptive, protective, compensator and reparative reactions). The pathologic process may be localized at any hierarchic organizational level of the organism: cellular, tissue, organ, system and whole organism. The pathologic process localized in a certain structure induces through different pathologic mechanisms a lot of reactions only to the affected structures by the harmful factor. The pathologic process and the induced reactions form the disease . Or, the pathologic process is an event of a limited structure like cell, tissue, organ, system while the disease an event characterized for the whole organism. The relation between pathologic process and disease may be represented by the following examples:

22

gastric ulcer ulcerative disease; burn burn disease; arterial hypertension hypertensive disease etc. A notion of general pathology is the typical pathologic processes a pathologic process with an essential similar character indifferently of the etiologic factor, biologic species of the individual and organ where is localized. The species and individual peculiarities of the ill organism, peculiarities of the affected organ, the pathogen factor qualities modulate the clinic picture of typical pathologic processes. The combination between typical pathologic processes and etiologic, sex, age, constitution etc. peculiarities forms the unique and unrepeatable picture of the disease. The typical pathologic processes develop at different organizational levels of the organism cellular (cellular lesions, cellular dystrophies, and cellular necroses), tissue and organ (inflammation) and integral level (metabolic, hydro, acid basic deregulation). Or, the disease structure includes the following elements: lesions, pathologic reactions, adaptive, protective, compensator and reparative physiologic reactions, pathologic processes. The interrelation of these processes subject to dialectic laws the totality of all disease elements determines the impulse, motive force and disease evolution vector. 5. The general sanogenesis The general sanogenesis (lat. sanitas health, genesis-a birth) is general compartment of nosology, studying general laws of healing and recovery - restoration of damaged structures and disordered function in disease outcome. The special sanogenesis - studying processes of convalescence in each concrete disease. The notion of sanogenesis was formulated by S. Pavlenco, the russian pathophysiologist, 1966 - and represents a dynamic complex of adaptive-protective mechanisms triggered by the action of pathogen factor of the organism. Sanogenetic mechanisms operate throughout the morbid process (the premorbid period until convalescence) and are aimed to restoring self-regulation body. Sanogenesis (recovery mechanisms) is the dialectical counterpoint of pathogenesis (mechanisms of disease). Sanogenetic mechanisms start right from the onset, not only in a particular period, clinical disease marked by involution. While the pathogenetic mechanisms are aimed at disintegrating the body (as a biological entity), the sanogenetical mechanisms are oriented to maintain homeostasis and body integrity. Throughout the disease - occurs oppose pathogenetic mechanisms (disorder, injury) with sanogenetical mechanisms (adaptation, protection, compensation, repair) - and the result will depend on the ratio of these two forces. Classification The sanogenetical mechanisms are divided into: - primary sanogenetical mechanisms; - secondary sanogenetical mechanisms. Primary sanogenetical mechanisms include the adaptative, protective and compensatory reactions. General characteristics of these mechanisms are that they are activated until lesions - and are aimed at maintaining homeostasis of the body, configured with pathogenicity. Unlike general adaptive mechanisms which takes place in the physiological regulation of healthy body functions (located under the variable external environment) -sanogenetical adaptive mechanisms adapts the body to the action of pathogenic factors, thus preventing the onset of injury (ex. spasm of peripheral vessels adapts the body to the action of low temperatures and thus preventing the development of hypothermia). Protective primary sanogenetical mechanisms - protects the body from harmful action of pathogenic factors avoid entering the body, causing their destruction, or remove them from the body until the appearance of lesions and so preventing disease (e.g. mechanical natural barriers, nonspecific immunity factors from skin secretions, liver reactions of detoxication). Compensatory primary sanogenetical mechanisms - return the body functional deficit of structures altered by pathogenic factors, so stop progression of the disease process (e.g. a lung vicarial hyperfunction to damage its pair). Absolute or relative failure exhausted sanogenetical primary

23

mechanisms, installs the pathological condition, while starting the work of secondary sanogenetical mechanisms. Secondary sanogenetical mechanisms include the protective, compensatory and terminal mechanisms (as seen in this group lack adaptive mechanisms). Secondary sanogenetical mechanisms are the same processes of premorbid period but evolve during pathological process already started and are designed to prevent its progression. Terminal sanogenetical mechanisms - occur in extreme situations, critical for the body and are a last reserve of the body under severe structural damage and functional disorders, which threaten the existence of the body. Biological significance of secondary sanogenetical mechanisms, unlike the primary, is not preservation, but to restore homeostasis, already unbalanced. Example of practical interpretation of sanogenetical mechanisms: in hyperthermia all physiological reactions, which starts once the action of high temperatures and maintain thermic homeostasis, are primary sanogenetical mechanisms; same physiological reactions since the rise in body temperature above the norm (hyperthermia itself) are already secondary sanogenetical mechanisms. Pragmatic importance of the concept of sanogenesis - is the possibility to prevent the disease in premorbid period - by strengthening of primary sanogenetical mechanisms or stop disease progression at any time of it by stimulating secondary sanogenetical mechanisms. Another aspect of this concept is the coexistence and confrontation of sanogenetical and pathogenetic mechanisms throughout the disease and possibility of physician to tip the balance of these processes in favor of organism so by reducing the destructive processes as by amplifying the sanogenetical mechanisms.

TYPICAL PATHOLOGICAL PROCESSES The cellular pathological typical processes 6. Cell injury 6.1 The cellular membrane lesions 6.2 Cell nucleus lesions 6.3 The endoplasmic reticulum lesions 6.4 Mitochondrial lesions 6.5 The lysosomes lesions 6.6 The consequences and general manifestations of cell injury 6.6.1 Enzymemy 6.6.2 Hyperpotassemia 6.6.3 Acute phase reaction 6.6.4 Fever 6.6.5 Stress 7 8 9 Cell dystrophy Apoptosis Necrosis

Cell injury is the persistent change of biochemical, structural and functional homeostasis of the cell appeared to the action of harmful factor. Because cell damage initiates adaptive, protective, and compensatory and repair responses is justified vision of cell injury as pathological cellular process.

24

Lesions arising from the direct action of harmful factors of any cellular structure are called primary lesions. Any primary lesion of the cell generates alterative secondary phenomena. Secondary lesions are spreading consecutively on all cellular structures eventually lead to her death. Cell injury also initiates pathological processes in tissue and organ of residence (pathological processes in tissue and organs - atrophy, sclerosis, inflammation) and internal environment (integrative pathological processes - dishomeostasis). Then secondary pathological processes of tissue and organs retrograde affects both primary affected cells, as well as those affected by pathogenic factors, thus enlarging the area of pathology until the limits of body integrity. Such pathological cellular processes, although occurring locally, leading to the generalization process. Thus, the process is generalized with predominant localization at the cellular level. Later the whole processes are localized again at the cellular level, thus amplified and multiplied cell injury. Injuries caused by harmful factors leading to the onset of reparative cellular reactions, which in some cases, depending on the degree of alterations, recover lesions with restoration of cell structure and function. The relative failure of cellular reparative reactions develops non-lethal pathological processes - cell dystrophies. In case of irreparable damage cell triggers apoptosis, the mechanism of auto annihilation of damaged cells without harmful consequences for the population of healthy cells. In most cases the sunk cellular disease leads to necrosis - uncontrolled cell dies with harmful consequences for the population of healthy cells and the bodys internal environment pollution. Although the character of cellular injury depends on the specificity of nuisances factor and the particularities of the cells subject to disturbing action, however lesions possesses non-specific characters depending on the general proprieties of the cells. The nonspecific manifestations of cellular lesions are: increase of the nonselective permeability of the cellular membranes and organelles; activation of cellular enzyme systems proteinkinase, phospholipase, systems of proteins bio synthesis, and the energy-producing processes decay etc. The specific manifestations of cell injury represent the abolition of their specific functions by releasing specific cellular components from damages cells to bodys internal environment (e.g. intracellular enzymes etc.). All body cells originate from the totipotent cell- zygote - have common structural features (plasmalemma, hyaloplasm, cellular organelles) and functional features (metabolism, multiplication). Since the main structure and basal functions of all body cells are similar, also are similar the essential manifestations of the pathological cellular processes, that is why they can be defined as cellular typical pathological processes. Only at the initial phase the cellular pathological processes and the first pathogenetic factors bears the imprint of specific nuisances on when the later pathogenetic processes are stereotyped and are determined by the morpho-physyological and genetic proprieties of the cells. In some cases cellular alteration and pathological cellular processes have the role of primary factor to development of tissue injury and whole bogy (local thermal trauma lead to the integrative pathologic process in burned disease). In other cases the cellular alteration may be the result may be the result of primary disorder of body homeostasis (hypobaric atmosphere lead to hypoxic hypoxia and cellular pathological processes, even the cell death). Classification of cell injury A. by the sequence of appearance a) primary lesion arising from the direct action of harmful factor; b) secondary lesion arising as a cause of primary pathogenetic factors. B. by the nature of lesions a) specific lesions corresponding to harmful factor; b) non-specific lesions proper to several harmful factors. C. by the character of etiologic factor a) mechanical damage, b) physical injuries (burns, frostbite, electrical), c) osmotic injury, d) lesions by lipid peroxidation,

25

e) f) g) h) i) j) k) l) D. by location a) b) c) d) e)

infectious lesions, immune (allergic) injury, toxic injury, enzymatic injury, hypoxic injury, damage of circulation, dysmetabolic damage, injury of homeostasis membrane lesion mitochondrial lesion, lysosomal injury, nucleus lesions (including lesions by mutations), endoplasmic reticulum damage and Golgi apparatus

E. by degree of injury a) reversible, b) irreversible. Pathogenic action of harmful factor is mostly oriented toward the cell membrane, where the primary lesions are located while the injuries of cellular organelles more frequent have second order. Here is a possible direct action of harmful factors on cellular organelles with the development of primary pathological processes. Etiology and pathogenesis of membrane lesions Cytoplasmic membrane dysfunction may be caused by different causes: mechanical, physical and chemical factors, hyper- and hypoosmolarity, enzymes, antibodies, sensitized lymphocytes, hypoxia, hyperoxia, dyshomeostasis of nutritional factors, starvation, acidosis and alkalosis, hydric and mineral imbalance, vascular disorders. The cellular typical pathological processes are initiated by primary lesions of the cell membrane under the action of pathogen factor. These lesions represent the first specific pathogenetic factor to the challenging cause. Secondary lesions are stereotyped and genetically determined what justify qualifications of cellular pathological processes as typical processes, independent of causal factors. The primary lesions of cytoplasm membrane bear the imprint of the specific etiologic factor and can be classified according to its nature. A. Primary mechanical injury of cytoplasmic membrane (expansion, rupture, formation of defects, fragmentation) caused by mechanical forces which act directly on the cell. Primary pathogenetic factor is the mechanical disintegration of the membrane, opening of the mechanical barrier cell-interstitium, uncontrolled formation of direct communication between the intracellular and the intercellular space, and the free passage of substances in both directions: interstice-hyaloplasm and vice versa. The final result is the mixing between the extracellular and intracellular space with penetration of Na+ ions into the cell and emission of K+ ions outside the cell. This causes functional failure of the cell with further development of pathogenetic chain of alterative processes. B. Injury caused by electricity power - depend on the nature of electricity (DC or AC) and the cell type. Initially occurs arouse of potential dependent ion channels (Na +, K+, Ca+) with their concentration gradient annihilation and the rest potential - membrane depolarization, and the cell excitation with these effects - the generation and propagation of electrical impulse, and the myocyte contraction.

26

The continuous action of electric current prevents membrane repolarization and restoration of resting potential and leads to depolarising inhibition. Later hyaloplasm polarization occurs - accumulation of negative ions (anions) to the positive electrode (anode) and positive ions (cations) to negative electrode (cathode). Under the action of electric current occurs electrolysis of substances decomposition of substances with ionic structure up to neutral atoms. Under the action of electric current occurs cytoplasmic membrane electrical break ( electrical break-down). This occurs when the electrical potential applied the cell exceeds the force of membrane cytoplasmic surface tension and viscosity. Breaches that have formed tend to be large until the complete destruction of cytoplasmic membrane and cell death. C. Oxidative stress - is caused by oxygen free radicals. Oxygen free radicals is called oxygen or oxygen compound, which contains the latest electronic layer an unpaired electron, single electron, what gives these compounds a extremely high chemical reactivity - the cause why they are called active oxygen species. Oxygen radicals are byproducts formed by some physiological processes (e.g. electron transport chain in mitochondria). Under normal conditions, their damaging action is counteracted by antioxidant systems. Pathological processes that generate free radicals are: inflammation, hypoxia, hyperoxia, phagocytic reaction, and ionizing radiation, chloroform poisoning etc. Formation of free radicals accompanies virtually all body pathologies. Free radicals forms are: oxygen superoxide, hydrogen peroxide, hydroxyl radical. The main antioxidant systems are: superoxide dismutase (superoxide anion action annihilates), catalase (helps break down hydrogen peroxide), peroxydase (helps break down peroxides), ceruloplasmin, ferritin, transferrin (associated iron ions, preventing peroxidation chain reactions of lipid radicals), vitamin E, polyphenols. So the mechanism of action of harmful free radicals consists of peroxidation of endogenous substances: fat, polyunsaturated fatty acids, nucleic acids, proteins, amino acids, enzymes. Among the worst consequences of free radicals are gene mutations and peroxidation of polyunsaturated fatty acids in cytoplasmic membrane component. The hydroxyl radical OH is considered the most aggressive. Being very small penetrates the lipid bilayer where peroxides the poly-non-saturated fatty acids from the membrane component that contain double bond of carbon. Under the action of the hydroxyl radical take place the first reaction ravishment of one lipid proton (LH) (more exactly of AGPN poly-non-saturated fatty acids) with water and lipid radical formation, noted as L: 1) OH +LH = H2 O + L. The lipid radical formed in the first reaction interacts with dissolved molecular oxygen in the internal medium or intracellular forming LOO lypoperoxide radical according the 2 reaction: 2) L + O2 = LOO. The lypoperoxide radical interacts with a new lipid molecule LH forming two new radicals: hydroperoxide radical LOOH and the lipid radical L (third reaction): 3) LOO +LH = LOOH + L. in this way the reaction becomes autocatalytic forming a long chain affecting more lipid molecules. The result of this reaction is the formation of three new radicals: lipid radical, lypoperoxide radical and hydroperoxide radical. In some conditions the autocatalytic chain may give branches according the 4 reaction: 4) LOOH + Fe+ = Fe+ + OH + LO; LO + LH = LOH + L.

