INFLAMMATION

By : Gaurav Kansal PG student 2nd Yr

Definition
Defined as the local response of living tissues to injury due to any agent. Inflammation is a protective response intended to eliminate the initial cause of cell injury as well as the necrotic cells and tissues resulting from the original insult .

DARK SIDE OF INFLAMMATION

Although, inflammation is a protective reaction, it can even prove to be fatal in the form of life threatening anaphylactic reactions to insect bites or drugs as well as in certain chronic diseases like rheumatoid arthritis or atherosclerosis.

PROVOCATION OF INFLAMMATION
1. Physical agents: Heat Cold Radiations Mechanical Trauma 2. Chemical agents: Organic & Inorganic poisons 3. Infective agents: Bacteria Viruses Parasites 4.Immunological agents: Antigen antibody reactions Cell mediated reactions

CARDINAL SIGNS OF INFLAMMATION

As given by CELSUS :Rubor (redness) Tumor (swelling) Calor (heat) Dolor (pain) As given by VIRCHOW:Functiolaesa (loss of function)

Cells OF INFLAMMATION
1. Circulating blood cells a. Polymorphonuclear neutrophils. b. Eosinophils c. Basophils d. Lymphocytes e. Monocytes f. Thrombocytes

2. Plasma proteins a. Clotting factors b. Kininogens c. Complement components. 3. Vascular wall cells a. Endothelial cells b. Smooth muscle cells

4. Connective tissue cells a. Macrophages b. Mast cells c. Lymphocytes d. Fibroblasts. 5. Extracellular matrix a. Fibrous structural proteins (collagen & elastin) b. Proteoglycans c. Adhesive glycoprotein ( fibronectin)

TYPES OF INFLAMMATION
Depending, upon the intensity of injury, duration of the response, & defence capacity of the host , inflammation can be classified as : (i) Acute inflammation (ii) Chronic inflammation

ACUTE INFLAMMATION

Short duration (few minutes to few days ). Characterized by exudation of fluid & plasma proteins. Neutrophils are the predominant cell type Usually followed by repair.

CHRONIC INFLAMMATION

Longer duration (days to years). Macrophages & lymphocytes are the predominant cells. Characterized by the vascular proliferation & scarring.

ACUTE INFLAMMATION
It is better described under two headings :

1.Vascular events:
Vasodilation after a transient vasoconstriction (cause of redness & heat) Increased vascular permeability (cause of oedema / swelling). 2. Cellular events: Extravasation of leukocytes from the vessels to the extravascular space Phagocytosis and degranulation.

VASCULAR EVENTS
These changes begin immediately after injury but may develop at variable rates depending upon the severity of the injury. Vascular events include:

1.VASODILATION:

Initial transient vasoconstriction (from 3-5 sec. to 5 min.) Followed by vasodilation of mainly arterioles but to lesser extent that of venules & capillaries.

The changes are seen within half an hour of injury.

Vasodilation results in increase in the blood volume of microvascular bed (responsible for redness and heat) which increases the local hydrostatic pressure. Due to increased hydrostatic pressure, the microvasculature becomes more permeable to the leaking of protein rich fluid into the extravascular tissues. So, red cells becomes more concentrated, thereby increasing the viscosity of blood and slowing or stasis of circulation.

As stasis develops, leukocytes begin to settle out of the flowing blood and accumulates along the vascular endothelial surface (margination) and finally squeezes themselves through the gaps into the extravascular tissues (emigration).

The loss of vascular proteins reduces the intravascular osmotic pressure and increases the interstitial osmotic pressure which facilitates more outflow of water and ions into the extravascular tissues (oedema).

Leukocyte dependant endothelial injury :

Occurs as a consequence of leukocyte accumulation during inflammatory response.

The leukocytes releases toxic oxygen species & proteolytic enzymes which then causes endothelial injury or detachment.

