Cell Injury:

Cellular Injury
(year 2010 )

Dr. Huda M.Zahawi, FRC.Path. 90-37

Cell Injury:

Topic Outline

Causes of cell injury Types of Injury Priciples & Mechanisms of cell injury Outcome : ?Reversible ? Irreversible Morphology Adaptation to Injury Patterns & types of Cell Death Process of Aging

Cell Injury:

Cellular Injury & Adaptation

Normal cell is in a steady dynamic state Homeostasis : The ability or tendency of an organism or cell to maintain internal equilibrium by adjusting its physiological processes.

Cell Injury:

Cells are constantly exposed to stresses.

Normal physiologic stress Severe stresses: injury results, and alters the normal steady state of the cell, consequently,

It can survive in a damaged state and adapt to the injury (reversible injury or adaptation) It can die (irreversible injury or cell death).

STRESS

INJURY

NORMAL CELL

Adaptation Atrophy Hypertophy Hyperplasia Metaplasia

Reversible injury Cellular swelling Vacuolar change Fatty change

Irreversible injury Necrosis Apoptosiss

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Causes of Cell Injury

Hypoxia and ischemia Free radicals Chemical agents Physical agents Infections Immunological reactions Genetic defects Nutritional defects Aging

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TYPES OF INJURY

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1- Hypoxia & Ischemia

Causes of Hypoxia low levels of oxygen in the air poor or absent Hemoglobin function decreased erythropoiesis respiratory or cardiovascular diseases, or ischemia (reduced supply of blood)

Cell Injury:

Ischemia & Hypoxia induce mitochondrial damage.

This results in decreased ATP which in turn reduces energy for all cell functions ! If persistent CELL DEATH

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Hypoxia is a common cause of cell injury Result : Cell resorts to anaerobic glycolysis Ischemia is the commonest cause of hypoxia, & injures the cells faster than pure hypoxia Why ?? Restoration of blood may lead to recovery OR Ischemia/ Reperfusion injury Progressive cell damage Examples : Myocardial & Cerebral infarction

Cell Injury:

Ischemia/Reperfusion Injury

Restoration of blood flow influx of high levels of calcium Reperfusion increases recruitment of inflammatory cells free radical injury Damaged mitochondria induce free radical production & compromise antioxidant defense mechanisms Dead tissue becomes antigenicAB activation of complement immune response

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Recommendation : In some cases , high oxygen therapy to improve hypoxia is NOT given because it generates oxygen derived FREE RADICALS ( Reactive Oxygen Species ROS)

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2- Free Radicals

Free radicals are chemical species with a single unpaired electron in an outer orbital, they are chemically unstable and therefore readily react with other molecules, resulting in chemical damage. To gain stability, the radical gives up or steals an electron. Radicals can bind to proteins, carbohydrates lipids, producing damage.

Cell Injury:

Sources of Free Radicals in pathology

Chemical injury Physical injury Inflammation Oxygen toxicity Reperfusion injury Malignant transformation Aging

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Formation of Free Radicals :

Endogenous from normal metabolism Reduction Oxidation reaction (REDOX) in mitochondria Transition metals (Copper, Iron) catalyze Free Radicals formation by donating or accepting free electrons (Fenton reaction) Ferric iron
superoxide

Ferrous iron

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Exogenous formation : Ionizing radiation Drug metabolism

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Free Radicals (Examples)

Reactive Oxygen Species (ROS) generated

by mitochondrial respiration :

Oxygen Superoxide

H2O2 (Hydrogen peroxide)

OH (hydroxyl group) Accumulation of leucocytes NO (Nitric oxide) reactive nitrite

Inflammation :

Cell Injury:

Mechanism of injury by Free Radicals 1-Lipid peroxidation (oxidative degradation of lipids):

Destruction of unsaturated fatty acids by binding to methylene groups (CH2) that posses reactive hydrogen molecules

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2-Protein destruction: By cross linking proteins forming disulfide bonds (S-S) inactivate enzymes, & polypeptide degradation 3- DNA alteration: By producing single strand breaks in DNA Induce mutation that interfere with cell growth

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Inactivation Free Radicals Spontaneous decay Enzymes Superoxide dismutase, glutathione peroxidase, and catalase Antioxidants Block synthesis or inactivate free radicals Include Vitamin E, Vitamin C, albumin, ceruloplasmin, and transferrin

Cell Injury:

3- Chemical Agents

Chemical agents can cause cellular injury by: direct contact of the chemical with molecular components of the cell. Indirect injury formation of free radicals, or lipid peroxidation.