27

after the 4 reaction takes place the L lipid radical that may initiate a new chain etc. The final result is the peroxidation and denaturizing of a big number of phospholipids molecules that have a lot of membrane distractive effect: a) membrane distraction and unrecoverable breaches forming with mechanic resistance diminishing; b) nonselective permeability increase and ionic gradients liquidation; c) electric resistance diminishing of the membrane and its electric breaking; d) electric potential annihilation on the excitable cells membranes with depolarized inhibition; e) increase of calcium ion concentration in the cytoplasm with all the associated effects; f) cell organelles function deregulation; g) necrosis and cell autolysis. Another target for the oxidative action may be substances from the cytoplasm membrane. Under the action of free radicals takes place the sulfur hydrilic group reduction of thiolic enzymes (for ex: Ca+ - ATP) till the disulphide groups with loss of enzyme activity and all the associated effects. One more consequence of the oxidative stress may be DNA alteration with mutagen effects. D. Enzymatic cellular lesions - provoked by endogen and exogenous enzymes action. The source of endogen enzyme can be phagocytes cells from the inflammatory foci, lysosomal enzymes from all organism cells released as a result of the lysosomal membrane destabilization, pancreatic digestive enzymes released in the blood in case of pancreatitis or pancreonecrosis. From the exogenous one there is the microbial one (for ex: streptococci lecitinase that splits membrane phospholipids). The cell pathogen enzymes have a large spectrum: proteases, peptidase, collagens, lipase, amylase etc. The pathogenic chain of the harmful effects of the cell pathogens is initiated by specific substrate splitting for these enzymes: membrane phospholipids, membrane proteins, glycoproteins etc. The final result of enzymes pathogen action is membrane disintegration and cell distractive processes. E. Imunocytopathogen lesions are mediated by the immune reactions, autoimmune and allergic those take place at the level of cytoplasm membrane. As an example may be cytolytic allergic reactions of II type, autoimmune reactions. The consequence of this action is cell death. In this way the antigen antibody interaction in II type allergic reactions leads to cell membrane perforation and loss of cell integrity. In the same time the immunoglobulin and fixated complement induces phagocytosis through interaction between Cf (constant fragment) of the immunoglobulin and C3b of the complement associated to the attacked cell and the receptors for Cf and C3b from the macrophages with intracellular digestion of the phagocyte cells. In the cytolytic reaction of IV type initiated by sensitive lymphocytes takes place the attacked cell distraction through specific immune mechanisms or nonspecific cytolytic mechanisms (cationic proteins etc.) F. Heat [thermal] injury of the cell occurs at the action of extreme temperatures and contains specific pathogenic mechanisms. Extreme (high) temperatures lead to thermal distortion of the component substances of the cytoplasmic membrane (proteins) to abolish specific functions of channels, pumps, ion, enzymes, antigens, formation of auto antigens. Low temperatures leads to crystallization of water in the cell with subsequent mechanical destruction of the cell. E. Hypoxic lesions of the cell - are caused by cellular hypoxia. Energy necessary for all cell functions is provided almost entirely by processes of oxidation of nutrients. Coupling oxidation with phosphorylation processes leads to storage of energy-rich forms. Stored energy is used for vital cell functions: anabolism, recovery of affected structures, ion pump activities, and maintaining intracellular homeostasis. The main causes of hypoxia are all the forms of general hypoxia (hypoxic, respiratory, circulatory, anemic, hystotoxic hypoxia), regional blood flow and lymphatic disorders (venous hyperemia, ischemia, stasis), direct affection of cellular processes of oxidative phosphorylation, systemic circulation disorders (cardiogenic circulatory failure, vascular failure, hematogenous, collapse, shock). Mentioned that in circulatory disorders along with energy deficit caused by cellular hypoxia may

28

evolve and cyto-destructive pathogenetic factors - hypo-perfusion, hypo-nutrition, hypercapnia, acidosis, accumulation of metabolic waste. The effects of cellular hypoxia are initiated by energy shortage below compatible threshold with vital cellular activity. Pathogenetic chains of adverse effects are variations and numerous: a) Cellular hypoxia -- reducing oxidative processes -- reducing the amount of available ATP --Na-K -ATPase pump activity reducing -- Na-K gradient abolition -- cell hyper-osmolarity -- intracellular hyper-osmolaritaty cellular intumescences - cytolysis. b) Membrane potential annihilation at rest -- depolarising inhibition of excitable cells. c) Decrease the activity of Ca pump-ATPase -- the abolition of the gradient of concentration of Ca+ -- increased activity of phospho-lipases proteases endonucleasis ATPase -swollen mitochondria -- the endoplasmic reticulum -- lysosomal destabilization. d) Activation of glycolysis -- gathering lactic acid -- acidosis cell -- activating protease and phospholipase -- cytolysis. H. Dyshomeostatic cellular lesion - caused by the disturbances of homeostasis of internal environment. Bodys internal environment (living environment of the cell) is characterized by maintaining strict physical, physical-chemical and biochemical data. Extreme deviations of interstitial space parameters are direct consequences of the changing of blood composition which can become harmful factors triggering cellular pathological processes. The most severe and most common homeostatic deviations can be determined on the states of hyper- or hyponatremia, hyper- or hypopotassemia, hyper- or hypocalcemia, hyper- or hypochloridemia, hyper- or hypo- H+-emia all of this associated with hyper hydration or dehydration, hypo- or hyperosmolarity. I. Metabolic cellular injury- caused so hereditary enzyme defects and how extracellular metabolic imbalance. Extracellular metabolic imbalances that can affect cells are: hyper- and hypoglycemia, galactosemia, hypo-proteinemia, dysproteinemia, hyper-lipidemia, dyslipidemia, ketonemia. J. Infectious lesions - Primary cellular lesions of infectious origin are caused by biological factors (viruses, bacteria, and protozoa) and subsequent inflammation of the affected organ leads to secondary cellular injury. Secondary cellular injuries are multifactorial and its pathogenicity is complex, determined by the action of many harmful factors of inflammatory site (acidosis, circulatory disorders, oxidative stress, immune attack, hypoxia, metabolic disorders). Manifestations of cell membrane lesions Regardless of the etiological factor and the nature of primary lesions, the disintegration of the membrane triggers following secondary pathogenetic factors, which continues the secondary pathological process. 1. Disruption of cell membrane permeability and transmembrane transfer of substances. Following alteration of cytoplasmic membrane, including glycocalyx, takes place disruption of membrane structural integrity with the abolition of barrier function. Consequently allow indiscriminate penetration of substances normally shipped only by selective transport mechanisms (Na +, K+, Cl-, Ca+, Mg+) and later the excessive intracellular passage of water through osmosis leading to hydropathic dystrophy and vacuolation, deformity and swelling of the cell with mechanical destruction of the cytoskeleton. Subsequently gradual deformation cell is possible uncreasing villi of cells with the loss of their functions (e.g. micro-villi enterocytes loss is associated with the development of malabsorption; renal epithelial cell deformation in case of renal disease is accompanied by reabsorption disorder). 2. Transmembrane active transport of substances disorders. Following the destruction of cytoplasmic membrane are altered the transport mechanisms of all active substances. Consequences of substance active transport disorders are concentration gradients of

29

electrolytes annihilation (Na+, K+, Ca++, Cl-) between interstitium and cytoplasm, cytoplasm and organelles. Simultaneously takes place annihilation of membrane electric potential. 3. Annihilation potassium gradient. In normal cell intracellular and extracellular potassium concentration ratio is about 4:1, which, along with other electrolytes, creating electric resting potential gradient for excitable cells, necessary for the functioning of mitochondria. Intracellular and extracellular potassium balance annihilates the cell resting potential (depolarization) and makes it impossible to excite the cell (depolarising inhibition). Due to the increased concentration of potassium ions in the extracellular, reduces transmembrane potential of adjacent cells, increased excitability, which can serve as a stimulus to trigger action potentials. This phenomenon can be observed in myocardial infarction, when increase potassium levels in the focus of necrosis contribute to the occurrence of cardiac fibrillation. Potassium released from cells also invade the bodys internal environment, including, blood (hyperpotassemia), which similarly influence on other excitable cells away from the primary outbreak (neurons, cardiomyocytes). The increase in blood concentration of potassium ions as a result of their release from cells was detected in the mechanical trauma in allergic states and hypoxia, to excessive doses of mineral corticoid hormones and cardiac glycosides, which is manifested by changes of electrocardiogram and electroencephalogram.

4. Annihilation of the sodium gradient. In a normal cell the concentration of sodium ions intracellular and extracellular in equal to 1:20, fact that creates the electric gradient and resting electric potential, active electric potential for excited cells along with the potassium and other electrolytes gradient. The Na+ and K+ gradient is maintained by ionic canals depending on the potential and ionic pumps which are membrane selective Na, K, ATPase. Because of the non-permeability of the cytoplasmatic membrane for macromolecules their intracellular concentration (proteins mostly) is higher than extracellular, fact that creates a concentration gradient of proteins and an. Excess of intracellular oncotic pressure. In this situation the iso-osmolarity of hyaloplasm can be maintained by a low concentration of Na in the cell. Thus, the onco-osmotic equilibrium is maintained by Na exposure from the cell, decrease of intracellular concentration and increase of extracellular concentration of Na ions. The annihilation of the Na concentration gradient is being associated with intracellular movement of this element, increasing the intracellular osmotic pressure, creating an osmo-oncotic gradient that initiates the process of water entering the cell by osmosis, swallowing the cell, cytolysis. 5. Annihilation (neutralization) of the resting potential. Because of the difference of concentration between ions in the intra and extracellular spaces on the cytoplasmatic membrane of excited cells a difference of potential is being determined of 70 mV. In case if pumps stop to work the permeability for ions increases and the concentration of ions in the intra and extracellular spaces equalizises. As a consequence the transmembrane potential decreases, the membrane is depolarized the resting potential is unable to be reestablished and finally the cell is inhibited by depolarization. 6. Decrease of electrical resistance for cytoplasmatic membrane. The cytoplasmatic membrane and the one which covers the organelles is a dielectric (electric isolator) that can resist at a potential difference equal to 200 mV (break potential ) fact that goes beyond the usual potential for this kind of structure (75 mV for cytoplasmatic membrane and 175 mV for mitochondrial membrane). In usual condition proper electric potential can not break through the membrane, because the force of superficial tension and cytoplasmatic membranes viscosity gas beyond the electric potential and the breaches formed in the bilipidic level by the brainian movement are easilly repared. Decrease of electrical resistance of the cytoplasmatic membrane (ex. Membrane lipids, breakdown by phospholipase, membrane proteins breakdown by protease) leads to the increase of curents intensity and lowering of the break through electric prague. When the break through prague is beyond critical limits, the proper electric potential is higher than the face of superficial tension and cytoplasmatic

30

membranes viscosity, and the breaches formed in the bilipidic layer by the brainian layer are not only unrepareable by also have the ability to increase in size till complete distruction of the membrane. This way the proper membrane potential breaks through the membrane and destroys it (electric breakthrough, electric breakdown. 7. Neutralisation of Ca gradient. The reduction of ATP generation in the cell inhibits the activity of Ca- ATP-ase is inhibited, the speed of Ca exposure from the cell is decreased, that contributes to the Ca acumulation in the cytoplasm till *10 -5 mmol/l. As a consequence modification of cityskeleton appear, activation of contractile structures ( actine and myosine), activation of cellular ensymatic systems occurs (ATP-ase, phospholipase, protease, endonuclease) intracellular membranes are altered, metabolique processes are altered. 8. Activation of intracellular ensymes. The overall effect of enlarging the concentration of intracellular calcium is to activate intracellular enzymes: ATP-ase, protease, endonuclease, phospholipase. Activation of ATP-ase leads to ATP sources breakdown, that induces a lack of energy and diminishing of energogenetic processes. Activation of intacellular proteases leads to initiation of cellular autolysis breakdown of proper proteins and cellular desintegration. Activation of endonucleases leads to nucleoproteins break down (DNA, RNA) and initialion of apoptosis reaction. Activation of cellular phospholypases (phospholypase A) leads to phospholipids breakdown from the cytolema phospholipids, formation of unrepareable defects, decrease of mechanical and electrical resistance, increases non selective permeability. This effect is simillar to the action of the first cause lesion of the membrane induced by the action of pathogenec agent this way the vicious circle is closed. The breakdown of phospholipids of the membrane decreases the resistance and induces breakthrough of the membrane. 9. Dysfunction of the transmembrane exchange mechanism of Na and H cellular acidosis. Cellular alteration is accompanied by decrease of intracellular pH (beyond 6:0) causing cytoplasmatic acidosis . Acidosis can be determined by the following mechanism: a) Increased influx of H+ ions from extracellular space, determined by dyshomeostasis of acidbasic equilibrium. b) Excessive formation of acid intermediary agents after glycolysis, degradation of Krebs cycle, phospholipid breakdown, adenilique nucleotide breakdown. c) Usage and insufficiency of buffer system causing increased concentration of H + ions. d) Inefficiency of elimination mechanism of H+ ions. The increase of H+ concentration leads to the deregulation of protein functions by changing their conformation, activation of lysosomal enzymes, and increase of permeability by deregulation lipidic layers structure. 10. Cellular hyperosmolarity. Cellular normal hyperosmolarity- the intracellular osmotic pressure equal to the interstitial pressure is assured by an optimal equilibrium between the concentration of proteins and electrolyses on both parts. Iso-osmolarity maintains constant volume of the cell and its organelles. In a normal cell there is a bigger quantity of proteins than in the extracellular medium. This may lead to a osmo-oncotic gradient establishment and increase of cell volume. Due to the activity of Na-K-ATP-ase pomp alteration, in intoxications with heavy metals salts, at deregulation of energy genesis processes, hypoxia, intoxication with CO; the surplus of Na + is exposed and intracellular hyperosmolarity is created. Hyperosmolarity created by an influx of Na ions leads to an influx of water causing cellular intumescence, cell bloating, increased intracellular mechanical pressure, and even breaking the cytoplasmic membrane. Similar processes occur at the level of cellular organelles. 11. Intensification of anaerobe catabolic processes (mostly glycolityc species) is a universal answer of the cell to the energy lack. This mechanism initially has a compensatory importance for the injured

31

cell. Further the intense catabolism leads to intermediary metabolic products accumulation in the cell (lactate), H accumulation, and cellular acidosis; with pH decrease till cell death. Consequence: membrane lesions lead to cellular dystrophies, necrobiosis, inflammation, atrophy, sclerosis. Cell nucleus lesions The causes of direct cell nucleus lesions are different physical, chemical, biological factors. Nucleus lesions have different morphological and functional manifestations. Chromatin condensation and bounds is a reversible alteration of the nucleus, which is manifested by the appearance under the nuclear membrane -several chromatin conglomerates. This process can be determined in cases of cell pH reducing during the intensification of glycolytic processes. The action of harmful factors nuclear membrane formed vacuole by invagination of internal layers. 1. Karyopyknosis - is the consequence of condensation and marginalization of chromatin all over the nucleus. Chromatin fibers condense from the action of lysosomal enzymes and DNA-ase. 2. Karyorrhexis is the process of fragmentation of condensed chromatin, which can be located both in the nuclear membrane as well as in cytoplasm. 3. Karyolysis - is core damage with total disintegration of chromatin. Karyopyknosis, Karyorrhexis and the Karyolysis processes of consecutive dying are nucleus. Mitosis rhythm disorders and anomalies. Mitotic rhythm, appropriate to the restoration of flaky or dying cells in pathological conditions may be changed. Decreased mitotic rate is determined in newly vascularization or aging tissues; increased mitotic rate is determined in inflammation, tumors and hormone action. Some pathogens (ionizing radiation, metatrexat, 6-mercaptopurine) acts on cells in S phase of cell cycle and decrease DNA synthesis and duplication. The same factors act on cells in M phase of mitosis can induce metaphase block and acute cell death mitonecrosis. Mitonecrosis - is determined in tumor tissues and inflammatory foci with necrosis. At the action of ionizing radiation, chemical agents, inflammation, tumors, mitosis results in a number and abnormal chromosome structure - multipolar mitoses. One of the manifestations of mitosis pathology - is the appearance of polynuclear cells, which contain many nuclei. Polynuclear cells are found in normal states, for example in osteoclasts, in megakaryocytes. In pathology such cells are found in tuberculosis and tumors. Cytoplasm of these cells contains granules and vacuoles, the number of vacuoles ranging up to several hundred. Origin of these cells is different - epithelial, mesenchymal, histiocytic. In some cases giant polynuclear cell formation occurs, which is determined by the fusion of mononuclear cells, in other cases, by splitting the nuclei without division of cytoplasm. Mitotic abnormalities may occur under the action of ionizing radiation, the administration of cytostatic preparates in the tumor process. Lesions of endoplasmic reticulum The swelling of ER is a typical pathologic process as a consequence of hyperosmolarity and swelling of cytoplasm that leads to the detachment of ribosomes from it, polysomes disintegration with disturbances of cellular protein synthesis and for export protein synthesis with the following consequences. Lesions of mitochondria Mitochondrial lesions have different aspect. Swelling of mitochondria is a qualitative modification common for multiple alterations of mitochondria that lead to the disturbance of oxidative phosphorilation processes. The swelling of mitochondria is conditioned by the rising of external membrane permeability, in case of hyperosmolarity and swelling of cell cytoplasm. This pathologic phenomenon is met also in inanition, hypoxia, intoxications, fever, and thyroxin administration.