Leakage from new blood vessels:

During angiogenesis, the vessels sprouts remain leaky until proliferating endothelial cells differentiate sufficiently to form intercellular junctions.

CELLULAR EVENTS
The extravasation of the leukocytes from the vascular compartment to the extravascular compartment occurs as follows: 1.Margination and rolling. 2.Adhesion. 3.Emigration. 4.Chemotaxis 5.Phagocytosis & degranulation.

Margination and rolling

Under normal conditions, the normal axial flow consists of a central stream of cells and cell free plasma layer closer to the vessel wall. As a result of stasis (due to increased vascular permeability) and because of the fact that RBC move at a faster speed than WBC , central stream of cells widens and the peripheral plasma zone narrows ,so leukocytes get a better chance to interact with the endothelial cells i.e. margination. Finally, the leukocytes tumble on the endothelial surface and transiently stick along the way (rolling).

ADHESION
After pavementing, leukocytes stick firmly to the endothelial cells. Actually, injury neutralizes the normal negative charge on the leukocytes and endothelial cells so as to cause adhesion. Adhesion is mediated by the molecules of immunoglobulin superfamily on endothelial cells that interacts with integrins present on leukocytes.

EMIGRATION
After sticking to the endothelial cells, the leukocytes move along the endothelial surface till a suitable site between the endothelial cells is found, wherefrom the leukocytes throw out cytoplasmic pseudopods and squeeze themselves between the cells at intercellular junctions. PECAM-1(platelet endothelial cell adhesion molecule-1)belonging to immunoglobulin superfamily mediates this process.

Finally, the leukocytes cross the basement membrane by focally degrading them with secreted collagenases. Simultaneous, to the emigration of leukocytes, escape of RBC through the gaps between endothelial cells (diapedesis) occurs. It is a passive phenomenon which takes place either by the raised hydrostatic pressure or due to defects left after emigration of leukocytes. Diapedesis gives hemorrhagic appearance to the inflammatory exudates.

CHEMOTAXIS
In this process, the leucocytes are directed towards the foci of injury along a chemical gradient. Different leucocytes have different chemotactic substances : (i) Agents for Neutrophils : C5a product Leukotrienes B4

(ii) Agents for Monocytes: C5a products Bacterial products Products of activated Clotting, Fibronolytic, & Kinin systems Lymphokines from sensitized lymphocytes

(iii) Agents for Eosinophils: Eosinophil chemotactic factor of Anaphylaxis (ECF-A) Parasitic products Products of Complements

(iv) Agents for Basophils: Not known , but takes part in some immediate & delayed hypersensitivity reactions. (v) Lymphocytes donot show any chemotactic movement towards any attractant.

PHAGOCYTOSIS & DEGRANULATION

Defined as the process of engulfment of solid particulate material by the cell eating cells i.e phagocytes.They are:(i) Microphages i.e Neutrophils which arise early in acute inflammation (ii) Macrophages i.e Tissue monocytes in late inflammation .

STAGES IN PHAGOCYTOSIS

Phagocytosis is accomplished by :(i) OPSONISATION i.e recognition & attachment of the particulate to the leucocytes. (ii) ENGULFMENT (iii) KILLING & DEGRADATION of the ingested material

ATTACHMENT stage:The phagocytic cells as well as the microorganisms to be ingested are negatively charged and as such repel each other. In order to establish a bond between the two, the micro-organisms get coated with OPSONINS (serum proteins) which facilitates binding between the two.

ENGULFMENT STAGE
The opsonised particles bound to the surface of phagocytes is now ready to be engulfed. This is done by the formation of cytoplasmic pseudopods by the phagocyte around the particle to be ingested forming a phagocytic vacuole.

Eventually, the plasma membrane enclosing the phagocytic vacuole breaks from the cell surface so that the membrane lined phagocytic vacuole lies free in the cytoplasm. The lysosome of the cell fuses with phagocytic vacuole & forms PHAGOLYSOSOME or PHAGOSOME.