Cell Injury:

Examples of injurious chemicals

Cyanide disrupts cytochrome oxidase. Mercuric chloride binds to cell membrane in cell resulting in increased permeability. Chemotherapeutic agents & antibiotics may act in the same way. Carbon Monoxide (CO) Ethanol Lead

Cell Injury:

Action of Carbon Monoxide :

Has a very high affinity to hemoglobin (carboxyhemoglobin: COHb) The effect of large quantities of COHb is death (carbon monoxide poisoning). Smaller quantities of COHb leads to tiredness,dizziness & unconsciousness.

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Action of Ethanol :

The conversion of ethanol to acetaldehyde leads to formation of free radical. Acetaldehyde initiates changes in liver Fatty change Liver enlargement Liver cell necrosis.

Cell Injury:

liver enlargement with deposition of fat

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Action of Lead :

Mimics other metals (calcium, iron and zinc) which act as cofactors in many catalyzing enzymatic reactions. Acts on the CNS by interfering with neurotransmitters, blocking glutamate receptor. (May cause wrist, finger,&foot paralysis). Affects hemoglobin synthesis

Cell Injury:

Indirect injury of some chemicals :

Activation in the liver by the P- 450 mixed function oxidases in SER .

CCL4 CCL3 (FR) membrane phospholipid peroxidation & ER destruction:

protein lipid No apoproteins for lipid transport Fatty liver Mitochondrial injury ATP Failure of cell function increased cytosolic Ca+ cell death

Acetaminophen may act similarly

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4- Physical agents

Mechanical injury resulting in tearing, or crushing of tissues. e.g.: blunt injuries , car accidents. Ionizing Radiation Water and DNA are the most vulnerable target

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Physical agents (cont)

Extreme temperatures Hypothermia Hyperthermia

Atmospheric Pressure Blast injuries Water pressure increased or decreased

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5-Infectious Agents

Bacteria: produce toxins Endotoxin Exotoxin Viruses : Decrease the ability to synthesize proteins Change host cells antigenic properties

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5-Immunological reactions

Cell membranes are injured by contact with immune components such as lymphocytes, macrophages.etc Exposure to these agents causes changes in membrane permeability

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6- Genetic Diseases

Genetics play a substantial role in cellular structure and function. A genetic disorder can cause a dramatic change in the cells shape, structure, receptors, or transport mechanisms.eg : Enzyme deficiencies Sickle Cell Anemia

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7- Nutritional Imbalances

Adequate amounts of proteins, lipids, carbohydrates are required. Low levels of plasma proteins, like albumin, encourages movement of water into the tissues, thereby causing edema. Hyperglycemia, hypoglycemia, Vitamin deficiencies (vitamins E, D, K, A, and folic acid) Excess food intake is also classified as a nutritional imbalance

Cell Injury:

Mechanism of cell injury & sites of damage

Cell Injury:

General Considerations:

Function is lost before morphological changes occur EM changes Microscopic changes Gross changes

Cell Injury:

Result of injury depends on :

Injury : Type Duration Severity Type of cell: Specialization Adequacy of blood supply, hormones, nutrients Regenerative ability or adaptability Genetic make up

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Steps & Cellular targets in Injury :

Cell Injury:

1- Mitochondria: Interruption of oxidative metabolism Loss of energy due to formation of mitochondrial permeability transition pore (MPT) loss of membrane potential prevents ATP generation (ATP depletion) Cytochrome c released into cytosol activates apoptosis. O2 depletion ROS