32

In vitro 2 types of swelling were found. The first is low amplitude swelling. In this case the growing energy genesis activity leads to reversible alteration of the protein structures. The swelling of low amplitude is accompanied by the entering of the water through the external membrane of mitochondria in the space formed between the crista and mitochondrial matrix. In the same time mitochondrial matrix contracts and becomes harder. After this contraction phase the mitochondria turn to their initial state. The second type of swelling high amplitude swelling appears as the result of increasing of the internal membrane permeability. The result of this process is the smoothing and fragmentation of crista. It may be corrected through increasing of ATP level and of Mg2+ concentration. Disturbance of the external membrane is a reversible process coupled with loosing of the matrix granules. The final stage is characterized through destroying of the internal and external membranes, forming on the internal membrane calcium phosphate precipitates that contribute to the irreversible calcification of mitochondria. Deformation of crista with decreasing of their number shows a low functional activity of mitochondria; however, the increasing of crista number shows an intensification of energy synthesis according cellular requirements. In the same time with quantitative and qualitative levels of mitochondria crista are determined the structural changes of matrix granules. These granules having the diameter from 20 to 50 nm accumulate bivalent cations. The matrix granules are formed from proteins, lipids, potassium ions, magnesium, and phosphorus. The increasing of granules volume is determined in cells that contain an excess of calcium ions. Hypertrophy of the granules can be seen in mitochondrial ischemia, in hepatocytes in CCl intoxications, in muscle cells in the case of tetanus. The decreasing in number of granules and even their absence is seen in tumor cells, in intestinal epitheliocytes and hepatocytes with ischemia. The increasing in number and dimension of mitochondria is encountered in tumor cells, in cells of hypertrophied tissues and in inflammation, in thyroid granulocytes, mammary glands, salivary and bronchial glands. A functional disturbance of mitochondria that are common for all lesions described is the decoupling of oxidation and oxidative phosphorilation. The mitochondrial crista contains ATP-synthetase, that couple oxidation of substances in Krebs cycle and ADP phosphorilation until ATP. After coupling of these processes the released energy in the oxidation process is stocked in macroergic bonds of ATP. After all the released energy released from ATP can be used for accomplishing the multiple functions. The process of oxidative phosphorilation from mitochondria has an energetic output bigger comparing with the process of anaerobic glycolysis from cytosol. Therefore, from a molecule of glucose in the first case are formed 38 molecules of ATP, but in the second just 2 molecules. Are known numerous factors like 2,4-dinitrophenols, dicumarol, bilirubine, that can decouple oxidation from phosphorilation with energy releasing in the heat form. Decoupling of these processes lead to decreasing of ATP synthesis and energetic penury of the cell that alter the energy dependent processes in the mitochondria and in other cell structures (ionic pumps from plasmalemma). In this way, as a result of decoupling of phosphorilation processes the mitochondria loose their ability to accumulate the calcium and potassium ions that decrease the membrane potential, brings about the getting out of Ca2+ ions from mitochondria. According contemporary vision the mitochondria alteration is a decisive factor in developing of irreversible cellular pathologic processes. Lysosomal lesions Lysosomal lesions are manifested by swelling and destabilization of lysosomal membranes. Normally lysosomal membrane prevents contact between the cytoplasm and lysosomal enzymes, and so are avoided the possible autolytic processes. Lysosomal membrane destabilization or breaking leads to the exit hydrolases in the cytosol, the hydrolysis of organic compounds from hyaloplasm and ultimately to cell autolysis. Destabilization of lysosomal membranes and swelling accompanied by increase in their permeability are caused by hypoxia, acidosis, membrane lipid peroxidation, bacterial endotoxins, all types of shock, hypovitaminosis etc. Consequence of lysosomal lesion - is escape of lysosomal hydrolases into hyaloplasm with specific degradation of substances (including proteins) and initiation intracellular autolytic processes that lead to cell disintegration. Leaving the cell, lysosomal enzymes can penetrate into the blood so install the

33

enzyme-emia. As a lysosomal membrane stabilizers can be called cholesterol, corticosteroids, vitamin E, antihistamines. General consequences and manifestations of local lesions Consequences of cellular lesions are irreparable and irreversible: typical pathological cellular processes (dystrophies cell apoptosis, necrobiosis, and necrosis), typical pathological processes in organs and tissues (inflammation, atrophy, and sclerosis), and integral typical pathological processes (acute injuries, hyperkalemia, enzymemy, fever); functional failure of vital organs - circulatory failure, respiratory, kidney, liver, endocrine secretion failure, anemia. Pathological cellular processes have repercussions for the entire body. Mechanisms of generalization of the cellular processes are: neurogenic, hematogenous, lymphogenous. General consequences of cell destruction, for the body are mediated by cellular release ingredients in the internal environment - electrolytes, enzymes, biologically active proteins and peptides. 1. Enzymemy Any specialized cell has only those enzymes, which effectively catalyze reactions in conformity with a certain species. Some enzymes ( or sets of enzymes ) are present in all types of cells for example the enzymes involved in fundamental metabolic pathways as are the biosynthesis of proteins and nucleic acids, glycolysis, Krebs cycle, etc.). In some cases, the same enzyme appears in forms that differ from one type of cells to another. On the other hand, every type of specialized cell has enzymes, which catalyze characteristic metabolic reactions: the enzymes involved in biosynthesis of thyroid hormones are located only in thyreocytes, those that participate in biosynthesis of urea are localized only in hepatocytes, creatinkinase is located almost all in muscles etc. Subcellular structure, in which are present different enzymes coincides with the place of specific ways of metabolism for this structure: glycolytic enzymes and some enzymes of urea biosynthesis are localized in the cytoplasm, the enzymes of Krebs cycle in mitochondria, enzymes involved in RNA biosynthesis are localized in the cell nucleus. There is a series of enzymes, which manifest their catalytic activity at the level of circulating blood. Among them are mentioned especially the enzymes involved in blood coagulation, a series of lipases and pseudo-cholinesterase (cholinesterase unspecific). These enzymes are synthesized by different organs, especially by liver, and are secreted in active form into blood, were catalyze specific reactions. Other enzymes, which circulate in plasma their number is quite big dont have a catalytic role at this level. Their presence in plasma is put in the relation with physiological renewal of the cells, as well as the secretion of enzymes during physiologic activity (i.e. kreatinkinase at physical effort). Secretion of intracellular enzymes into the blood is due to membranes permeability of the cell, which allows in a constant way the passing of some very small quantities of enzymes into plasma. This process amplifies or during physiologic activity (i.e. at big muscle efforts), or during cell destruction. In normal conditions the enzyme concentration, with or without a catalytic role in plasma, is included in certain limits considered normal values. The concentration constant in plasma of each enzyme is the result of the equilibrium between the speed of cellular destruction, on one hand, and of urinary inactivation and elimination, on the other hand. Indeed, the duration of enzyme circulation in plasma is much smaller than in cell. It is expressed as half - time the time, after which the enzyme activity is reduced by half. Cell lesions of any etiology are the causes of rising or decreasing of cellular enzymatic activity in blood of enzymemy. The spectrum of enzymemy and the enzyme concentration in blood corresponds as to the injured organ (the presence of organ specific enzymes), as well as the deepness of cellular alteration (the presence of specific enzymes for different cellular organelles). Thus, two enzymes ACAT and ASAT (alaninaminotransferase and aspartataminotransferase) are specific for hepatocytes, however ACAT is localized exclusively in cytoplasm, while ASAT is in proportion of 60% in cytoplasm and 40% in mitochondria. At a discrete lesion of hepatic cells, without affecting the mitochondrias will be secreted into the blood predominantly cytoplasmic enzymes. This will make the relation ASAT/ALAT named the relation De Rites, which at healthy individuals have the mean value of 1.3, to decrease less than 1.0 (between 0.7 0.4) at those suffering from hepatitis. Note that in case of hepatocellular jaundice. The serologic activity of ASAT and ALAT raise nearly

34

one week before bilirubine rises. The normalizing of these indexes is made, in case of a favorable evolution, nearly after 5 7 weeks, and the values remaining rose as much as cytolyses processes persist. Alkaline phosphates have high values in obstructive jaundice, but also in case of some osteoblasts sarcomas, in hyperparathyroidism and metastasis carcinoma. The level of acid phosphates is high in case of prostatic cancer and in some neoplasm of the mammary gland. High values of the amylase activity are reported in case of intestinal obstruction, acute pancreatitis and diabetes. Cholinesterase is one of the few enzymes, which provide information concerning the renal function; it is highly active in nephrotic syndrome. 2. Hyperkaliemia Cell lesions associate with releasing of potassium from altered cells and with consecutive hyperkalemia. Potassium concentration growth in blood reduces the gradient of concentration of this electrolyte between cytoplasm and interstitium, reduces the depolarizing potential, modifying the excitability of excitable cells first it is increased, then it is decreased till depolarizing inhibition. Especially sensible to potassemia are myocardiocytes, which react first at this dishomeostasis through characteristic modifications of ECG. 3. Response of the acute phase One of the stereotypic reactions of the organism to cell lesions is the response of the acute phase. The response of acute phase represents an integral pathologic process consecutive to pathologic cellular, tissue and in organs processes characterized by a complex of reactions from systems of regulation and protection with modification of the organism homeostasis. The causes of the response of the acute phase are the pathologic cellular and tissue processes cell lesions, necrosis, dystrophy, regional dyscirculatory deregulation, inflammation, allergy, and neoplasia. The response of the acute phase is started by active biologic substances released at activation, degranulation or lesion of cells of mesenchymal origin: mastocytes, macrophages, lymphocytes, neutrophils, endotheliocytes, and fibroblasts. The most important mediators of cells are interleukins IL 1 and IL 6, tumor necrotic factor (TNF - ), acute phase proteins. Mediators released from cells into interstitium start a local inflammatory reaction but being secreted into the systemic circulation interact with specific cellular receptors from other organs, initiating different systemic reactions of the acute phase CNS reactions, fever, activity of the endocrine, leucocytes and immune system. Under the action of the primary mediators, the liver secretes the proteins of the acute phase, which also mediates different general effects. The effects of the acute phase mediators are multiple and different. IL 1 is a polyfunctional cytokine secreted by leukocytes, macrophages, fibroblasts, neuronal and glial cells. It stimulates cycloxygenase and the production of prostaglandins (pro-inflammatory effect), cause fever (pyrogen effect), stimulate the immune system by Th lymphocytes activation, and activate the secretion of corticotrophin and glucocorticoids (stressing effect). The pro-inflammatory effect of IL 1 serves as a pathogeneses factor in evolution of atherosclerosis, septic shock, rheumatoid arthritis, respiratory depression in adults, inflammation of intestines, kidneys. IL 6 is produced by more cells (macrophages, endotheliocytes, epitheliocytes, immunocytes and others) activated by bacterial action, heterogenic antigens, inflammatory mediators. IL 6 is the main stimulator of synthesis and secretion of proteins of the acute phase from the liver. The main effects are the activation of corticotrophin and glucocorticoids secretion, fever, stimulation of leucopoiesis with leucocytosis, differentiation of B and T lymphocytes. Hyperactive production of IL 6 initiate autoimmune, osteodystrophic processes, inflammatory reactions. TNF is produced by macrophages, lymphocytes, neutrophils, mastocytes under the action of bacteria and bacterial toxins, of IL 1 and of IL 6 and other. TNF process anti-humoral action and a strong pro-inflammatory action, cause in chronic diseases. TNF hyper production exercise toxic systemic effects myocardium contractibility diminution, circulatory insufficiency, arterial hypotension, diminution of the venous flux to the heart, vascular hyper permeability, DIC and, in general, the shock with polyorganic insufficiency. From acute phase proteins synthesized and secreted by liver are C reactive protein, serologic amyloidal A, fibrinogen, haptoglobine, antitrypsin 1, antihimotripsine 1 and other. The

35

production and concentration in blood of the acute phase proteins rises in cell lesions. Simultaneously, the concentration of other proteins (transferrin, albumins) is decreasing. It is considered that glucocorticoids and IL 1 stimulate the synthesis of acute phase proteins in the liver. The major functions of the acute phase proteins are the starting of inflammation, phagocytosis stimulation, fixation of free oxygen radicals, and inactivation of serologic enzymes. C reactive protein, component of the natural protective system, stimulate the secretion of cytokines, activate the component, recognize and associate to the heterogenic antigens from the microbial cells, opsonization them and thus contributing to their phagocytosis. Serologic amyloid A from HDL composition cause the adhesion and chemotaxis of lymphocytes and macrophages, contribute at the initiation of inflammation in atheromatous plaques from the vascular wall, predispose to amyloidosis. Fibrinogen has anti-inflammatory action, creates the necessary carcass for plaques repair. Ceruloplasmin has an antioxidant effect, but haptoglobine associate hemoglobin released from erythrocytes in the process of hemolytic. Anti-enzymes inhibit the activation of enzymes penetrated in blood during cell lesion (tripsin, and chemotripsin, elastase, colagenase, plasmin, thrombin, rennin, leucocytary proteases), attenuating the pathogenetic effects of these. The manifestation of the acute phase answer is expressed by activation of nervous, endocrine, immune, blood systems. Clinically these are characterized by general symptoms (fever, apathy, anorexia), arthro-myogenic (myalgia, arthralgia), endocrine (hyperactive secretion of corticotrophin and glucocorticoids, insulin, vasopressin), metabolic (catabolism intensification), sanguine (hypoalbuminemia, appearance in circulation of acute phase specific proteins, VSH acceleration, complement activation, of the fluid coagulant system, neutrophilia). The biologic significance of the acute phase reaction is dialectically ambiguity at an adequate intensity it is favorable for the organism, having a protective role, reparative, but at an exaggerated intensity causes hyperergic inflammatory processes and integral pathologic processes cachexia. 6.6.4. Fever Simultaneously with the inflammation of the damaged organ and the acute phase reaction, cellular lesions appeared in the organism at the action of pathogenic factor cause also fever. Fever (lat. Febris, gr. pyrexia) typical integral pathologic process that appears in human and homeothermic animals as a response to cell lesion and to inflammation and is characterized by thermoregulation restructuring changing of the set point to a higher level. Fever is manifested by temporary of the body temperature indifferently from the surrounding medium temperature, being accompanied usually by metabolic characteristic modifications and functions of systems and organs. In broad biologic context fever represent the organisms general reaction to eventually harmful biologic factors or to cell lesion and is oriented to elimination of the pathologic factor from the organism and the restoration of the lesion organisms integrity. Alternatively, the action of the harmful factor, cell lesion, inflammation and fever are inseparable associated processes that develop concomitantly and visa a general strategic objective restoring of the organisms homeostasis. Etiology Fever is caused in an exclusively way by specific substances pyrogens. In function by their origin, pyrogens classify into: I. Primary pyrogens: 1) exogenous pyrogens - infectious exogenous pyrogens - noninfectious exogenous pyrogens 2) endogenous pyrogens II. Secondary pyrogens Primary pyrogens. A distinctive peculiarity of the primary pyrogens is that they do not cause the fever itself, but contribute to releasing of secondary pyrogens (leukocyte). Exogenous pyrogens divide into infectious pyrogens and noninfectious one. From infectious exogenous pyrogens are the products of vital activity (endo- and exotoxins) or the products of

36

microorganism decomposition, of viruses, parasites (i.e. mycobacterium tuberculosis, strepto- and staphylococci, gonococci, hepatitis viruses, infectious mononucleosis etc.). They constitute an integral part of microbial endotoxins. From the point of view of chemical composition, infectious pyrogens represent lipopolysaccharides, proteins (i.e. progeny of the dysentery pathogenic agents, tuberculosis). Gram-positive membranes of bacteria and of those grams negative contain a very active substance muraminic acid, component of membrane peptydoglicans and strong stimulator of secondary pyrogens synthesis. Note that the toxic properties of the exogenous pyrogens do not reflect their pyretogen character toxic dozes exceed for a few thousands times the pyrogen dozes. In case of repeated administration of bacterial lipopolysaccharides into the organism (i.e. under the form of purified pyretogen preparates, as is pyrogenal), their pyretogen action weakens, by appearance of tolerance. Non infectious exogenous pyrogens represent immune serums, human immunoglobulin, blood or plasma substituents and plasmatic protein fractions obtained from blood, which are administrated with aim of treatment or prophylaxis. Endogenous substances with pyrogen properties are contained in organisms cells, but being released may cause fever (i.e. in case of mechanical lesions of the tissue, necrosis, myocardial infarction, aseptic inflammations, hemolysis etc.). In some cases can take place fever like reactions known as endogenous hyperthermia. Unlike fever, these are not conditioned by pyrogens action, but appear because of sympathy nervous system stimulation (i.e. in stress) or by direct action upon organs and tissues cells with uncoupling of oxidation of phosphorilation (i.e. in case of thyroid hormones excess). Endogenous hyperthermia classify into: - neurogenic (centrogenic appear in case of brain traumatism), - psychogenic nervousness, emotional and intellectual overload, hypnotic suggestion, reflexes in case of urolythiasis, billiary lythiasis, peritoneal irritation accompanied by pain); - endocrine hyperthyroidism, feochromocytosis; - drug induced pyrogens, proteins, polypeptides, caffeine, ephedrine, antibiotics, sulfamides; - metabolic family hereditary fever, Fabri disease (distopic lypomatosis). Secondary pyrogens represent polypeptides or proteins with the molecular mass between 155 and 4000 Daltons and are assigned leukocyte pyrogens (LP.). LP include 2 polypeptides more active that, concordantly to J. Oppenheim proposal (1979), now are determined as IL-1 IL 1 is considered as one of the mediator in fever pathogenic and of acute form of inflammation. IL 1 stimulates the secretion of acute phase prostaglandins and protein A and P amiloids, C reactive protein, haptoglobin, antitripsine and ceruloplasmine. Under the action of IL 1 is initiated the production of T lymphocytes of IL 2 and is intensified the expression of cell receptors. Except these, takes please the amplification of B lymphocytes proliferation, stimulation of antibody synthesis and the expression of membrane receptors for immunoglobulin. In normal conditions IL 1 doesnt protrude through hematoencefalic barrier, but in case of its permeability deregulation (i.e. in inflammation) IL 1 passes to the preoptic region of hypothalamus and interact with neuronal receptors of the thermoregulation center. Pyrogen properties posses also IL L alpha (eliminated by vascular endothelium cells, fibroblasts), IL 6, lymph toxin, necrosogen factor, interferons etc. source of LP are blood phagocytes (neutrophils, monocytes) and tissular macrophages, astrocytes, and also T and B lymphocytes. Secondary pyrogens dont make part of cells, but are synthesized under the influence of appropriate stimuli. Such a stimulus for initiation of leukocyte pyrogens synthesis may be the fagocytosis of microorganisms or of the lesion cells, of immune complexes, heterogeneous particles. Formation of endogenous pyrogens constitutes the main link of fever pathogenity, independently of etiology. Pathogenesis Passing into the organism (from exogenous substances or endogenous) the primary pyrogens lead to synthesis secondary pyrogens. From the moment of contact of primary pyrogens with macrophages, takes place the initiation of secondary pyrogens synthesis. The mechanism that conditions the synthesis and elimination of endogenous pyrogens is insufficiently studied. In this moment is the