KILLING & DEGRANULATION STAGE

Now, killing ,digestion & degradation of the micro-organisms occurs by various hydrolytic enzymes secreted by leucocytes. The antimicrobial agents act by either of the two mechanisms:(i) oxygen dependant bacteriocidal mechanisms (ii) oxygen independent bactericidal mechanisms

CHEMICAL MEDIATORS OF INFLAMMATION

The various mediators that lead to vasodilation, increased permeability, chemotaxis, fever, pain, & even tissue damages are classified into two groups:(i) Mediators released by the cells locally at the site of inflammation. (ii) Mediators originating from plasma synthesized by liver.

LOCAL MEDIATORS
1. Histamine:

Present in the granules of mast cells, basophils & platelets. Released from these cells in response to various stimuli like (i) physical injury like trauma or heat. (ii) Immune reactions binding IgE receptors on mast cells. (iii) C3a, C5a (anaphylatoxins) fragments of complement system.

Actions of histamine :(i) Vasodilation (ii) Immediate increased vascular permeability (iii) Itching (iv) Pain

2. Serotonin (5- hydroxytryptamine ) Secreted from platelets. Present in tissues like chromaffin cells of GIT, spleen, nervous tissue, mast cells & platelets. Its actions are same like histamine but is a less potent mediator.

3.Arachidonic acid metabolites

It is a fatty acid. Source is either directly from diet or by the conversion of essential fatty acid linoleic acid to arachidonic acid. Metabolites are formed by one of the following two pathways:via lipooxygenase pathway or via cyclooxygenase pathway.

4.LYSOSOMAL ENZYMES
The inflammatory cells like neutrophils and monocytes contain lysosomal granules which on release elaborate a variety of mediators of inflammation. These may be released during cell death by leakage during the formation of phagocytic vacuole .

5.PLATELET ACTIVATING FACTORS

It is released from membrane phospholipids of neutrophils, monocytes, basophils, endothelium & platelets. Apart from its action on platelet aggregation , the various action of PAF , as mediators of inflammation are (i) increased vascular permeability (ii) enhanced leucocyte adhesion . (iii) leukocyte degranulation . (iv) oxidative burst .

1.KININ SYSTEM
First kallakrein is formed from plasma prekallakrein by the action of prekallakrein activator which is a fragment of factor XIIa. Kallakrein then acts on high molecular weight kininogen (HMWK) to form bradykinin which induces Vasodilation Smooth muscle contraction Increased vascular permeability Pain

2.CLOTTING SYSTEM
Factor XIIa initiates the clotting cascade by forming fibrinogen which is acted upon by the thrombin to form fibrin & fibrinopeptides . The action of fibrinopeptides are: Increased vascular permeability Chemotaxis for leukocytes Anticoagulant activity.

3.FIBRINOLYTIC SYSTEM
This system is activated by the plasminogen activator, the source of which is kallikrein of kinin system, which converts plasminogen to plasmin. Plasmin further breaks fibrin to fibrinopeptides & fibrin split products. The various actions of plasmin are : splits Complement C3 to form C3a . degrades fibrin to form fibrin split products which increases vascular permeability & are chemotactic for leukocytes.

4.COMPLEMENT SYSTEM
The activation of complement system occurs either by the classic pathway through antigen antibody complexes or by alternate pathway via non immunological agents like bacterial toxins , venoms, IgA . After activation , complement system yields C3a &C5a which are anaphylatoxins .

The actions of anaphylatoxins includes :Release of histamine from mast cells and basophils. Increased vascular permeability causing edema. C5a is chemotactic for leukocytes .