Cell Injury:

2- Cell Membranes

Important sites of damage : Mitochondrial membrane ATP Plasma membrane failure of Na pump leads to cellular amounts of water Lysosomal membrane enzyme release, activation & digestion of cell components

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3- Influx of Calcium: Ca stability is maintained by ATP + Loss of Ca homeostasis cytosolic Ca activation of:

phospholipases proteases ATPases Endonucleases

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4-Protein synthesis: High fluid levels cause ribosomes to separate from the swollen endoplasmic reticulum protein synthesis, glycolysis Metabolic acidosis 5- Genetic apparatus DNA defects & mutations

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Injury at one locus leads to wide ranging secondary effects

Cascading effect

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Subcellular response to injury

Cell Injury:

1- Hypertrophy of Smooth Endoplasmic Reticulum in liver induced by some drugs e.g. barbiturates , alcohol. etc. 2-Mitochondrial alterations in size & number e.g. in atrophy, hypertrophy, alcoholic liver 3-Cytoskeletal abnormalities e.g. microtubule abnormality involved in cell mobility

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4- Lysosomal Catabolism: Enzymatic digestion of foreign material (Heterophagy / pinocytosis & phagocytosis) or intracellular material (Autophagy).

Persistent debris residual body (Undigestible lipid peroxidation products Lipofuscin pigment.

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Morphology of reversible cell injury:

Ultrastructurally :

Generalized swelling of the cell and its organelles Blebbing of the plasma membrane Detachment of ribosomes from the endoplasmic reticulum Clumping of nuclear chromatin.

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Transition to irreversible cell injury :

Increasing swelling of the cell Swelling and disruption of lysosomes Severe swelling & dysfunction of mitochondria with presence of large calcium rich densities in swollen mitochondria Disruption membranes phospholipase Irreversible nuclear changes

Ultra structural changes in irreversible injury

Cell membrane
Breaks in cell & organelles membranes Amorphous density,bizarre forms, calcification

mitochondria lysosomes

rupture

Endoplastic retic

fragmentation

Nucleus

See by light mic

Nuclear changes in irreversible changes by light microscopy

Pyknosis Nuclear shrinkage+Increased basophilia Pyknotic nucleus

karyolysis

karyorrhexis Anucleated cell

Cell Injury:

After death

Cellular constituents are digested by lysosomal hydrolases enzymes & proteins leak into extracellular space useful in diagnosis Myocardial Infarction ( creatine kinase & troponins) Liver injury (biliary obstruction): Alkaline phosphatase Dead cells converted to phospholipid masses (Myelin Figures) Phagocytosis or degraded to fatty acids calcification

Summary

Cell Injury:

IF INJURED CELLS DONT DIE, THEY MAY ADAPT TO PROTECT THEMSELVES !

Cell Injury:

Cellular Adaptations

Cells change to Adapt to a new environment Escape from injury Protect themselves

Cell Injury:

Cellular Adaptations:

Growth adaptations:

Hyperplasia, Hypoplasia, Hypertrophy, Atrophy, Metaplasia , Dysplasia.

Degenerations: (Accumulations)

Hydropic change (water collection in cell /edema) Fatty Change Hyaline Change Pigment storage wear & tear..

Cell Injury:

Cellular Adaptation to Injury

The most common morphologically apparent adaptive changes are Atrophy (decrease in cell size) Hypertrophy (increase in cell size) Hyperplasia (increase in cell number) Metaplasia (change in cell type)

Cell Injury:

Atrophy

Decrease in cell size due to loss of cell substance (protein degradation & lysosomal proteases digest extracellular endocytosed molecules )

Often hormone dependent (insulin, TSH, etc).

Atrophic cells have diminished function.

Cell Injury:

Atrophy

Physiologic:
Uterus following parturition

Pathologic:
Decreased workload (Disuse atrophy) Loss of innervation (Denervation atrophy) Decreased blood supply (Brain atrophy) Malnutrition (Marasmus). Lack of hormonal stimulation.