37

following concept about LP synthesis. For febrile reaction induction is insufficient the action of only one pyrogen; it is necessary the presence of a complex stimulant factors (usually the presence of an inflammatory focus). The synthesis and elimination of secondary pyrogens need a latent period, during which takes please leucopenia, caused by leukocytes adhesion to the vascular wall, by following diapedesis and their sequestration in tissue. The synthesis of secondary pyrogens is realized de novo and is determined by depression of specific physiologic repressor (by feed back mechanism), that is manifested by mRNA synthesis acceleration respectively. Elimination of secondary pyrogens from cells needs the presence of Ca and K cations. Unlike as primary pyrogens (bacterial and nonbacterial), those secondary have a strictly specific character and can be considered the real mediators of fever. Secondary pyrogens secreted from organisms humors are transported to the central nervous system (CNS) where they act upon the nervous of the thermoregulatory center of the hypothalamus. The nervous hypothalamic zone has membranes containing specific receptors, that interacting with secondary pyrogens thus activates the adenilatcyclase system. As a result in cells, grow the quantity of cAMP. In addition, upon the influence of secondary takes place the activation of cycloxygenase by prostaglandins synthesis intensification from E1 group, which increases the concentration of cAMP from the hypothalamus by phosphodiesterase inhibition. cAMP modifies the sensibility of thermoregulatory center neurons at blood temperature and at signals from skin thermo-sensible receptors. It is thought that under LP action the regulation point of the thermoregulatory center it is commuting at a higher level of temperature then in norm and as result the thermoregulatory center perceives the normal body temperature as being lowered. In consequence, are emitted impulses to the centers of the vegetative nervous system (VNS), and by these and upon endocrine glands (suprarenal, thyroid). The effect consists of sympathy system excitation and mutual inhibition of the parasympathetic system. Sympathetic nervous system excitation leads to peripheral vessels spasm, sweat secretion decrease, epinephrine and nor-epinephrine secretion increase, of thyroid hormones, that, on one hand limits heat yielding (thermolysis), and on other hand, intensify thermo genesis in the organism. Thermogenesis intensification is realized on the catabolic processes amplification and myogenous thermogenesis by involuntary skeletal muscles contraction muscular tremor. Thermolysis reduction is realized by skin and fatty subcutaneous tissue vessels spasm, decreasing of sweat production and elimination and diminution of external respiration. In such a way the thermic homeostasis is installed at a higher level, characterized by intensified thermo genesis, reduced thermolysis and thermoregulatory center activation oriented to active maintaining of body temperature to a higher level. Thus, restructuring of thermo regulation in fever is accompanied by active retention of heat in the organism indifferently from the surrounding medium. This is the essential difference between fever and overheating at the action of high temperature of the surrounding medium, when hyperthermia is an evidence of thermoregulatory center activity deregulation. Fever stages In development of febrile reaction, we can differentiate three stages: 1) stage of body temperature elevation (stadium incrementi); 2) stage of maintain of temperature at a high level (stadium fastigii); 3) stage of body temperature decrease (stadium decrementi). Stage of body temperature elevation is characterized by thermo genesis predomination upon thermolysis by diminishing of heat loss. Was reported that in this period thermo genesis can increase maximum only with 50% from the initial level, what is insufficient for body temperature increase. This shows that the maximum contribution in body temperature elevation has the thermolysis limitation. Thermogenesis amplification is conditioned in a big way by oxidation processes intensification in the internal organs (especially in muscle and liver non-contractile thermogenesis). Thermogenesis in muscle is realized by involuntary contractions tremor. Thermolysis reduction in this period of development of fever are obtained also by elaborate during evolution reaction contraction of mm. erectors pylorus, which result double effect tousled hair (at animals) and circularly muscles spasm of sweat glands ducts, this stops sweat elimination and heat loss by evaporation (this reaction in human appears as chicken skin). Body temperature elevation continues until a new level will be achieved, to which the thermoregulatory point is displaced. The maximum growth of temperature almost never exceeds

38

42,2C (in rectum) and rarely passes 41,1C. it is thought that exist a special protector mechanism that stops the excessive body temperature growth in case of fever (in hyperthermia caused by medium elevated temperature this mechanism doesnt function and the body temperature can exceed 42,2C). The fever is divided in respect with maximum body temperature: 1) sub febrile till 38C; 2) moderate or febrile from 38 till 39C; 3) elevated 39,1C till 40C; 4) hyper pyretic over 40C the maximum level of body temperature in fever depends on the pyrogen properties of the biologic factor, that caused the disease, as well as on the organisms peculiarities age, sex, constitution, CNS functional state, endocrine and other systems. In asthenic and exhausted patients the infectious disease may unfold without fever, this constitutes an unfavorable symptom and worsens the disease evolution. On the background of narcotic drugs, administration in the organism fever also doesnt manifest. Thus the biological significance of fever is the organism protection from biological pathologic factors, hyper pyretic fever becomes harmful itself, causing cell lesion and CNS deregulations, convulsions (especially in children until 3 years), coma. These conditions accompany frequently the viral infections, grave intoxication. Hyperpyrexia represents a big danger also for old people. Stage of high temperature elevation The stage is characterized by equilibration of term genesis and thermolysis processes that take please at a higher level than the normal one. Thermo genesis remains at a high level while thermolysis amplifies by peripheral vessel dilation, respiratory acceleration, and moderate intensification of sweat secretion. High temperature maintains as much as pyrogen factors are present in the organism. Fever represents a sign of disease evolution and of anti-infectious treatment efficacy. The second stage of fever - it is divided into the following types: 1) continous fever (febris continua) nictimeral oscillations of the temperature that dont exceed 1C (i.e. viral pneumonia, franc lobar pneumonia, pseudo tuberculosis, typhoid fever); 2) remittent fever (febris remittens) nictimeral variations are not less that 1C, but the minimal body temperature never decrease till normal values; 3) intermittent fever (febris intermittens) is characterized by considerable nictimeral variations of the body, with temperature decrease in the morning till normal values (i.e. in brucellosis, iersiniosis, infections mononucleosis, exudative pleurisy, tuberculosis); 4) hepatic fever (febris hepatica) some times is confined as septic fever; is manifested by temperature climbing alteration (over 40C) with its sudden decrease, nictimeral variations of temperature constituting 3 - 5C (i.e. in legionilosis, septicemia, generalized toxoplasmosis etc.); 5) atypical fever (febris attypica) is characterized by total deregulation of circadian rythous of temperature in the morning the temperature can be higher than in the evening (i.e. in grave septicemia, tuberculosis); 6) recurrent fever (febris recurrent) is distinguished by fever reinstallation after an afebrile period (i.e. in typhoid fever, lymphogranulomatosis, malaria); 7) recidivant fever in chronic disease (i.e. in uncured osteomyelitis); 8) undulating fever is distinguished by rhythmic increasing and decreasing of body temperature and by periods with normal values (i.e. in brucellosis, leishmaniosis, lymphogranulomatosis, ornitosis etc.). temporary climbing, in short periods (few hours), of body temperature till 37, 5 - 38C (febris ephemera) is reported sometimes in different neuroendocrine deregulations (i.e. during menopause), in some chronic infections.

39

Stage of temperature decrease With elimination of the primary pyrogen from the organism and with stop of secondary pyrogens synthesis also stops their action upon thermoregulatory center nervous with the return to normal value of the reference point approximately 36,6C. After this commotion of the reference point body temperature in fever is perceived as elevated, sympatric system inhibits, and the parasympathic is activated. This result the thermolysis intensification and term genesis diminution. Thermolysis rises as a result of skin vessels dilation, sweat secretion intensification and intensification of external respiration. Simultaneously thermo genesis decreases and body temperature begins to lower. Decrease of temperature may be rapid (crisis) or slow (lysis). Crisis leads frequently to acute circulatory insufficiency (collapse) and can have a lethal exit. Temperature decrease by lysis is more easily supported by patients and usually doesnt cause complications. Usually after fever the normal function the thermoregulatory center is restoring gradually, that is manifested by the unstable character of the temperature during a certain period. The functional state of organs and systems in fever The fever is accompanied by modification of all systems of the organism, but it has a different character in regard with fever stage. Central nervous system Fever leads to functional deregulation of cortex. In human is reported increased excitability (especially in the first of fever). A clinical symptom frequently met in fever is cephaleea. Fevers with high temperatures are accompanied frequently by delirium, hallucination, is possible loss of consciousness. In children can appear convulsions. Endocrine system The hypothalamus hypophyses system is activated, are reported stress symptoms. Sympathy nervous system excitation in the first and second stage of fever is accompanied by intense formation of epinephrine. Thyroid function is activated that contributes to basal metabolism intensification. Cardiovascular system Fever is characterized by essential modification of heart and blood vessels function. According to Libermeister rule, the body temperature elevation by 1C is accompanied by acceleration of cardiac contraction with 8 10 beats per minute. This is because of local heating of sinusal knot. Beside this, has an importance the elevation of sympathic nervous system tonus. As consequence the systolic volume and the cardiac output increase. The first stage of fever the arterial pressure may increase as result of peripheral vessels spasm and the redistribution of blood to the internal organs (centralization of blood circulation). In the third stage the critical decrease of temperature may lead to collapse development, caused by sudden decrease of arterial vessels tonus. Note that some grave infections diseases pass without being accompanied by pronounced tachycardia, for example typhoid fever, recurrent fever. Strong intoxication that appear in this cases decrease the functional activity of the sinusal knot bradycardia develop. In case of high fever in some patients appear cardiac arrhythmias. Respiratory apparatus In the first stage of fever the respiratory frequency decreases, and then increases, that contributes to initial reduction of thermolysis with its further intensification. Digestive apparatus and liver Fever is accompanied by pronounced modification of digestion, conditioned by hypo secretion of all digestive glands (salivary glands, gastric, pancreas, liver, intestinal glands), hypotonic and total hypokinesia, fecal bole stagnation (spastic or atonic constipation). Because of salivary secretion diminution appears xerostomia. Is reported loss of appetite, hypo secretion with gastric hypoacidity. The endocrine function of the digestive tract is deranged (gastrin secretion, secretin, of intestinal vasoactive peptide etc.), that worsens even more the existent deregulation. Cavitary and parietal digestion deregulations cause disbacteriosis, meteorism, intestinal autointoxication.

40

As a result maldigestion and malabsorption may develop. The livers function is also modified in fever. The function of detoxication and the barrier one is intensified. The moderate fever stimulates the phagocytic activity of the Kupffer cell in the liver.

Kidney and hydro electrolytic metabolism At the first stage of fever diuresis increases as a result of efferent vessels spasm and increase of filtration pressure. Simultaneously is increased elimination of water and colloids. In the second stage the diuresis decrease, water, sodium and colloids are retained in the organism that is caused by aldosterone secretion intensification. In the stage of lowering the temperature of body the elimination of water and chlorides increased (especially in case of intense sweat secretion), diuresis increase. This can have as consequence the dehydration of the organism. Metabolic changes Fever is accompanied by modifications of all types of metabolism, these being mainly nonspecific, characteristic also for other types of pathologic processes (i.e. hypoxia, stress). As a specific feature of fever is considered increased oxidative processes, and increase basal metabolism. Was reported that increase of temperature with 1C the basal metabolism grows with 10 12%. Simultaneously grows the necessity of oxygen. The content of CO2 in the arterial blood decreases because of alveolar hyperventilation. A consequence of hypocapnia is cerebral vessel spasm, decrease of blood and oxygen afflux to brain. Carbohydrates metabolism modifications in case of fever are conditioned by sympathy nervous system excitation that is manifested by intense glycogen disintegration in the liver, glycogen depletion in hepatocytes, glucose level elevation in blood (hyperglycemias). This modified condition, together with lipid metabolism deregulation and accumulation of ketones bodies in the organism leads to development of ketoacidosis. Fever is accompanied also by lipid metabolism deregulation. Lipid metabolism from deposits is intensified (lipolysis in fatty tissue), that represent the main source of energy in patients. Because of glycogen supplies depletion the oxidation of superior aliphatic acids is deranged, the elaboration of ketones bodies is intensified. Patients have hyperketonemia and hyperketonuria. Protein metabolism also considerably modified: the nitrogen balance becomes negative, caused by intense protein disintegration, as much as by insufficient protein share in the organism, conditioned by anorexia and digestive deregulations. On this background may intensify the phenomenon of protein deficiency. Water-salt metabolism deregulation in case of fever may lead evolution of a grave isotonic dehydration accompanied by CNS function deregulation. In children rapidly develop derangements of thermoregulation, hyperthermia, often appear convulsions. The water-salt metabolic deregulations in case of fever often correlates with acid base balance deregulations moderate fever is frequently accompanied by gaze alkalosis; but high fever and hyper-pyretic one by nongaseous acidosis. Fever leads to decrease of free iron content in the blood serum; meanwhile increase the content of ferritin. In case of prolonged fever is possible to develop iron deficiency hypochromic anaemia appear. Decrease of ferment activity that contains iron lead to deregulations of the tissular respiratory processes, especially in brain. In fever decreases the quantity of zinc and increases the quantity of cuprum. Biological importance of fever Fever as a typical pathologic process appeared during evolution has a big importance and in a big part determines the beneficial resolution of diseases. The moderate fever has a series of protective properties: 1) stimulate elaboration, cytokine activity (i.e. interferon); 2) stimulate the cell immunity; 3) stimulate phagocytosis;

41

4) diminish allergic reactions development; 5) inhibit microbes and viruses multiplication and exert a bactericidal action (i.e. was reported gonococci and treponema die at a temperature of 40 - 41C); diminish the microbes resistance to antibiotics. Taking into account the previous affirmation, now it is recommended the administration of antipyretic substances in the therapy of moderate fever. The protective importance of fever found itself application in elaboration of drugs for so called pyretotherapy a treatment method of chronic infections with a torpid evolution (i.e. of syphilis) by artificially induced fever. The negative impact of fever upon the organism is that the high fever may alter in a direct way the CNS cells, imposes functional overload of the cardiovascular system, derange the digestive processes, and intensify the metabolism. The fever is supported extremely hard by aged people, as well as by children of a fragile age. Prolonged fever (i.e. in case of tuberculosis, chronic septic processes) may exhaust the patient. Doctors tactics vis a vis from the patient with fever needs an individual attitude taking into account the specific and gravity of the disease, the character of fever, the way how the patient supports fever, possible contraindication for antipyretic therapy. 6.6.5. Stress. General syndrome of adaptation The pathologic processes at a cell, tissue, and organ level (cell dystrophy, necrosis, inflammation) by non-specific generalisation mechanisms (neurogenic, humoral) cause unavoidable and general reaction of the organism by integrative systems (CNS and endocrine glands). These general reactions, like any biologic phenomenon, has dualist character they represent biologically beneficial reactions (adaptation, compensation, protection, repair), but have and eventually pathologic qualities, alterative. The complex of general reaction as an answer to cell lesion in historical aspect were obvious as homeostasis (W. Kennon), physiologic measure of the organism against lesion (I. Pavlov), adaptive trophic sympathic nervous system (L. Orbeli). The further development of the concept about general adaptive compensatory system was HansSelye theory about stress (1936). Note that during almost 7 decades the notion about stress was enriched with new informations was branched. In the contemporary view the notion of stress transformed from a physiologic, medical phenomenon into a biologic universal, psychological, philosophic, social one. In the following the stress phenomenon will be described just as a general stereotypical reaction of the organism to pathologic cells, tissular and organ processes. The stress (general syndrome of adaptation) represent a complex of non-specific reactions of the organism as an answer to the action of exogenous and endogenous factors of a high intensity (stresses), characterised by adaptive compensatory and reparatory reactions, that concern homeostasis restoring and the survival of the organism in new conditions. Initially the stress was described as a general non-specific reaction, predominantly adaptive, of the organism to the lesions caused by many pathogenic factors parenteral inoculation of the extracts from organs, substances, toxins, the action of low temperatures and the high one, infections, traumas, haemorrhage, nervous system irritation and many others. The systematic study done by Hans Seley about morphologic and functional modifications, often identical, produced by different factors of physical, chemical, biological, psychological and social aggression showed the non-specific character of the reaction common for different agents of the ambient medium. Predominantly these reactions represents the ensemble of neuro-endocrine and metabolic answers of the organism to the action of stress factors named by Selye general syndrome of adaptation GSA (1939), and by Laborit oscillating post aggressive reaction (OPAR) (1955). The neuro endocrine metabolic reaction adequate to the stress factor and that ensures the resistance and restoration of the homeostatic balance without harmful consequence for the organism was called eustress. Inadequate answers (excessive or insufficient) generators of pathologic reactions; pathologic processes or disease is called distress. Etiology As stress factors, Selye obvious mechanic factors (mechanical traumas), physical (high or low temperature), and chemical (toxins), biological (infections), psychogenic (psychological traumas). The stress factors are divided according to their nature into bio ecologic, psychological, and social.