OUTCOME OF ACUTE INFLAMMATION

Acute inflammation has got one of the three outcomes depending upon: the nature & intensity of injury the site & the tissues affected the ability of the host to elicit a response viz (i) Resolution (ii) Scarring / Fibrosis (iii) Progression to chronic inflammation

RESOLUTION
It occurs when : The injury is limited or short lived. The tissue is capable of replacing any irreversibly injured cells

The various chemical mediators are neutralized

Vascular permeability restored

.
Lymphocytic drainage & macrophagic ingestion of necrotic debris lead to the clearance of oedema fluid and inflammatory cells

SCARRING / FIBROSIS
It occurs when : The destruction is extensive The tissues donot have the capacity to regenerate. Extensive fibrinous exudates may not be completely absorbed and are organized by the ingrowth of connective tissue or fibrosis . Abscess formations also end in scarring .

PROGRESSION TO CHRONIC INFLAMMATION

Sometimes the signs of chronic inflammation are present at the onset of injury eg :- in viral infections, immune responses of self antigens. Chronic inflammation may itself be followed by the regeneration of normal structure and function (regeneration ) or may lead to scarring .

CHRONIC INFLAMMATION
Considered as the inflammation of prolonged duration (weeks to months to years ) in which acute inflammation , tissue injury and healing proceeds simultaneously . chronic inflammation is characterized by the following : Infiltration with chronic inflammatory cells macrophages, lymphocytes & plasma cells. Tissue destruction by inflammatory cells. Repair involving angiogenesis & fibrosis.

TYPES OF CHRONIC INFLAMMATION

Conventionally, (i) Non-specific eg:chronic osteomyelitis chronic ulcers (ii) Specific eg:tuberculosis leprosy syphilis

CELLS OF CHRONIC INFLAMMATION

1.MACROPHAGES : Main cells in chronic inflammation. These are tissue cells that are derived from the circulating monocytes after their emigration from the blood stream . Scattered diffusely in :Connective tissues (Histiocytes ) Liver cells (Kuffers cells ) Spleen & lymph nodes (Sinus histiocytes ) In lungs (alveolar macrophages ) In skin (Langerhans cells ) etc

Within 24-48 hours of acute inflammation, the monocytes begin to emigrate at the site of injury
When they reach the extravascular tissues, they undergo transformation into larger cells called macrophages . They are also called epitheloid macrophages because under light microscope with hematoxylin & eosin staining they resemble squamous cells .

Macrophages on activation by lymphokines released by T lymphocytes or by non immunologic stimuli secretes a number of biologically active substances like:
(i) Proteases (collagenase & elastase ) which degrades collagen and elastic tissues (ii) Plasminogen activators which activates fibrinolytic system (iii) Complement products (iv) Coagulation factors (factor V thromboplastin ) which converts fibrinogen to fibrin . (v) Chemotactic agents for others leucocytes

When the macrophages fail to deal with the foreign particles , they fuse together & forms multinucleated giant cells. The various giant cells are:(i) Foreign body giant cells. (ii) Langhans giant cell. (iii) Tumor giant cells. (iv) Touton giant cells. (v) Miscellaneous.

1.Foreign body giant cells : Contains numerous nuclei upto 100 which are uniform in shape and size resembling the nuclei of macrophages which are scattered throughout the cytoplasm . Seen commonly in foreign body tissue reactions.

2. Langhans giant cells : Their nuclei resembles those of macrophages & epitheloid cells . They are arranged either around the periphery in the form of horse shoe clustered at the two poles of the giant cells Seen commonly in Tuberculosis , Sarcoidosis etc.

3. Tumor giant cells : They are larger cells, have numerous hyper chromatic nuclei which are derived from the dividing nuclei of neoplastic cells and from the macrophages . Seen commonly in carcinoma of liver, various sarcomas etc.

4. Touton giant cells : The have vacuolated cytoplasm due to lipid content . Seen commonly in Xanthomas . 5. Miscellaneous : Aschoff cells of rheumatic nodule Reed Sternberg cells of Hodgkin's disease etc .