Ageing:

Senile atrophy

Cell Injury:

Disuse atrophy of muscle fibers

Cell Injury:

Atrophy of frontal lobe

Cell Injury:

Atrophy: Undescended testes

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Hypertrophy

Hypertrophy is an increase in cell size by gain of cellular substance With the involvement of a sufficient number of cells, an entire organ can become hypertrophic Hypertrophy is caused either by increased functional demand or by specific endocrine stimulations With increasing demand, hypertrophy can reach a limit beyond which degenerative changes and organ failure can occur

Cell Injury:

Hypertrophy

Physiological & Pathological Skeletal muscles in manual workers & athletes Smooth muscles in pregnant uterus

(Hyperplasia accompanies hypertrophy here)

Cardiac muscles in hypertension Remaining kidney after nephrectomy

Cell Injury:

Left ventricle hypertrophy - HPTN

Compare normal & pregnant uterus

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Hyperplasia

Hyperplasia is an increase in the number of cells of a tissue or organ, from an increased rate of cell division. If cells have mitotic ability and can synthesize DNA, both hyperplasia and hypertrophy can occur. Hyperplasia may be a predisposing condition to neoplasia

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Cells differ in their capacity to divide :

High capacity: Epidermis, intestinal epithelium hepatocytes, bone marrow, fibroblasts.

Low capacity: Bone cartilage, smooth muscles Nil capacity: Neurons, cardiac muscle, skeletal muscle.

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Types of Hyperplasia

Physiological Hyperplasia (hormonal or compensatory), Examples: Uterine enlargement during pregnancy Female breast in puberty & lactation Compensatory hyperplasia in the liver

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Pathological Hyperplasia of the endometrium (excessive hormone stimulation). Wound healing (Effects of growth factors). Infection by papillomavirus

Cell Injury:

Endometrial Hyperplasia

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Metaplasia

Metaplasia is a reversible change (adaptation ) in which one adult cell type is replaced by another adult cell type that are better suited to tolerate a specific abnormal environment. May occur in epithelial or mesenchymal tissue. e.g. Bronchial , gastric, & cervical epith., and bone in injured soft tissue

Cell Injury:

Some disadvantages occur :

Because of metaplasia, normal protective mechanisms may be lost. Persistence of signals that result in metaplasia often lead to progression from metaplasia to dysplasia and possibly to adenocarcinoma.

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Example of Metaplasia

Replacement of ciliated columnar epithelium with stratified squamous epithelium in respiratory tract of a smoker.

Cell Injury:

Columnar (gastric) metaplasia in esophageal squamous epithelium

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Dysplasia

Abnormal changes in size, shape, appearance, and organizational structure of the cells Sometimes atypical hyperplasia can progress to neoplasia Caused by persistent injury or irritation Cervix, oral cavity, gallbladder, and respiratory tract
Cells having disordered arrangement

Cell Injury:

Cervical dysplasia

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Intracellular Accumulations & Deposits

Cell Injury:

May occur in any one of the following ways : Excessive production of a normal product but metabolic function is inadequate
Normal or abnormal substance accumulates but there is genetic or acquired defective enzyme mechanism for removal Abnormal exogenous substance accumulates because the cell does not possess a mechanism for removal

Cell Injury:

Accumulations include

Water

( Hydropic degeneration/cloudy swelling)

Fatty change Cholestrol & cholestrol esters Proteins Glycogen Pigments Calcium Amyloid deposition

Cell Injury:

Hydropic degeneration

Cell Injury:

1- Fatty change

Accumulation of excessive lipid in cells

The liver is the main organ involved, to lesser extent heart and kidney Fatty acids hepatocytes triglyceride + apoproteins lipoprotein exit liver Excess accumulation may result from defect in any of the above steps

Cell Injury:

Causes of fatty change :

Toxins including alcohol Starvation and protein malnutrition Diabetes mellitus Oxygen lack (anemia & ischemia ) Drugs, Complicate pregnancy & Obesity

Cell Injury:

Morphology of fatty liver

Gross appearance in liver depends on severity

Normal to large size, looks yellow and greasy when severe Fat accumulates in hepatocytes as small vacuoles in cytoplasm with nucleus in the center (Microvesicular fatty change ). The whole cytoplasm is replaced by fat and nucleus is pushed to one side of the cell (Macrovesicular fatty change).