42

1. Bio ecologic factors (somatic) traumatisms, temperature (cold and warm), air currents, humidity, ionizing radiations, chemical toxins, alimentary factors, infectious agents, parasite, physical effort etc. 2. Psychological factors fear, anxiety, frustration, psycho emotional over load, conflicts, affective states. 3. Social factors confliction interrelation of work, family, social. Pathogenesis Post aggressive biologic reactions from the general syndrome of adaptation develop in animals and humans in 3 stages described by Hans Selye: 1. stage of alarm (the shock and counter shock level); 2. stage of resistance (adaptation); 3. Stage of exhaust. The stage of alarm is composed of 2 phases shock phase and counter shock phase. Shock phase appeared immediately after the action of stress factor and is manifested by primary lesion syndrome appeared instead of pathogen factor action. Local modifications produced by stress factor (cell lesions, dystrophy, necrosis, inflammation) by reflex and humoral mechanisms which lead to sympathy nervous system excitation, stimulate medullar adrenals and cortical adrenals. Epinephrine and norepinephrine released into blood circulation mobilize the protective forces of the organism which represent the alarm phase and which are manifested by shock the cardiac activity, external respiration are intensified, peripheral vasoconstriction with myocardial, brain and pulmonary circulation (hem circulatory centralisation), vasodilatation appears, the arterial pressure grows, catabolic processes are intensified glycogenolysis, lipolysis, proteolysis parallels with gluconeogenesis, the negative survey of nitrogen, increased oxygen consumption and CO2 formation, phagocytosis is intensified. Epinephrine hyper secretion, hyperlipidemia, iron release from haemoglobin and myoglobin, ATP breakdown till ADP and AMP lead to activating of cytoplasmic lipid membrane and cellular organs peroxidation process with typical harmful effects. Simultaneously the pathogenic effect of lipid peroxides is amplified by exhaust of antioxidant system (ODS, cathalase etc.). Counter shock phase begins with sympathy adrenergic system prevalence, followed by ADH hormone increased secretion. Involving into this process of hypothalamic hypophysial corticoadrenal axe is manifested by RF ACTH hyper secretion, hypophysial corticotrophin (ACTH) and consecutively by corticoadrenal activation with significant hyper secretion of gluco and mineral corticoids, that interfere in the carbohydrates, proteins, and mineral metabolism and increase the organisms adaptability and resistance. Ortho-sympathic system stimulation and post aggressive discharges of catecholamine lead to a marked growth of energy disposability necessary for biologic activity specific to the adaptation mechanism by pronounced and efficient mobilisation of carbohydrates (hepatic glycogen) and lipid (from adipose deposits) reserves, macroergic compounds formation intensification (ATP) etc. The synergist action of catecholamine and corticosteroids especially upon the vascular sector and catabolism intensification ensure conditions for a biologic activity more efficient. Thus, the local and systemic circulation is intensified, especially in organs of vital importance: brain, heart, and lungs take place peripheral vasoconstriction and redistribution of blood, mobilisation of deposited blood. Glucocorticoids intensify neoglucogenesis, that amplify the hyperglycemias initiated by catecholamine have anti-inflammatory action; intensify erythropoiesis, increased the leucopoiesis activity of haematopoietic organs with a preponderant growth of neutrophils. Under the action of glucocorticoids takes place the activation of blood coagulation factors, thrombocytopoesis increase, protein catabolism increase, cell membranes and organelles stability maintain, especially of those of mitochondrial and lysosomal. Consecutively to water-salt balance disturbance takes place the secretion of mineral corticoids, in this way warning the excessive loss of Na and K, as well as water economy by AND secretion. From the major clinic manifestations of the first stage are adrenal hyperplasia and hyper secretion, lymphoid organs involution followed by lymphocytopenia, phagocytosis depression, eosinopenia, arterial pressure and muscular tonus increase, hyperglycemias, body temperature normalisation, hyper secretion with gastric hyperacidity, that, simultaneously with blood vessels spasm and inhibition of gastric mucosa proliferation, diminish the mucosa protection and may lead to stomach ulcers appearance.

43

Stage of resistance is characterised by maximal intensity of adaptive and protective reactions adequate to stress factor with restoration and maintain of organisms homeostasis, that ensures a normal vital activity in new conditions of life, often unfavourable. This stage is the longest, being controlled by anabolic hormones (somatotropin, androgens, insulin). Takes place glycogen deposits restoration, also of lipids and proteins in blood and normalisation of organisms internal medium constants.

The stage of resistance has the characteristic manifestations in all systems of organism. The cardiovascular system reacts by tachycardia and arterial hypertension because of catecholamine effects, blood centralisation through selective vasoconstriction and vasodilatation, growth of circulating blood volume through mobilisation of deposited blood in liver, spleen, subpapilary plexus and erythropoiesis intensification. The respiratory system - increase of respiration frequency, bronchi dilation, increase of alveolar surface etc. In kidneys takes place vasoconstriction and decrease of renal blood debit, of effective pressure of glomerular filtration and diuresis, which even more decreases together with ADH secretion. Endocrine glands reaction in stress is different. From the most important reactions are suprarenal hypertrophy with increase of catabolic hormones secretion catecholamine, glucocorticoids, glucagon hypersecretion, somatotropin with catabolising reaction upon the carbohydrates and lipid metabolism; simultaneously takes place the inhibition of anabolic hormones secretion testosterone and insulin. Metabolic changes glycolysis intensification in liver and striated muscles with hyperglycaemic effect, lipolysis intensification with transport hyperlipidemia with free fatty acids in plasma, proteolysis in organs and gluconeogenesis. The stress ends with morphologic and functional modification in the haematopoietic and immune system thymus and lymphoid tissue atrophy with decrease of lymphocytes number in the peripheral blood, redistribution of lymphocytes from the intravascular compartment into the spleen, lymphatic knots, thoracic duct and bone marrow, T lymphocytes suppression, decrease of eosinophils and monocytes by redistribution. These entire phenomenon determine the stress immunodeficiency. Simultaneously takes place the growth of neutrophils number in circulation by their mobilisation from bone marrow, but with their inhibition of migration and accumulation in the inflammatory foci. The pathogenicity of stress includes nervous and endocrine mechanisms. Hypothalamus and its adjacent areas are considered to be the central components of the answer in stress. They receive stimuli from the reticular zone of the cerebral trunk, from the limbic areas and from thalamus. Psychogenic stress signals arrive to the hypothalamus by cortical descendent ways (cortical - hypothalamic), while the physical stress (somatic) is started by ascendant nervous ways from the spinal cord. The reticular formation is other primary nervous component in stress answer, through which takes please the non-specific brain activity. Sympathic nervous system is the common efferent way, that connects to the peripheral effectors organs and by which is realised the alarm state of the nervous system. The peripheral neurotransmitter, that acts at the level of organs and determine the physiologic reactions characteristic to stress, is norepinephrine. One of the effects of pre-ganglion fibbers stimulation that synapse with suprarenal medulla is growth of synthesis and secretion of epinephrine into the blood.

44

Also epinephrine seems to have an interconnection effect at the level of some cerebral areas, especially at the level of reticular formation. Thus, exist an auto amplification of the nervous system answer to stress. The endocrine pathogenetic mechanisms comprise hyper secretion of epinephrine and norepinephrine, somatotropin, corticotrophin and glucocorticoids. Stage of exhaust appears at the prolonged action of stress factor and shows the exhaust of protective and adaptive mechanisms, especially glucocorticoids insufficiency and energy supplies depletion. The stage of exhaust is manifested by adaptability limitation of the organism, suprarenal hypoplasia and hypofunction, corticosteroid secretion decrease, that leads to arterial hypotension, bradycardia, hypothermia, increased capillary permeability, anaemia, osteoporosis, glands atrophy, grave metabolic disturbances, decompensate acidosis, cachexia, exhaust and organism death. The biological significance Moderate and of short period stress has a favourable effect for the organism that is determined as by adaptability and organism resistance growth at the action of pathologic factors, that started the stress reaction, as well as at the action of other stress factors (cross linked resistance). In consequence takes please the attenuation of hyperergic inflammatory reaction, eventually harmful for the organism, allergic reactions warning, of cardiac affectation, kidneys and of other organs. Also exacerbated stress and of long duration may end with harmful consequences, sometimes fatal, for the organism. Population studies demonstrated that the action of psychogenic stress factors may lead to psychosomatic diseases appearance (duodenal ulcer, bronchial asthma, myocardial infarction, neurodermites, hyperthyroidism etc.). Released catecholamine under the action of stress factors act upon the cardiovascular apparatus, kidneys, pancreas etc. Although the stress represent a complex of non-specific reactions, was demonstrated that the psychogenic stress by his effects differ from the physical one. The psychological stress is manifested especially by tachycardia, hyperlipidemia cause by predominant growth of epinephrine, while the physical stress leads to cardiac output increase and of arterial pressure linked with norepinephrine predomination. The factors that determine maladaptation are divided into necessary and promoting factors. Necessary factors are the frequent stress, prolonged overload of the organs. From promoting factors are hereditary predispositions with respect to other stresses, diminished resistance of organs in stress, harmful habits drugs (medicine) abuse, smoking, alcoholism etc., type of personality, variability of individual stresses that act simultaneously on the individual. Pathogenicity of diseases caused by stress The researches showed that about 70 80% from health problems are worsened or caused by stress. The disease caused by stress is in direct relation with the activity of nervous, endocrine and immune system. Vegetative imbalance (with sympathoadrenal or parasympathic predomination) may involve microcirculatory, rheological disturbance, with modifications of blood debit and vascular permeability that may lead in the end to local metabolic disturbances, oedema, haemorrhage, irreversible lesion, tissular necrosis and may serve as pathogenetic factor of some diseases, like bronchial asthma, gastric ulcer, colitis, syndrome of irritated colon, stenocardia, allergy, rheumatoid arthritis, cancer etc. Being grouped by systems, the diseases induced by stress may be: immunodeficiency, cardiovascular diseases, digestive, dermatologic, respiratory. Stressing arterial hypotension may be due to individual specific reactivity of the organism. It is possible that specific life, heredity or experience to determine the answer of brain to different types of stress by arterial hypertension. Ischemic cardiopathy and myocardial infarction also have in pathogenesis the stress component. In some persons exposed to strong stress was determined the appearance of gastro duodenal ulcers. The mechanism, that could explain the link of stress with peptic ulcer, consists of decrease of gastro duodenal mucosal resistance (vasoconstriction produced by catecholamine and mucin secretion insufficiency, that normally protects the mucosa from harmful factors), simultaneously with amplification of aggressive actions upon mucosa (hyperacidity caused by cortisol). Neuro-endocrine deregulation started in stress may influence and the immune system.

45

Was demonstrated the psychological stress increases the frequency of respiratory infections, tuberculosis, mononucleosis, streptococci infections. The influence of the nervous system upon the immunity became easier to understand after discovery of lymphocytes, near receptors for antigen and for interleukins; they also have receptors for glucocorticoids, catecholamine, dopamine, histamine and endorphins, whose number may increase in stress. IL-1, secreted by lymphocytes also may act on the nervous system, producing sleep disorders, of respiration, appetite etc. More studies have shown a positive correlation between cancer susceptibility that is psychological characters. Seems that extravert capable to show emotional the negative feelings like fear, fury, have more chances not to have cancer than the introvert individuals, with stoic character and tendency to internalize of feelings.

7. Cell dystrophy. Cellular metabolic imbalance Dystrophy typical cellular pathologic process caused by metabolic deregulations general or cellular and manifested by functional deregulations and structural modifications of the cell. Classification I. II. by the degree of cell affectation - dystrophy may be: with functional deregulation predomination in combination with obvious structural modifications reversible irreversible in conformity with deranged metabolism - dystrophy may have: monovalent character (with derangement of one type of metabolism protein, lipidic, carbohydrate, hydro, mineral) polyvalent with simultaneous derangement of few substances metabolism.

Dystrophies (with the exception of those congenital) dont represent nosologic entities, but only syndromes in maladies composition. III. in function of dystrophic area affection dystrophies may be: - general, that comprise the majority of organisms tissues - local with predominant affection of an organ (liver dystrophy, kidneys, myocardium). IV. in function of predominant altered metabolism are distinguished: - protein dystrophy - lipidic dystrophy - carbohydrate dystrophy mineral dystrophy V. in function of provenience dystrophies are classified in: - congenital dystrophy, - acquired dystrophies. Etiology The general causes of congenital dystrophies are the hereditary factors that cause congenital cellular enzymopathy absence, defect or lack of cell enzymes. The effects of these abnormalities are gathering in excess of deficient catabolic enzyme substrate (i.e. congenital lack of glucoso-6-phosphatase enzyme lead to glycogenolysis impossibility and excessive accumulations of glycogen in cells) or synthesis and accumulation of abnormal substances into the cell. The general causes of acquired dystrophies are the factors that cause cell lesions, cellular metabolic deregulations and integral metabolic imbalance. The causes that cause cell lesions are mechanic, physical, chemical, biological factors, cell hypoxia, energy deficiency, transmembrane and intracellular transport deregulations of nutritive substances, and exocytose deregulations of intracellular substances. From the general deregulations of metabolism, that cause cell dystrophies,

46

are carbohydrate, lipidic, protein dyshomeostasis with all structures and interstitial spaces infiltration with proteins, lipids, and carbohydrate. Pathogenesis of cell dystrophies The main pathogenetic mechanism of dystrophies is the primary or secondary deregulations of cellular enzymatic systems with further modifications of protein, lipid and carbohydrate metabolism, with consecutive deregulations of cell structures. In pathogenesis of cell dystrophies are important more mechanisms. In congenital enzymopathies the genetic defects manifested by lack, insufficiency or defect of responsible gene of enzyme synthesis induced cell dystrophies by process deregulation of synthesis, storage, mobilisation and utilisation of nutritive substances (proteins, lipids and carbohydrates). Cell lesions induce dystrophies by different pathogenic ways, from which the most important are the following. Energetic lack is the most common mechanism of dystrophic processes. From most common cases of ATP synthesis decrease are hypoxias of any genesis, ischemia, nutritive substances deficiency, direct affection of oxidative processes (i.e. in intoxications, avitaminosis etc.). Energy deficiency diminishes anabolic cell processes glycogen synthesis from glucose, phospholipids and lipoproteins synthesis from tri-acil- glycerides, protein synthesis from amino acids etc. As result takes place the accumulation of unnecessary substances in anabolic processes (i.e. of monosaccharide, triglycerides, ketones bodies, amino acids), that invade the cell, lead to dystrophy. Also the energy lack deregulates the intracellular transports, creating lack or excess of stored substances. Free radicals and lipid peroxidation are the second cause of cell lesions and dystrophies. Formation of free radicals of oxygen and halogens is a physiologic mechanism of annihilation xenobiotes (also of living organisms) pervaded into the internal medium of the organism and that vices the homeostasis maintained. On the other hand, free radicals formed in excess or not removed in time because of antioxidant system insufficiency become pathogen, promoting by themselves cell structures alteration in direct way or by lipid peroxidation of cell membranes. Consequence are biological membranes permeability increase with passing of lysosomal enzymes into hyaloplasm and out of the cell, mitochondrial tumefaction and deregulation of oxidative processes and those of phosphorilation, decomposition of nucleus and deregulation of genetic processes, synthesis and release of prostaglandins. These pathologic processes are annihilated by natural alffa- tocopherol (antioxidant system, carotinoids, riboflavin, super-oxy-dismutase, catalase, glutation- peroxidase). In case of absolute or relative insufficiency of antioxidant system formation of free radicals leads to deregulation of intracellular metabolic processes and dystrophy, and even to cell death. Dystrophy by intensification of formation process of free radicals and peroxides occurs in hypoxia, ischemia, stress, shock, inflammations, infections, intoxications, hyper secretions of catecholamine and other. Intracellular accumulation of calcium is the third pathogenic mechanism of dystrophies. The intracellular biologic role of calcium consists in the initiation of cellular activation processes (neuron, myocyte, and thrombocytes), myofibrils contraction from other cells. Calcium in the cell in resting state is concentrated in endoplasmic reticulum by active capitation from hyaloplasm. Calcium pumping from hyaloplasm into endoplasmic reticulum is done by Ca/Mg dependent ATP-ase by active transport, with energy consumption against the concentration gradient. At cell activation calcium is released from the endoplasmic reticulum into cytoplasm, having the role of intracellular messenger, that links physiologic cell processes: in muscle links excitation and contraction, in nervous excitation and release of mediators, in thrombocytes activation and secretion of stored substances and others. After effectuation of cellular act (excitation, contraction) calcium from cytoplasm is again pumped into the endoplasmic reticulum by the same enzyme Ca/Mg dependent ATP-ase. Or, the resting state is equal to calcium storage into the endoplasmic reticulum, while cell activation with calcium passing out of endoplasmic reticulum into hyaloplasm. Thus, intracellular homeostasis of calcium is ensured by the balance of 2 couples of processes: a) by passing into the cell elimination from the cell of calcium through the cytoplasmic membrane and b) by