2.LYMPHOCYTES
These are the second most numerous cells . Apart from the blood they are also found in spleen, thymus ,lymph nodes & lymphoid tissue of the gut . They have scanty cytoplasm and consists entirely of nucleus . Besides, their role in antibody formation (B lymphocytes ) and in cell mediated immunity (T lymphocytes), they participate in chronic inflammation and later stages of acute inflammation

3.PLASMA CELLS
Plasma cells are terminally differentiated end products of B cell activation . These cells are larger than lymphocytes with more abundant cytoplasm and an eccentric nucleus which has a cart wheel pattern of chromatin . They can produce antibodies directed against antigens in the inflammatory site or altered tissue components. Most commonly seen in Syphilis, Rheumatoid arthiritis,Tuberculosis, Hypersensitivity states, Multiple myeloma etc .

4.EOSINOPHILS
These are characteristically found in inflammatory site around parasitic infections or as in immune reaction mediated by IgE associated with allergies. Their emigration is driven by adhesion molecules similar to those used by neutrophils. Eosinophil granules contain major basic protein (MBP) that is toxic to parasite but may also cause lyses of epithelial cell.

5.MAST CELLS
They are widely distributed in connective tissues and can participate in both acute and chronic inflammatory responses. Mast cells are armed with IgE against certain antigens. When these antigens are encountered, the mast cell releases histamine and arachidonic acid metabolites that starts the early vascular changes of acute inflammation .

Mast cells elaborate cytokines like TNF thereby participating in more chronic responses. Mast cells also play beneficial role in variety of infections particularly those involving the parasite.

MORPHOLOGICAL PATTERNS OF ACUTE AND CHRONIC INFLAMMATION

Various types of inflammation (acute and chronic) can generally be seen depending upon (i) The severity of the inflammatory response (ii) Its specific cause (iii) Tissues involved

TYPES : Serous inflammation Fibrinous inflammation Suppurative inflammation Ulceration

SEROUS INFLAMMATION : Characterized by out pouring of watery, less proteinous fluid (effusion) . Derived either from the serum or mesothelial cells, lining of various cavities (pleural, pericardial, peritoneal). Examples are skin blisters either from a sun burn or from a viral infection .

FIBRINOUS INFLAMMATION :
Occurs as a result of serious injury . Vascular permeability is greatly increased allowing even fibrinogen to pass through the endothelium . Fibrinous exudates may be degraded by fibrinolysis and the accumulated debris removed by macrophages resulting in resolution (restoration of normal tissue structure) . However, failure to completely remove the fibrin results in the ingrowth of fibroblasts & blood vessels leading to scarring . (organization) .

SUPPURATIVE (PURULENT INFLAMMATION) :

Characterized by the presence of large amounts of purulent exudates (pus) consisting of neutrophils, necrotic cells and edematous fluid . Abscesses are focal collections of pus that may be caused by the deep seeding of pyogenic organisms (staphylococcus) into the tissue or by secondary infections of necrotic foci .

ULCERATION : This condition occurs when any epithelial surface becomes necrotic and eroded often associated with sub epithelial acute or chronic inflammation . May arise as a consequence of toxic or traumatic injury to the epithelial surface (peptic ulcers) or due to the vascular comprising conditions (diabetic foot) .

Granulomatous inflammation
Characterized by formation of granulomas It is a distinctive pattern of chronic inflammation characterized by aggregates of activated macrophages that assume a squamous like (epitheloid) appearance. Granuloma is defined as a circumscribed, tiny lesion,1mm in diameter composed of epitheloid cells, rimmed at periphery by lymphoid cell.

Common Granulomatous Conditions

1. Bacterial : Tuberculosis Leprosy Syphilis Actinomycosis Cat scratch fever

2. Fungal: Blastomycosis Cryptococcosis 3. Parasitic : Schistosomiasis

4. Miscellaneous : Sarcoidosis Crohns disease Silicosis Foreign body granuloma

REFRENCES

Textbook of pathology - Harsh Mohan Andersons Textbook of pathology Pathologic basis of disease - Robbins