Histology

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Fatty Liver (Alcoholism)

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2- Cholestrol & Cholestrol esters

Accumulate in macrophages ( foam cells ) & in foreign body giant cells : Atherosclerosis Hereditary & Acquired hyperlipidemia Xanthomas (a yellow nodule or plaque, especially of the skin, composed of lipidladen histiocytes).

Cell Injury:

3- Protein accumulation:
kidney in the nephrotic syndrome. Plasma cells as immunoglobulins. Mallory Bodies: Alcoholic liver disease as (Eosinophilic intracellular hyaline body)

Glycogen accumulation in Glycogen Storage Diseases.

Liver - Mallory hyaline - Alcoholism

Cell Injury:

4- Pathologic Calcification

A- Dystrophic calcification : Abnormal deposition of calcium phosphate in dead or dying tissue Dystrophic calcification is an important component of the pathogenesis of atherosclerotic disease and valvular heart disease. Areas of caseous, coaggulative or fat necrosis. Dead parasites & their ova

Cell Injury:

cont

B- Metastatic calcification : Calcium deposition in normal tissues as a consequence of hypercalcemia: Increased PTH with subsequent bone resorption Bone destruction: METASTATIC BONE CANCERS Vitamin D disorders Renal failure Organs affected:

Kidney, stomach, lungs.

Cell Injury:

Dystrophic calcification - Stomach.

Cell Injury:

5-Pigments
Pigments
EXOGENOUS Anthracosis Hb-derived Non Hb -derived Melanin Lipofuscin ENDOGENOUS

Tattooing
Iron Bilirubin

Cell Injury:

Exogenous pigment :

Anthracosis : Accumulation of carbon, black pigment Smokers Tatooing

Cell Injury:

Exogenous pigment : Anthracosis

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Endogenous pigments :

1- Melanin pigment : Brown pigment synthesized in melanocytes. Melanin protects the nuclei of cells in basal layer of epidermis against effects of UV light Lesions associated with melanocytes
Moles (nevi)..benign Melanoma.malignant

Lesions can occur anywhere e.g.rectum,eye.

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2- Lipofuscin pigment

Brown pigment in cytoplasm of cells, represents residue of oxidized lipid derived from digested membranes of organelles. It is called wear and tearpigment accumulates as a part of the aging process and atrophy, in which lipid peroxidation take part in it. It is harmless to the cell. Large amounts in atrophic organs gives rise to Brown atrophy e.g brown atrophy of the heart.

Cell Injury:

Lipofuscin

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3- Bile pigment (Bilirubin )

Derived from heme of Hb from destroyed RBC in reticuloendothelial system. Conjugated in hepatocytes with glucuronic acid and excreted as bile. Hyperbilirubinemia may present clinically as jaundice Causes may be hemolysis, liver diseases or obstruction to the outflow of bile

Cell Injury:

4- Excess iron accumulation

Total body iron.. 2 - 4gm. Functional pool Hb, myoglobin, cytochromes & catalase Storage pool in macrophages of RES in the ferric form as ferritin & / or hemosiderin which is golden brown. Potasium ferrocyanide + hemosiderin = ferric ferrocyanide. This is known as Prussian Blue reaction or Perl`s

Cell Injury:

Iron overload: Localized or systemic

Local increase of iron in tissues Localized hemorrhage in tissues Chronic venous congestion of lung in heart failure Systemic increase of iron Hemosiderosis .. Iron in RES without much damage Occurs in: Excessive hemolysis Multiple blood transfusions Intravenous administration of iron

Cell Injury:

Hemosiderin granules in liver cells. A- H&E section showing golden-brown, finely granular pigment. B- Prussian blue reaction, specific for iron.