47

calcium release from endoplasmic reticulum into cytoplasm and rebinding of this element from cytoplasm into the endoplasmic reticulum. At translocation deregulation of calcium and its persistence in the cell membrane are possible dystrophic processes initiated by the calcium ions itself. The cause of accumulation and persistence of calcium in cytoplasm are membrane lesions with permeability and free diffusion stream of calcium increase from endoplasmic reticulum or interstitial space, ATP-ase inhibition or energy depletion, which reduces the elimination processes of cytoplasmic calcium into exterior or into endoplasmic reticulum. The harmful mechanism of action of calcium consists in phospholipase A2, proteases, ATP-ases and endonucleasis activation, that respectively breakdown membrane phospholipids, cell proteins, ATP and nuclear nucleaproteides. Thus, calcium is the trigger of autocatalytic and dystrophic mechanism in hypoxia and ischemia. Additionally passing of calcium ions into mitochondria decouples oxidation phosphorilation processes with previous energy lack. Calcium also causes lysosomal enzymes activation with initiation of intracellular digestive processes and cell autolysis. Intracellular accumulation of non-esterificate fatty acids excess represents an important mechanism of lipidic cell dystrophy. It consists of abundant passing of lipids from blood (in case of hyper-lipemia), excessive intracellular synthesis of lipids or inhibition of lipid usage by cell in catabolic processes (lipolysis), as well as in those anabolic (synthesis of phospholipids, lipoproteins). Intracellular fatty acids are exposed to peroxidation processes with formation of peroxides, which after the cytoplasmic membranes, mitochondrial membranes, lysosomes, endoplasmic reticulum and other, activate phospholipase A2, fix the cations with formation of soaps and cause intracellular acidosis. Lysosomal mechanism of dystrophies constitutes of non-specific liposomes activation, membrane permeability increase, passing into hyaloplasm of hydrolytic enzymes and initiation of autolysis processes. Catecholamine in excessive quantity also alter cells and start dystrophic processes by multiply mechanisms: by cell hyperfunction initiation, that creates a relative energy depletion, by glycolysis activation (generation of lactic acidosis), by lipolysis activation with formation of fatty acids excess, by lysosomes activation with hydrolytic autolysis, by intensification of peroxidation processes of lipids. From general metabolic imbalance producing dystrophies are hyperglycemias, galactosemia, hyperlipidemia, hypercholesterolemia, that lead to intracellular spaces infiltration with respective substances, overload and exhaust of metabolic systems with the following infiltration and dystrophy of the cell. Cellular dystrophies manifestations Cellular dystrophies are manifested by structural change of the cell and functional deregulations. The ultra structural morphologic manifestations dystrophies in majority have a non-specific character, stereotype and are represented by mitochondrial intumescences, the crests alteration, decrease and dislocation of endoplasmic reticulum membranes and of Golgi apparatus with ribosomes disruption, cytoplasmic oedema, lesion of cellular organelles membranes and of cytoplasmic membranes with permeability increase, lysosomes destruction and enzymes passing into hyaloplasm, nucleus destruction, cell necrosis. From specific modifications are only metabolic deregulations characteristic for the metabolism of each substrate with accumulation in cell of different non-metabolised substances (glycogen depositions, lipids, abnormal proteins etc.), abnormal substances, catabolites. Marker modifications (pathognomical) for each form of congenital dystrophy would be the trace out of cellular enzymes alteration processes until the respectively locus from the genome of the specification of accumulated abnormal substances. Intracellular structural modifications lead to functional deregulation in conformity with the predominant altering structure. Or, the dystrophic process consists of metabolic deregulations, functional and structural stereotypical modifications of the cell. In function of predominant alternant metabolism dystrophies divide into protein, lipid, carbohydrates and mineral dystrophies. Note that this dividing has a relative and conventional character, because the metabolism of all nutritive substances is in tight interrelations, but metabolism deregulation of a substance inevitable involves deregulation of other substances metabolism.

48

In function of predominant localisation of the dystrophic process (by predominant affectation of different cell structures) dystrophies are divided into parenchymatous (predominant alteration of specialised cell of organs), mesenchyme (predominant alteration of non-specific mesenchyme elements of organ) and mixed (simultaneous alteration of parenchymatous structures). Parenchymatous dystrophies represent metabolic deregulations in highly differentiated and specialised cells of organs parenchyma, while mesenchyme dystrophies affect the cells of mesenchymal origin and intracellular structures. In present this division is considered poorly justified, because even the structure; that is defined as mesenchyma (connective tissue), contains also parenchyma highly differentiated and specialised cells as would be fibroblasts, mastocytes, plasmocytes and mesenchyma collagen, elastic fibres, the fundamental substance. More than that, the dystrophic modifications from extracellular structures in the majority of cases represent the result of pathologic activity of parenchyma connective tissue, fibroblasts, mastocytes, plasmocytes. Only in the case of trans-endothelial transport deregulations because of increased permeability of the vessel wall or in general metabolic imbalance takes place blood substances extravasations, their accumulation in the interstitial space and the dystrophic modifications in the interstitial mezenchyma independently from the parenchymatous cells activity. Forms of cell dystrophies (parenchymatous) Parenchymatous proteinosis represent forms of dystrophies with predominant deregulation of protein metabolism, which involves the modification of physico-chemical properties of cytoplasmic proteins and formation in the cytoplasm of protein inclusions. Further, protein metabolism deregulations lead as consequence to hydro salt metabolism modifications with cell hyperactivity intracellular oedema. From morpho-pathogenetic mechanisms of dysproteinosis are cellular infiltration with extracellular proteins, synthesis and accumulation in the cytoplasm of abnormal proteins, intracellular transformation if initially normal proteins, proteins decomposition with formation of abnormal catabolites. The concrete forms of dysproteinosis are granulous dystrophies, hyalinosis, and hydropic dystrophy. It is considered that these dystrophies are not forms by themselves, but are different stages in cell degeneration. Dysproteinosis consequence in the end is necrosis cell death. From dysproteinosis causes are cell lesions caused by physical, chemical, biological factors, cellular energy synthesis deregulations, hypoxia, blood and lymph circulation deregulations, inflammatory process, and intoxications. More frequently are affected kidneys, myocardium and liver. Typical morphologic manifestations depend on dysproteinosis forms. Thus, in granulous dystrophy appear in the cytoplasm protein inclusions. From non-specific manifestations are cytoplasm opacity, mitochondrial intumescences, and mitochondrial crests destruction. In hyaline dystrophy in cellular cytoplasm appear hyaline inclusions protein substance with vitreous character. In hydropic dystrophy the cellular cytoplasm contains vacuoles filled with liquid. Parenchymatous dyslipidosis are lipidic dystrophies of organ parenchyma (liver, myocardium, kidney), that is morphologically manifested by inadequate accumulations of normal lipids in adequate places (in fatty tissue), normal amounts of lipids in inadequate places (in parenchymatous organs) or accumulation in structurally modified lipids. In function of type of accumulated lipids we distinguish accumulation of tri-acil-glycerides (neutral fats) fatty infiltration and dystrophy, gangliosidosis, cerebrosidosis, sphingomyalosis. Fatty dystrophy is met more frequent in liver, myocardium and kidneys. The predominant pathogenetic mechanism (morphogenetic) is infiltration with lipids from blood in case of general deregulations of lipid metabolism (alimentary hyper-lipidemia, of transport, retentionally), lipid usage deregulation in anabolic processes of synthesis of lipoproteins and phospholipids, lipid catabolism deregulation intracellular lipolysis, fatty acids oxidation, synthesis of abnormal unusable lipids, lipids transformation, decomposition. Fatty dystrophy of liver represents the excessive and for long period accumulation of fats in hepatocytes and is manifested by few morphologic variants: pure fatty dystrophy, substance dystrophy associated with mesenchymal reaction and fibrosis (cirrhosis). Causes of liver fatty dystrophy are the following: a) excessive passing of fats into hepatocytes from blood in alimentary hyper-lipidemia, of transport and retentionally; b) excessive synthesis of fatty

49

acids in hepatocytes in transport hyper-lipidemia; c) primary hepatocytes affection of toxic, infectious origin, with block of fat catabolism (lipolysis, fatty acids oxidation), lipoproteins synthesis, phospholipids; d) lack of necessary proteins for lypolytic enzymes synthesis; e) congenital enzymopathies. In the aetiology of liver fatty dystrophy more common is present intoxication with ethanol, diabetes, exaggerated consumption of fats and carbohydrates (that further transform into lipids), protein starvation, intoxications with hepatotoxic forms has its specific mechanism and characters. Fatty dystrophy of myocardium has at the base 3 pathogenetic mechanisms: hyperlipidemia with passing of exaggerated quantities of fatty acids from blood into cardiomyocyte, intracellular lipid metabolism deregulations and lipoprotein complexes disintegration from cell structures. The most frequent causes are myocardial hypoxia, phosphor intoxications, chloroform, arsenic, diphtheria. Fatty dystrophy of kidney affect predominantly distal and collector tubes and are met in nephritic syndromes. From dystrophies also are tesaurismosis congenital diseases, lipids and carbohydrates defects of catabolised enzymes that are manifested by accumulation in big quantities of nutritive substances in the cell that can not be metabolised because of lack of respective enzymes. From tesaurismosis are lipidosis and glycogenosis. Consequences of dystrophy Cell dystrophies lead to other pathologic processes (apoptosis, necrosis), tissular and organ processes (inflammation, atrophy, sclerosis) and integral processes (cardiac, renal, hepatic insufficiency, endocrine glands insufficiency). 8. Apoptosis Apoptosis represents a genetic mechanism of maintained of quantitative and qualitative homeostasis of cell population by reduction of cells excess or removal of nonviable cells. Quantitative homeostasis of cell population is maintained by individual and organised removal of cells excess that exceeds the functional necessities (i.e. myofibrils death of muscular resting, physiologic involution of the organism thymus, postpartum reduction of myometrium). Qualitative homeostasis of cell population is maintained by induced death of defected cells, with different nonviable mutations, incompatible with life, of cancerous cells, of infected cell by viruses etc. Apoptosis, although initiated by cellular pathologic processes, thus represent a physiologic mechanism of tissue homeostasis regulation. Apoptosis is the realisation of the genetic program of the cell of controlled death intrinsic thanatogen program - program of cellular suicide for maintaining of quantitative and qualitative homeostasis of the organism. Apoptosis, unlike the physiologic death, and especially of necrosis, that comprises whole cellular populations, is an individual process that takes place only in one cell. While, unlike necrosis, that is caused by extracellular pathogen factors (endogenous or exogenous), apoptosis is initiated by intrinsic cellular genetic program. Etiology Apoptosis can be triggered by physiological factors, but as seen in pathological conditions. Trigger mechanisms (of apoptosis start) are different signals of positive or negative order. Specific positive apoptotic signals for initiation of cellular suicidal process may be cell lesions produced by different pathogen factors (mechanical, physical, chemical, biological etc.), that dont immediately cause cell death. The same significance has the physiologic signals for example, glucocorticoids, that release lymphocytes. Specific negative apoptotic signals represent stopping the action of several hormones, that in a physiologic way maintain the existence of certain cells lack of growth factor, absence of

50

testosterone prostate cells death, absence of estrogens endometrial cells death, absence of prolactin mammary gland cells death and others. Pathogenesis In the pathogenesis of apoptosis are distinguished few stages. I. period of initiation - takes place the receiving of apoptotic stimuli (thanatogen) by specific receptors from cell membrane and further activation of genetic mechanism, that controls apoptosis. II. period of execution, started by genetic program with mitochondrial membrane permeability changes, decrease of ATP and generation of oxygen active species, free radicals. III. final period of apoptosis - takes place the cell degradation under the action of several factors, the main being specific enzymes caspases and mitochondrial mechanisms. Caspases (the name derives from cysteine and aspartate) represent proteases that have cysteine as active catalytic centre and produce the cleavage of peptide bindings after aspartic acid. Presynthesized caspases are placed in the cell in inactive form, being activated by thanatogen signals. After initiation of apoptosis, mitochondria synthesize ATP and thus continue to support energy - the process of apoptosis, that needs energy for cellular membrane integrity maintaining and warning of cell content pass out of the cell with potential harmful action upon other cells (In lack of initial apoptosis energy ends by necrosis). Biochemical apoptosis process has different morphologic equivalents. Thus apoptosis apparently develops in few distinct morphologic stages. I. Stage of cell isolation on the apoptotic process from the neighbouring cells by cell structures disorganisation - membrane micro-villi disappearance, of desmosoms, of intracellular adhesion complexes. The cell loses water, and the cytoplasm and nucleus condensate, cell volume decreases II. Stage of cell fragmentation with formation of cytoplasmic convolutions with cell fragments wrapped by cytoplasmic membrane fragments vacuolisation. The nucleus condenses (Karyopyknosis) and fragments (Karyorrhexis) and his fragments are included in the nuclear membrane convolution formats. III. In the last stage all cell appears transformed in closed cell fragments included in membrane convolutions apoptotic bodies, which are phagocytized by tissular macrophages, epithelial cells smooth muscle cells. In such a way, till the total annihilation of the cell undergoing apoptosis is maintained the structural integrity and cell membrane function (process that needs energy). It maintain intracellular (or inside the apoptotic bodies) component substances of the cell (electrolytes, enzymes, biologic active substances) potentially harmful for the surrounding healthy cells, that could cause their death or inflammatory process (as it happens in necrosis). Apoptosis, primary a physiologic phenomenon, has also different implications with pathology. There are diseases by apoptosis insufficiency, when despite of thanatogen stimuli (i.e. lethal mutations, cell malignancy, manifestation of forbidden non-self antigens, viruses infections) the cell does not start apoptosis, that would preliminary remove the mutant, cancer, non-self antigen carriers, infected by viruses cells and would stop the disease development, but takes place the survival of the cell with pathologic effects multiplication and invasion of the organism with mutant, cancerous cells, start of the autoimmune reactions with the alteration of the healthy cell, multiplication and dissemination of the viral particles into the organism, that commonly have fatal consequences on the organism. Another group represent the diseases by the acceleration of the apoptosis process with cell population depletion (i.e. in osteoporosis, AIDS, neurodegenerative diseases).

9. Necrosis Cell death represents the irreversible stop of cell activity in still living organism. In function of biological significance cell death is divided into:

51

a) physiological cell death; b) pathological cell death necrosis. In function of mortified cell volume the death may comprise individually one single cell, a cellular population and respectively a tissue, an entire organ in association with intercellular structures disintegration, derived from cells (Note that the notion of death refers only to cells and does not comprise non-cellular structures.). Physiological cell death is the removal from the organism of the old cells that completely realised their functional potential in the limits of the genetic program and follow to be replaced with the new ones physiologic regeneration. The majority of the cell have a limited period of life and activity, they die and are removed from the organism without any pathologic consequences, being thrown in the surrounding medium (desquamated cells of the skin, gastrointestinal and urogenital tract, bronchial tree) or are phagocytized by the phagocyte microphage system (i.e. old red blood cells). Necrosis is the irreversible stop of cell activity, death of the cell or one part of the tissue, organ in still living body. Necrosis may be defined as accidental death; violent occurred after the action of extracellular harmful factors endogenous, or exogenous. Or, necrosis is the local death, while the death in general means the death of the whole organism. In the same context necrosis differs also from post mortem modifications occurred after organisms death. Necrosis is followed by Necrobiosis the process of cell, tissue, organ death. Necrobiosis represents the transition stage of the structure from life to death (cellular agony). Necrobiosis represents the totality of path-biochemical, path-histologic and physiopathologic processes, that reflect the metabolic modifications, of the ultra-structure and cell, tissue, organs function in the dyeing process starting from the action of the pathogen factor (thanatogen) and till ended necrosis. The irreversible character (of different grade) of the necrobiotic modifications allow their correction and returning to life of the altered structures local, cellular reanimation. Etiology of necrosis Necrosis may be caused by different etiologic exogenous factors with direct pathogen action on the cells that result into irreversible cells lesions: mechanical, biological, chemical, physical factors. Necrosis may also be the consequence of other pathologic processes of the cells, tissues, organ and integral (dystrophies, inflammations, local circulatory modifications and the general one, hypoxia, dyshomeostasis, metabolic imbalance, nervous and endocrine deregulations etc.). In function of cell cycle phase, in which occurs, necrosis may be mitotic (occurs in the phase of cell mitosis) or interphase (occurs in the inter-mitotic period. Mitotic necrosis is linked with pathology of the mitotic apparatus, that indices pathologic mitosis and result nonviable cells. Interphase necrosis is the death of normal cells under the action of harmful factors. Etiologic factors induce necrosis by the affectation of vital systems of the cell: systems of receptors and secondary messages, of the ionic homeostasis, of the energetic systems, metabolic, reparatory, reproductive, etc. Cell necrosis inevitably indices 2 groups of reactions form the host organism. From the first group is inflammation. The inflammatory reaction as an answer to cell alteration vices the demarcation and isolation of dead cells, necrosis localisation, removal of dead cells residuals, regeneration and restores the lack of structures. From the second group are the previous reactions of the structure lack and organism function undergoing necrosis and oriented to maintain the biochemical, structural and functional homeostasis compensatory, protective, reparatory reactions. Note that necrosis includes not only cell death, but also non-cellular structures disintegration connective tissue fibres, fundamental substance. Or, necrobiosis of the organ includes thanatogen and sanogenetical mechanisms, the quantitative relations of which will determine the array of body processes: prevalence of sanogenetical mechanisms leading to convalescence; prevalence of thanatogen processes leading to organs death.