Cell Injury:

Idiopathic Hemochromatosis

Abnormality is lack of regulation of iron absorption & defect in the monocyte macrophage system. Iron accumulates in liver, pancreas, other parenchymal cells & to lesser extent in RES. Induce fibrosis, secondary diabetes, cirrhosis & liver cancer

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5- Amyloidosis

Extracellular deposition of an abnormal fibrillar proteins in various tissues and organs (kidney, heart, brain, liveretc.) The abnormal protein is called Amyloid. Many types associated with different diseases or primary forms H & E Hyaline-like acellular eosinophilic material Congo red stains amyloid pink or red and under polarizing microscopy gives apple green birefringence .

Cell Injury:

Amyloid deposition in kidney

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Congo Red Stain

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Classification of amyloidosis

Localized amyloid deposition larynx,lungs,urinary bladder,etc.. Systemic amyloidosis multiple myeloma associated . AL amyloid Reactive (secondary amyloidosis) AA amyloid RHEUMATOID ARTHRITIS, INFLAMMATORY BOWEL DISEASE, OSTEOMYELITIS, HODGKINS DISEASE AND RENAL CELL CARCINOMA. Hereditary amyloidosis

Cell Injury:

CELL DEATH

Cell Injury:

CELL DEATH

Ultimate result of ischemia, infection, reactions

injury, toxins,

following immune

Physiologically seen in embryogenesis, lymphoid tissue development, hormonally induced involution. Therapeutically in cancer radiotherapy and chemotherapy.

Cell Injury:

Types :

Necrosis: Morphologic changes seen in dead cells within living tissue. Autolysis: Dissolution of dead cells by the cells own digestive enzymes. (not seen) Apoptosis: Programmed cell death. Physiological, cell regulation.

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NECROSIS

Irreversible
Necrosis is local cell death and cellular dissolution in living tissues.

Necrosis involves the process of self/auto digestion and lysis.

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Morphologic changes :

Increased eosinophilia of cells Pyknosis of nuclei Karyorrhexis Karyolysis: dissolution of the nucleus from hydrolytic enzymes Release of catalytic enzymes from lysosomes cause either autolysis or heterolysis

Cell Injury:

Morphologic appearance of necrosis is due to: Enzymic digestion of the cell Denaturation of proteins Types: coagulative, liquefactive, caseous, fat necrosis, gummatous necrosis and fibrinoid necrosis. Sequels of Necrosis: Autolysis Phagocytosis Organization & fibrous repair Dystrophic calcification

Cell Injury:

1- Coagulative necrosis

Commonest type of necrosis, usually ischemic Infarction specially in heart (Myocardial Infarction) Also in kidney & in adrenals. Variable appearance mostly firm texture. It is suspected that high levels of intracellular calcium plays a role in coagulative necrosis. Results from denaturation of all proteins including enzymes .

Cell Injury:

Histology: Preservation of the tissue architecture & cellular outlines. The necrotic area stains more eosinophilic, often devoid of nuclei.

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Renal Infarction: Coagulative Necrosis

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2- Liquefactive Necrosis

Autolysis predominates and results in liquefied mass e.g. hypoxia in brain, bacterial infections (abscess). Brain cells have a large amount of hydrolytic digestive enzymes (hydrolases). These enzymes cause the neural tissue to become soft and liquefy. Liquefactive necrosis is what causes pus to form.

Hydrolytic enzymes are released from neutrophils to fight an invading pathogen. E. Coli, Staphylococcus, and Streptococcus

Cell Injury:

Stroke- Liquifactive necrosis

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Lung abscess: Liquefactive necrosis

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Liver abscess: Liquefactive necrosis

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3- Caseous Necrosis

Grossly cheese-like, appearance, being soft and white. Histology:

Central cheesy material , rimmed by chronic inflammatory cells, epitheloid cells & Langhans giant cells ( GRANULOMA)

Typical of tuberculosis, may be seen in others Is a distinctive form of coagulative necrosis modified by capsule lipopolysacchride of TB bacilli

Cell Injury:

Caseous necrosis in Tuberculosis

Cell Injury:

Caseous necrosis - Tuberculosis

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4- Fat Necrosis

Two types : Traumatic fat necrosis foreign body giant cells calcification hard lump Enzymatic fat necrosis due to acute pancreatitis Acute Pancreatitis : Medical emergency Enzymes released, digests fat Adipose tissues triglycerides & fatty acids saponification & calcification

Cell Injury:

Foci of fat necrosis with saponification in the mesentery

Cell Injury:

Fat Necrosis - Peritoneum.

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Gangrene

Necrosis plus putrefaction (rotting) by saprophytes. Wet gangrene: Coagulative necrosis due to ischemia and liquifactive necrosis due to superimposed infection. Dry gangrene: Drying of dead tissue, is a form of coagulative necrosis, applied to necrosis of the lower limbs distally, associated with peripheral vascular disease. Necrosis is separated by a line of demarcation from viable tissue. Gas gangrene: This caused by wound contamination by anaerobic bacteria (Clostridia perfringes)

Cell Injury:

Toes - Dry Gangrene

Cell Injury:

Wet Gangrene Amputated Diabetic foot

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APOPTOSIS

Programmed cell death by suicide The cells membrane remains intact Apoptosis is characterised by death of single cells or clusters and results in cell shrinkage, not lysis and swelling without an inflammatory reaction, unlike necrosis where there is death of large amounts of the tissue and there is an associated inflammatory reaction. Cell death involved in normal and pathologic conditions.

Cell Injury:

APOPTOSIS

Apoptosis depends on cellular signals, these signals cause protein cleavage (proteases) within the cell, causing cell death. Programmed and energy dependent process designed to switch cell off and eliminate them Cell shrinkage Chromatin condensation- most characteristic Formation of cytoplasmic blebs and apoptotic bodies Phagocytosis of apoptotic cells or bodies

Cell Injury:

Two main pathways

Intrinsic mitochondrial pathway: Increased permeability of mitochondrial membrane results in release of pro-apoptotic factors (cytochrome c and AIF) that activate downstream caspases death . Extrinsic death receptor pathway: FAS and TNF1 receptor families with death domain.

Cell Injury:

Cell Injury:

Physiologic apoptosis

During development, embryogenesis. Homeostatic mechanism to maintain cell population(Cell turnover in intestinal crypts). Immune reaction - defense mechanism. In aging. Shedding of menstrual endometrium. Involution of breast after weaning.

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Pathologic apoptosis

Prostatic atrophy after castration. Death of inflammatory cells after inflammation When cells are damage by disease or injurious agents DNA damage e.g. radiation, chemotherapy, Cytotoxic drugs Viral infections e.g. viral hepatitis Neoplasia: tumours that regress or involution Deletion of autoreactive T cells in thymus Others including rejection of transplants

Cell Injury:

A, Apoptosis of epidermal cells in an immune-mediated reaction. The apoptotic cells are visible in the epidermis with intensely eosinophilic cytoplasm and small, dense nuclei. H&E stain. B, High power of apoptotic cell in liver in immune-mediated hepatic cell injury.

Cell Injury:

Comparison of apoptosis with necrosis

Apoptosis Active process

Necrosis Passive process

Occur in single cells Physiological & pathological

Affects mass of cells Always pathological

No inflammatory reaction

stimulates Inflammation

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Aging and Cellular Death

Theories Aging is caused by accumulations of injurious events Aging is the result of a genetically controlled developmental program. Mechanisms Genetic, environmental, and behavioral Changes in regulatory mechanisms Degenerative alterations

Cell Injury:

Cellular aging

Genetic e.g. failure of repair mechanisms , Clock genes overexpression of antioxidative enzymes Telomerase activity .etc Telomerase activity stops in somatic cells, but continues in stem cells & germ cells Environmental: generation of FR, diet Accumulation of multiple defects Aging Aged cells show Lipofuscin pigment , abnormally folded proteins & advanced glycosylation end products ( AGESs)