52

Periods of necrosis Shortly necrosis passes the next stages of evolution (Policard, Bessis, 1970): 1) period of cell disease cell lesions and compatible with life modifications and recoverable, reversible; 2) the period of cell agony with the irreversible alteration of some structures, while other cell structures keep their functionality; 3) cell death irreversible stop of the cell functionality; 4) autolysis and autophagia of dead cells. Lushnicof E., 1982 divides the process of necrobiosis as: 1) prenecrosis includes the place, background, biochemistry, structure and function of the organ in the moment of action of the pathogen factor; the place may be normal or modified; in case of preexistent pathology lower the adaptive, protective, compensatory and reparatory capacities of the organ, and the process of death is accelerated; 2) period of dyeing irreversible modifications in some cell structures; 3) period of death stop of vital activity of the entire cell; 4) post-mortem period dead cells disintegration, their demarcation from the living tissues, autolysis and autophagia of the cell residuals. Pathogenesis Etiologic factors potentially necrobiotic may execute multiple functions on the cell, causing cell lesions. The most vulnerable cell structures, on which act the pathogen factors are: cytoplasmic membrane, cell nucleus, mitochondria, synthetic apparatus, lysosomes. At the action of the harmful factor on the cell membrane is affected - the specific reactivity of the cell and reception of extracellular stimuli, - the function of transport and selective permeability with intracellular ionic homeostasis deregulation - electrogenesis and maintains the resting potential, - intracellular osmotic pressure, - cellular hydration, - intracellular maintaining of the cell specific enzymes. In mitochondrial affectation is deranged the oxidation catabolic processes that further affect all cell processes energy dependent: anabolic, reparatory, protective reactions etc. The alteration of the endoplasmic reticulum deregulates the intracellular homeostasis of calcium and activates the autocatalytic processes induced by ribonucleases, proteases, endopeptidases, and phospholipases. Ribosomes alteration deregulates the synthesis of proteins and the possibility of regeneration of cellular structures. Lysosomes alteration leads to elimination and activation of lysosomal enzymes and the intensification of autolytic processes. Nucleus affections decreases the capacity of multiplication. In the process of necrobiosis conventionally may be evidenced the following order of pathologic stages: biochemical modifications subcellular ultrastructural modifications cellular structural modifications functional deregulations. Major pathogenetic importance in necrobiosis has the following pathologic phenomena: a) free radicals formation. Initially generators of free radicals are the pathogen factors themselves: hypoxia, ionising radiation, inflammation and other pathologic processes. In virtue of topography the cell membrane primary supports the oxidative attack with more harmful effects: the peroxidation of membrane lipids with the formation of lipid peroxides from polyunsaturated fatty acids and parallel lesion of the cytoplasmic membrane, binding of SH groups from proteins with their fragmentation, binding of thiamine from DNA with its chain rupture. The lesions caused by oxidative stress are more pronounced in the

53

conditions of depletion of the anti-oxidative protection system, that blocks the formation or removes free radicals (scavenger) vitamin E, cysteine, selenium, zinc, super-oxy-dismutase (catalyse the transformation of oxygen peroxide in hydrogen peroxide), glutathione peroxidase. Note that in dyeing cell the process of free radicals generation is accelerated, becoming a thanatogen factor; b) intracellular calcium dishomeostasis. Cytosolic calcium concentration is equal about 10 -7 M, while the extracellular concentration of calcium is about 10-3 M. Or, exits an essential gradient of cytosolic and extracellular concentration of calcium, that is maintained by the membrane enzyme Ca 2+ - ATP-ase by passing calcium outside the cell and cytosolic calcium uptake in the endoplasmic reticulum. In necrobiosis conditions energogenesis decreases, necessary ATP for ion pumps function, inclusively of those of calcium, is decreased and calcium persists in cytosol in high concentrations with different pathologic effects phospholipases activation, that breakdown phospholipids and breakdown cell membranes and those of cell organelles with all successive effects, ATP -ases activation with ATP depletion and worsening of energy lack, proteasis activation with simple proteins breakdown and of endonucleases with breakdown of fatty acids; c) cell hypoxia - appeared at primary harmful action or occurred after cell alteration reduces the aerobic metabolism (oxidation processes), and parallel are intensified the anaerobic processes (anaerobic glycolysis) with triple result: lowering of ATP because of small output of glycolysis, increasing of AMP, non-organic phosphor and lactate; d) increase of intracellular AMP activates phosphofructokinase and successively glycogen phosphorilase with intensification of glycogenolysis and glycolysis, lactic acid and organic phosphor accumulation. Finally is installed the cellular acidosis. e) ATP depletion - that limits all endometric reactions from the cell (proteins, enzymes, phospholipids synthesis) and paralyses all cell functions, inclusively the protection, reparatory reactions necessary for necrobiosis opposition; f) Membrane defects loss of selective permeability, active transport, loss of electrolytes (K+) and invasion of the cell with Na + and Ca+, loss of proteins and enzymes, intracellular hyperosmolarity, intracellular hyper-hydration (cellular oedema); The summary of the described processes of swallowing of the cell, dilatation of the endoplasmic reticulum, detachment of ribosomes from the rough reticulum, polysomes dissociation, disorganisation of microvilli. All this modifications continue until the reversible stage of necrobiosis. Continuity of necrobiotic processes lead to irreversible modifications, that depends on intensity of the harmful factor and necrobiosis duration, as well as on previous state of the cell. Thus the liver supports hypoxia of 1 2 hours, but brain only 3 5 minutes. The critical point of transition from the reversible stage of necrobiosis to that irreversible is the lesion of mitochondria and their incapacity to generate ATP and implicit to maintain cellular processes. In consequence takes place the prevalence of phospholipase A 2 activity, that breaks down the arachidonic acid from cell membranes upon the activity phospholipids syntheses and thus is deregulated the turnover of phospholipids with progressive breakdown of cell membranes. Another process is the activation of Ca2+ dependent reactions, inclusively cytoskeleton proteins breakdown, cell deformation. Necrosis manifestations The variety of necrosis manifestations gathers the biochemical, ultrastructural, morph pathologic modifications and functional deregulations in different cellular substructures. Shortly, they may be presented in the following way: in the cytoplasm takes place the intumescences, oedema, plasmorrhexis (fragmentation), plasmolysis (destruction), lesion of cell substructures with respective consequences. In nucleus its condensation (Karyopyknosis), hyperchromatism, fragmentation (Karyorrhexis), degradation (Karyolysis).

54

At the level of tissue and organ - the necrobiosis is manifested by colicvation necrosis and coagulation necrosis. Necrosis consequences The consequences of necrosis at cell level are post-mortem processes: cell lysis, autophagia and phagocytosis with usage of assimilable products and excretion of non-assimilable products. The consequences of necrosis for the organ constitute the pathologic processes (inflammation), demarcation (delimitation) of the necrotised zone with leucocytes, macrophages, fibroblasts, encapsulations, sequestration of the necrotised portion, complete recovery (restitution), incomplete recovery (sclerosis). Consequences for the organism are integral pathologic processes mediated by resorption of disintegration products (acute fever reaction, fever, toxaemia, hyperkalemia) and of abolition of function of the necrotised organ (cardiac, renal, hepatic, respiratory insufficiency). The severity of consequences depend on the vital importance of the necrotised organ, volume of necrosis, the ability of the organism to compensate the functions of the necrotised organ, the ability of repair of the necrotised structures. Typical tissular pathologic processes 10. Cellular differentiation Ontogenesis (individual development of the body) has several steps: zygote embryo fetus child teenager adult old person. These stages develop on the basis of several cellular processes: cellular proliferation, cellular differentiation and organogenesis. Cellular proliferation represents cellular multiplication, increasing of cell population due to continuous mitotic divisions in dichotomic growth: from one cell appear 2, from these another 4,8,16 etc. During mitotic division, mother-cell transmits to descendent cell the whole cellular genome, all genetic information of the body. So, every cell of the body contains genetic information characteristic for the entire body. Proliferation represents the basis of cellular differentiation and of organogenesis. Cellular proliferation starts from the zygote stage and continues in some organs till death. Cellular differentiation represents the process by which the cells with similar genetic potential lose a part of inherited properties, keeping just some of them, in such a manner specializing into different groups of cells with the same structure and functions. So, differentiation represents a progressive limitation of totipotent genetic program of the zygote with generation of cell population with reduced genetic potential. More precise, this process is realized by deactivation of some genes and selective activation of other genes that codify specific protein-coded genes with special functions. From the whole genome, which is presented in differentiated cells, active are only those genes that determine functional and structural specificity of the cell. Therefore, ontogenesis passes through some steps characterized by a different degree of cellular potency: 1) totipotent zygote, from which the cells of the body develop; 2) multipotent cells of the embryos envelopes (endo-, ecto-, and mesoderm) which give birth to different tissues; 3) pluripotent stem cells, which are head of cellular series; 4) unipotent cells of tissues and organs; Above exposed information corresponds to the concept about primordial totipotency of the zygote and progressive restrictive differentiation. There is an embryonal mechanism, by which the initial cellular groups are imposed to develop by an irreversible way from toti-, multi-, and pluripotency to unipotency one type of tissue. In such a way, cells become specialized biochemically, structurally and functionally. Differentiation is a process of cellular cloning in different groups specialized structurally and functionally. A clone is a population of cells, developed from a single mother-cell with similar biochemical, structural and functional properties. Cloning represents the process of cellular separation from a cocktail of different cells, from which by successive proliferations, from a single cell develops population of similar cells (clones). The cell from a clone becomes the head of the cell series stem-cell, source-cell. Differentiation and organogenesis are concomitant processes, nonseparable, which take place continuously and are accompanied by mitosis. Conventionally, there can be distinguished

55

differentiation from proliferation, by which the numeric population of cells is ensured proliferation from specialization and proliferation from organogenesis, by which cells become progressively more specialized. In most cases, the cells which achieve the final stage of specialization, lose their capacity of proliferation (multiplication) (ex. erythrocytes), for a period of time accomplishing their specific functions. In period of embryonal development, the primary differentiation in the totipotent phase, intermediary differentiation in multipotent phase and terminal differentiation in pluripotent phase is taking place. After organogenesis is accomplished, in postnatal period just some tissues preserve their omnipotent potential (germinative epithelium, sexual cells) and pluripotent potential (ex. hematopoietic stem cells from red bone marrow). Different types of differentiated cells are characterized by their own capacity and speed of proliferation, histological function and the final products of cellular biosynthesis. In this way nervous, epithelial, muscular, connective cells differ from one another. So, proliferation rate is maximal in the connective tissue and epithelial tissues, is limited in muscular tissue and absent in population of nervous cells. The general rule is that the speed of proliferation in all tissues of the body is limited in comparison with period before organogenesis has finished, and proliferation rate which is measured by incidence of mitosis in cell population, is constant, being regulated by adaptive, compensatory, protective and reparative needs of the tissues. So, some tissues present a regenerative proliferation (physiologic reparation), which is permanent (ex: basal layer of the epidermis, epithelium of digestive tract, urogenital epithelium, epithelium of bronchial tree, hematopoietic bone marrow). The cells of other organs (ex. liver) have a low proliferation rate and finally, third category of cells is deprived of proliferation abilities (ex. neurons). The basis of differentiation are explained by appearance in the cells of some active substances or structures able to execute specific functions enzyme, protein, contractile structure, secretory and others. These depend of activation of some genes by inductors that lead to activation or depression of certain genes. Cellular differentiation disorders in postnatal period are represented by cellular tumor transformation. Tumor transformation represents the process of dedifferentiation (loss of differentiation capability) of different cells, mainly with loss of biochemical, structural and functional peculiarities which are characteristic to this type of cell. Another characteristic of dedifferentiated cells is regained ability of rapid proliferation, which has an anarchic, unlimited character, which doesnt correspond to actual needs of tissue of the body. Cellular multiplication gets out of control mechanism of cellular mitotic cycle and that of tissular growth. Dedifferentiation is associated with cellular passage from mitotic pause to active mitosis, decreased length of cell cycle, increased number of dedifferentiated, proliferative cells. Mitotic process take place without differentiation stage, the cancer cells are continuously, uncontrolled and unlimited auto-productive. Etiology of tumor transformation is multiple and includes physical, chemical, biological factors. Pathogenesis of cancer dedifferentiation can be explained by reactivation of some cellular genes leading to loss of biochemical, structural and functional characteristics of the respective cells, but with concomitant recovery of embryonal characteristics, discordant with biological age of the body. This process of dedifferentiation is called anaplasia. 11. Disorders of regenerative process Regeneration represents the process of recovery of the structures lost in physiological or pathological way, oriented towards reestablishment of structural and functional homeostasis of the body. The capacity of recovery is a natural ability for all body structures. In function of hierarchic level of regenerative substrate, regeneration can be: a) molecular regeneration recovery of molecules (example: recovery of DNA molecules); b) subcellular regeneration reestablishment of subcellular structures (cellular organelle), injured by pathogenic factors; c) cellular regeneration - reestablishment of monovalent cellular population of injured tissue (hepatocyte regeneration in liver cirrhosis without structural recovery of the organ of hepatic lobe);

56

d) tissular regeneration recovery of all tissular components of cells and tissular infrastructures (cellular interconnection, intracellular matrix: fibers, fundamental substance); e) organ regeneration reestablishment of organ parenchyma and stroma (vessels, nervous structures with preservation of specific architecture of the organ); Molecular regeneration represents the DNA recovery after injuries caused by different pathogenic factors which imply specific enzymes activation which perform the biochemical resection of injured segment of ADN, its lysis and resynthesis of normal segment, what will replace the injured portion. Subcellular regeneration represents the multiplication of intact cell organelles; the same way as a cell can originate only from a cell, organelles can originate only from other cellular organelles (these cant be synthesized de novo). In this way, mitochondria, ribosomes, Golgi apparatus regeneration is performed. Cellular regeneration is performed by mitotic and amitotic cellular multiplication. Tissular regeneration and organ regeneration may include in addition to cellular regeneration, blood vessel and lymphatic vessels regeneration (angiogenesis) as well as recovery of nervous structures (axons, nerve endings). In function of biological significance, can be recognized physiologic and pathologic regeneration. Physiologic regeneration targets recovery of cells lost as result of physiological processes (old cell after normal functioning), as result of functional overuse and accelerated use or cellular necrosis under the influence of some pathogenic factor which lead to cellular injuries and targets the maintenance of structural and functional homeostasis of the body. Physiological regeneration occurs in the basis of the same biologic mechanisms and is qualitatively and quantitatively adequate to the organ of residence regeneration is performed with the same histologic structures and in sufficient volume to maintain the structural and functional homeostasis of the involved tissue or organ. To be mentioned that, after functional overuse of the organ, volume of physiological regeneration can overcome the characteristic normal regeneration necessary for maintaining the normal physiological function, in this case we speak about hyperegeneration associated with excess of structures. Physiological regeneration is classified in following types: a) homeostatic regeneration recovery of used and old structures in result of vital physiological processes; this is the continuous regeneration of the epithelial cells of the digestive tract, urogenital tract, bronchial tree, skin, blood cells during lifetime. b) adaptive regeneration regeneration which is initiated by a functional overuse of a tissue oriented toward increasing structural mass, such satisfying the functional requirements in new conditions. A typical example of adaptive regeneration is regeneration of erythroblasts in healthy mountain dwellers. c) compensatory regeneration regeneration initiated by compensatory hyperfunction of synergist organs with the aim to increase healthy structural mass, in order to maintain functional homeostasis of the body. An example of compensatory regeneration is regeneration of erythrocyte series of red bone marrow in cardiac vices or lung diseases. d) protective regeneration regeneration of mesenchymal structures of the organs in order to protect from harmful effects of pathogenic factors. Protective regeneration of connective tissue occurs in infectious-inflammatory focus. e) reparative regeneration regeneration oriented towards recovery of parenchymatous structures of the injured organ. By this type of regeneration parenchyma of majority of organs (liver, stomach, intestine, skin and so on) is reestablished. For every organ an own capacity and form of regeneration is characteristic. So, in some organs only cellular regeneration is possible myocardial cells, neurons; in other organs, cellular mitotic and amitotic regeneration is characteristic, and is accompanied by concomitant regeneration and hypertrophy of subcellular structures in the liver, kidney, pancreas. There is the third category of organs in which cellular regeneration occurs without hypertrophy of cellular organelles in the skin epithelium, bone marrow. Pathologic regeneration is initiated by the same stimuli as those of physiologic regeneration, but differs by inadequate qualitative or quantitative features. I. Quantitative inadequate regeneration heterometry

57

a.

hyporegeneration insufficient regeneration for maintaining structural and functional homeostasis (negative structure balance).

b. hyperregeneration with overproduction of structures, which outrun homeostatic necessities of the body (positive structure balance), for example development of keloid scars on the skin). II. Qualitative inadequate regeneration regeneration characterized by production of structures which histologically differ from initial one. Is manifested by: dysplasia regeneration with production of abnormal, embryonal, monstrous structures; - metaplasia regeneration with production of normal structures but with another histologic character in other words - heterotopy (cylindrical epithelium is replaced by squamous epithelium); - sclerosis regeneration with substitution of specific parenchymatous structures with nonspecific structures (connective tissue); malignization regeneration with production of tumor cells; Metaplasia represents a reversible replacement of adult cells (epithelial or mesenchymal origin) with other adult cells and is an adaptive phenomenon of substitution of sensitive cells with other more resistant cells (for example: during chronic irritation of respiratory airways cylindrical epithelial cells are replaced with squamous epithelial cells). Its important to mention that those stimuli which cause adaptive metaplasia can lead to pathologic metaplasia cancerous transformation. Metaplasia can occur not only in parenchymatous cell but also in these of mesenchymal origin. For example, fibrous connective tissue can be transformed into osteoblast, chondroblast. 12. Hyperplasia, Hypertrophy Hyperplasia represents the process of intensified cellular multiplication which leads to increased number of cell in cell population or in the organ. Hypertrophy represents increased volume and mass of an organ because of increased number of cells (hyperplasia) or increased volume and mass of every separate cell (cellular hypertrophy). Cellular hypertrophy represents growth in volume and mass of cells due to increased number of cell organelles. Because cellular hypertrophy is realized through increasing number and volume of cellular organelles, it is also called ,, intracellular hyperplasia or, in other words, multiplication of cellular organelles. Organs, which during evolution preserved the capacity of cellular regeneration, have both type of hypertrophy subcellular hypertrophy and cellular hyperplasia (for example: liver, pancreas, kidney); organs which during ontogenesis lost their ability of cellular regenerations manifest only subcellular hypertrophy (for example: myocardium). But, because the objectives and final effects of both processes (hyperplasia and hypertrophy) are the same - functional homeostasis or equilibrium between structure and function, these two phenomena, physiologically, can be examined together. In function of initial cause and biologic significance hypertrophy is divided in: I. Physiological hypertrophy: orientated to maintain structural and/or functional homeostasis of the body in different conditions of existence and during action of pathogenic factors; it is adequate qualitatively and quantitatively in order to maintain homeostasis and ensure stability of function in adaptive process. Physiological hypertrophy can be: a. Adaptive hypertrophy (hypertrophy of skeletal muscles in physical effort, absolute hypoxic erythrocytosis); b. Compensatory hypertrophy (hypertrophy of myocardium in heart failure, hypertrophy of one of the kidney when the second was removed); c. Protective hypertrophy (hyperplasia and formation of a capsule around a foreign body in the tissue); d. Functional hypertrophy (hypertrophy of pregnant uterus, of mammary gland during lactation) II. Pathologic hypertrophy hypertrophy which is inadequate qualitatively and quantitatively for maintaining homeostasis. Pathologic hypertrophy can be:

58

a. Endocrine hypertrophy develops during non-physiological hypersecretion of hormones (ex. tumoral secretion of estrogen with endometrial hypertrophy aside of menstrual cycle; hormonal mammary adenopathy); b. Neurotrophic hypertrophy - hypertrophy of adipose tissue in denervated organs; c. Inflammatory hypertrophy - excessive growth of connective tissue in chronic inflammation; d. Tumoral hypertrophy - hyperplasia of tumoral tissue; Pathogenesis of hypertrophy has common features in different organs and includes some stereotype processes. Hypertrophy begins with an initial period triggered by many stimuli: function deficiency (absolute or relative with increased demand); generation of specific biologic stimuli growth factor, hormones, hypoxia, oxidative stress, inflammation mediators, metabolic wastes and other biologic active substances). These initial factors act in a specific way, activate synthesis of cellular structures through induction of genetic process or stimulate the cellular multiplication (for example: action of erythropoietin); or acts as adjuvants which ensure the process of stimulation and multiplication (catabolic hormones glucocorticoids, glucagon, catecholamines and anabolic hormones estrogens, androgens, insulin, somatotropin). Under the influence of these factors growth is stimulated leading to hyperplasia/ hypertrophy. When the adequate grade of growth is achieved, sufficient to satisfy functional overload, hypertrophy process is stopped both, through cessation of triggering factor action as well as through action of some growth inhibiting factors. This kind of process is regulated through the feed-back mechanism on the cellular, tissular and systemic level. Biological significance of physiological hypertrophy and hyperplasia is determined by the final objective, which consists in maintaining the functional homeostasis of the body through structure modification. Meantime, hyperplasia ensured through acceleration of the cellular multiplication, leads to early consumption of genetic cell resources and probably decreased adaptive potential of the body. This, probably, explains premature aging of the hypertrophic heart, explained through decreased cellular population and myocardial sclerosis. 13. Atrophy Atrophy (from greek a negation, trophe -nutrition) represents a process of lowering in volume of cellular organelles, cells, tissues and organs associated with decreased or stopped functions. Atrophy can be regarded as a form of structural dyshomeostasis or as a disbalance between destructive processes (physiological or pathological) and relative or absolute insufficiency of the regenerative processes. Because structural homeostasis is a derivate of functional homeostasis, is necessary to underline the role of function in determination of structure volume. So, the volume of a necessary function to ensure the homeostasis of the body determines the structure volume. In other words, in the balance function/structure, the main role has the function. From this point of view, different normal equilibrium structure/function can be present: increased function increased structure; decreased function decreased volume of structures. So, atrophy has no equivocal biological significance: decrease in the volume structure can be with preservation of the normal balance function/ structure (when the function primary suffers); and with structure deficit which is not able to satisfy functional requirements (when the structure is primary affected). In function of biological significance and the balance between function and structures there can be recognized physiological and pathological atrophy: I. Physiological atrophy is the atrophy with preservation of the equilibrium between structure and function. a) hypofunctional atrophy develops through decreased functional requirements (ex. atrophy of the skeletal muscle in the physical inactivity, atrophy with demineralization of the bones in cast immobilization, physiologic anemia in prolonged physical inactivity); b) involutive atrophy atrophy of the organs and tissues characterized only for a ontogenetic period (thymus atrophy with age);

59

c) involutive senile atrophy atrophy of all organs especially skin, muscle, bones with aging; d) endocrine atrophy atrophy of the hormone-dependent organs, accompanied by reduction of the respective hormone concentration (prostate atrophy in insufficiency of androgens, atrophy of mammary glands in prolactin hyposecretion; atrophy of endometrium in insufficiency of estrogens; thymus atrophy during high doses of glucocorticoids); e) Atrophy developed as result of growth factor lacking (endocrine gland atrophy as result of insufficient or lack of tropic hormones); f) post-hypertrophic atrophy - involution of the hypertrophied organs as result of cessation of hypertrophic stimuli action (post-partum involution of the uterus, decreased mass of the hypertrophied myocardium in cardiac vices after surgical correction of the defect, involution of the skeletal muscle in sportsmen after stopping training). II. Pathological atrophy atrophy accompanied by function and structure deficit; develops as result of cellular necrosis of different origins associated with insufficiency of regenerative potential of the tissue. There are some types of pathologic atrophy: a) atrophy as result of long action of the mechanical forces (atrophy of cranial bones in intracranial hypertension); b) atrophy as result of destruction of structures caused by physical, chemical, biological factors (ex. inflammation); c) hemo- and lymph-dyscirculatory atrophy (ex: ischemia, venous hyperemia, hemolymphostasis); d) deficit atrophy atrophy and teeth destruction in fluor insufficiency. In function of structure which suffers atrophy, there can be recognized: a) atrophy of cellular organelles (mitochondria, nucleus, reticulus endoplasmaticus); b) cellular atrophy - parenchymal and stromal atrophy with decreased volume of the organ; - parenchymal atrophy concomitant with stromal hypertrophy, hypertrophy of the adipose tissue (false hypertrophy). Atrophy pathogeny Each form of atrophy has its own specific pathogeny, determined by some specific mechanisms: 1) Decreased functional requirements and reestablishment of the equilibrium between structure and function with diminished structural mass (hypofunctional atrophy, senile atrophy, posthypertrophic atrophy); 2) Decreased organo-morphogenetic stimulant actions -involutive atrophy, hormonal atrophy; 3) Insufficiency of the reparative processes in case of destruction of respective structures pathologic atrophy; Manifestations: characteristic manifestations of the atrophy are diminished volume and mass of subcellular structures, cells, tissues, organs, lower than normal limits. Consequences of atrophy depend on its character. Every atrophy is accompanied with proportional diminishing of function, but if in case of hypofunction due to physiological atrophy, this function is adequate to current requirements and is capable to ensure homeostasis of the body in optimal conditions (but with decreasing diapason of adaptation), in case of pathologic atrophy deficiency of function leads to dyshomeostasis in the body even in optimal conditions of existence. 14. Sclerosis The spectrum of pathologic regeneration phenomena includes sclerosis, fibrosis, cirrhosis and cicatrizations. Sclerosis is the process of pathological regeneration, consequence of cellular necroses, characterized by diffuse or focal induration of organs due to excessive growth of dense connective tissue, collagen fibers exceeding cellular structures. Sclerosis process means substitution of parenchymal specialized structures or of the specialized connective tissue with acellular structures.

60

Fibrosis from morpho-pathological point of view, represents moderate sclerosis of the organ without induration; should be mentioned that the delimitation of this two phenomena sclerosis a fibrosis doesnt exist; often there is the equivalent sign between them. Cirrhosis represents sclerosis accompanied by organ deformation. Cicatrization (scarring) represents sclerosis localized in foci of inflammation or necrosis. Etiology of sclerosis: a) action of harmful factors, which cause direct cellular injuries and disorganization of the connective tissue (mechanical factor, physical, chemical and biological factors); b) local and generalized hemo- and lympho-circulatory disorders, which cause cellular injuries (venous hyperemia, blood and lymphatic stases, systemic circular insufficiency); c) cellular dystrophy; d) all types of necrosis; e) productive chronic inflammation; f) thrombus formation, fibrin deposition. Pathogenesis of sclerosis: Generally, sclerosis represents excess growth of connective tissue structures, which replace specific parenchymal structures. Sclerosis develops through several general pathogenetic variants: a) through neogenesis (de novo formation) of connective tissue with fibroblast proliferation, synthesis by fibroblast of collagen, extracellular formation of collagen (fibrilogenesis); b) lack of fibroblast proliferation but with aging of connective tissue and intense formation of collagen (circulatory hepatic cirrhoses, nephrosclerosis); this process is also called fibrosclerosis; c) induration of organ due to collapse (annihilation) of the stroma but without sclerosis. From reversibility point of view, sclerosis process is divided in: a) labile sclerosis which is totally reversible; b) stable sclerosis partial reversible; c) progressive sclerosis irreversible; Histological base of sclerosis process are connective tissue structures. Lax connective tissue consists of cells and cellular structures with the support, trophic and protective functions. Fibroblasts of connective tissue are divided into: poorly differentiated fibroblast, mature fibroblasts which are functionally active and fibrocytes, which are weakly active. Fibroblasts produce intercellular components collagen, elastin, proteoglycans, glycoproteins. These cells participate in metabolism regulation, ensuring structural and architectonic stability of the organ and performing epithelialmesenchymal interrelation. A fundamental function of fibroblasts is the collagen synthesis, which is performed in ribosomes of rough endoplasmic reticulum, by molecular synthesis in form of alpha-spirals (key process, is synthesis of oxy-proline and oxy-lysine). From 3 molecules of alphaspiral tropocollagen (procollagen) is synthesized - a form of intracellular transport. Heads of tropocollagen molecules are blocked by non-spiral peptides which inhibits intracellular collagen polymerization. Leaving the cell, terminal peptides of procollagen are cut by special enzymes collagen-peptidase, subsequently, through transversal covalent binding, they aggregate in fibrils with involvement of lyzine-oxidase and Cu2+ ions. Fibrilogenesis of collagen begins with binding of 5 molecules of procollagen into a cylinder with a diameter of 3-5 nm - protofibrils spread spirally. Protofibers are joined in subfibers (14-30 nm), forming fibres, which finally are united in bundles visible on photonic microscope. In sclerosis, growth of connective tissue is modified through nervous and endocrine influences, through disorders of cellular interrelation of connective structures, collagen, proteoglycans and epithelial cells, through modification of intercellular contacts as result of action of soluble cellular mediators (lymphokine, monokine, fibrokine) or insoluble mediators (cellular debris, products of cellular and acelullar structures desintegration). All these mechanism act by feed-back mechanism on different levels. Sclerosis process includes several steps: a) alteration - destruction of cells and collagen fibres by pathogenic factors; b) phagocytosis of cellular destruction products by macrophages; c) production of fibrogenetic factors by activated macrophages (activated as result of phagocytosis), these finally intensifying collagen synthesis.

61

As result of intensified synthesis, collagen excess is created, which by feed-back mechanism inhibits collagenogenesis, transforming active fibroblast in inactive fibrocytes, such diminishing collagen synthesis. Another process initiated by collagen surplus and orientated toward reducing collagen mass is activation of collagenolysis through transformation of active fibroblast into fibroclast cells that phagocytize collagen. Concomitant with phagocytosis, extracellular collagenolysis occurs, and final result of these two processes is inhibition of connective tissue growth, remodeling and involution of this. So, scarring process forms a chain of injury effects inflammation reparation. These above described successive phenomena lead to stabilization of connective tissue by balancing processes of collagenogenesis and collagenolysis (ex: scar on the skin). This is the first mode of sclerotic process evolution. The second way of evolution of sclerosis represents connective tissue involution and reduction of mass by predominance of collagenolysis under collagenogenesis. The third variant represents progressive sclerosis, with prevalence of collagenogenesis over collagenolysis with connective tissue growth. Progressive sclerosis is the final result of many processes: massive injury of parenchyma and stroma collapse; long-acting activity of inflammatory pathogenic factor (ex., in chronic inflammation); abundant proliferation of fibroblast; induction of collagenogenesis in general hypoxia, in local hemo- and lympho-circulatory disorder (ex: venous hyperemia, ischemia, stasis); action of toxin, metabolic wastes, organ infiltration with blood cells and cells of other origin; local homeostatic growth disorder of connective tissue; congenital defects of collagenogenetic-collagenolytic system. The common feature of this process is development of sclerosis and cirrhosis of the organ. Concomitant with fibrogenetic mechanisms, which lead to progressive sclerosis, there are collagenolytic mechanisms, which can ensure involution of sclerosis process. From these mechanisms can be numerated: desmolytic function of epithelial cells, intracellular collagenolysis by phagocytosis of collagen fibres with further digestion of these (ex. in post/partum period, in the uterus, function of collagenolysis is realized by macrophages, fibroblasts-fibroclasts), enzymatic extracellular collagenolysis, especially of hepatocytes and hepatic macrophages. Collagen catabolism is performed by collagenolytic enzymes, both of lysosomal (catepsine B, D) and non-lysosomal (tripsine, extracellular collagenase) origin, released from epithelial cells, cells of mesenchymal origin (ex: in inflammatory process collagenolysis is performed by leukocytes, neutrophils, macrophages, fibroblasts). Production of collagenase is regulated by estrogen, androgen, mast-cells, eosinophils, lymphocytes. Consequences of organ sclerosis (cardiosclerosis, pneumosclerosis, nephrosclerosis, hepatic cirrhosis) are diminished mass of specialized cellular structures with functional insufficiency and respective consequences (cardiac insufficiency, respiratory failure, renal failure, hepatic failure). Biological significance of sclerosis is biologically ambiguous, the combination of favorable and unfavorable conditions. By one hand, sclerosis marks the end of a pathological process (ex: inflammation), assures reparation and regeneration of intercellular matrix, injured by the pathological process, such having a favorable signification. Concomitant with this, sclerosis assure regeneration, although incomplete, of organs submitted to action of all pathogen factors and in all form of tissular alteration. Thats why, in some skin affection, ex: in trophic ulcer or in gastric or duodenal ulcer, end of process through cicatrization represent a favorable resolution and a variant of barrier function reestablishment of these organs. But, on the other hand, functional incompetence of connective tissue, which substitutes specific functional tissue and structural deformations, failures the affected organs. In function of pathogenesis, the treatment principles of sclerosis process, comprise inhibition of fibrogenesis and stimulation of collagenolysis. Fibrogenesis inhibition can be performed through liquidation of chronic processes inflammation, hypoxia, dystrophic processes, through removal of some injurious factors of mechanic, physical and chemical nature; through administration of immunemodulators , immune- suppressors, steroid and non-steroid anti-inflammatory drugs, of some iatrogenic drugs (substances which inhibit intramolecular collagen association); of antioxidants, which inhibits formation of lateral joints in collagen molecule.

62

63