ACUTE AND CHRONIC INFLAMMATION

Lecturer : Fairuz, dr, spPA,

REFFERANCE

Kumar, Abbas, Fausto. Robbins and Cotran, Pathologic basis of disease. 7th ed. Elsevier. Philadelphia. 2005.

I. GENERAL FEATURES OF
INFLAMMATION

Inflammation is a complex reaction to injurious agents such as microbes and damaged, usually necrotic, cells that consists of vascular responses, migration and activation of leukocytes, and systemic reactions.

The unique feature of the inflammatory process is the reaction of blood vessels, leading to the accumulation of fluid and leukocytes in extravascular tissues. The inflammatory response consists of two main components, a vascular reaction and a cellular reaction.

CONTD

Many tissues and cells are involved in these reactions, including the fluid and proteins of plasma, circulating cells, blood vessels, and cellular and extracellular constituents of connective tissue. The circulating cells include neutrophils, monocytes, eosinophils, lymphocytes, basophils, and platelets. The connective tissue cells are the mast cells, fibroblast, macrophage, lymphocytes. The extracellular matrix consists of fibrous protein (collagen, elastin), adhesive glycoproteins fibronectin, laminin, others), and proteoglycan.

CONTD

Inflammation is divided into acute and chronic pattern.

Acute inflammation is rapid in onset (seconds or minute) and is of relatively short duration, lasting for minutes, several hours, or a few days. Its main characteristics are the exudation of fluid and plasma proteins (edema) and the emigration of leukocytes, predominantly neutrophils.

Chronic inflammation is of longer duration and is associated histologically with the presence of lymphocytes and macrophage, the proliferation of blood vessels, fibrosis and tissue necrosis.

CONTD
Inflammation is terminated when the offending agent is eliminated and the secreted mediators are broken down or dissipated. Celsus first listed the four cardinal signs of inflammation : rubor (redness), tumor (swelling), calor (heat), and dolor (pain) Typically more prominent in acute inflammation

a fifth clinical sign, loss of function (functiolaesa), was later added by Virchow

II. ACUTE INFLAMMATION

Acute inflammation is a rapid response to an injurious agent that serves to deliver mediators of host defense- leukocytes and plasma proteins. Has 3 major components : 1. Alteration in vascular caliber that lead to an increase in blood flow. 2. Structural changes in microvasculature that permit plasma proteins and leukocytes to leave the circulation. 3. Emigration of the leukocytes from the microcirculation, accumulation in the focus of injury, and activation to eliminate the offending agents.

CONTD
Acute inflammatory reaction are triggered by a variety of stimuli: 1.Infectious 2. Trauma 3. Physical and chemical agents 4. Tissue necrosis 5. Foreign bodies 5. Immune reaction

VASCULAR CHANGES Vasodilatation is one of the earlist manifestation of acute inflammation. Vasodilatation is induced by the action of several mediators, histamine and nitric oxide, on vascular smooth muscle. Vasodilatation is quickly followed by increased permeability of the microvasculature. Stasis the loss of fluid results in concentration of red cells in small vessels and increased viscosity of the blood, reflected by the presence of dilated small vessels packed with red cells and slower blood flow.

CONTD
As stasis develops, leukocytes, principally neutrophils, accumulate along the vascular endothelium. Mechanism of increased vascular permeability in inflammation : 1. Formation of endothelial gaps in venules 2. Direct endothelial injury 3. Leukocyte-dependent injury 4. Increased transcytosis 5. New blood vessels formation

CELLULAR EVENTS

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Leukocyte extravasation can be divided into the following steps : In the lumen: margination, rolling, and adhesion to endothelium Transmigration across the endothelium (diapedesis) Migration in interstitial tissue toward a chemotactic stimulus Leukocyte adhesion and transmigration are regulated largely by the binding of complementary adhesion molecules on the leukocyte and endothelial surfaces, and chemical mediators- chemoattractants and certain cytokines

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The adhesion receptors involved belong to 4 molecular families : Selectins : E-selectin, P-selectin The immunoglobulin family : ICAM-1, VCAM-1 Integrins : transmembrane heterodimeric glycoproteins, and chains. Mucinlike glycoproteins : CD 44

CONTD
After extravasation, leukocytes emigrate in tissues toward the site of injury by process called chemotaxis Both exogenous and endogenous substances can act as chemoattractants. Exogenous agent : bacterial product Endogenous agent : C5a, LTB4, cytokines Microbes, product of necrotic cells, antigenantibody complex, and cytokines, induce a number of responses in leukocytes that are part of the defensive functions of the leukocytes and are reffered to leukocyte activation

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The functional responses that are induced on leukocyte activation include : Production of arachidonic acid metabolites Degranulation and secretion of lysosomal enzymes and activation of the oxidative burst Secretion of cytokines Modulation of leukocyte adhesion molecules

CHEMICAL MEDIATORS OF INFLAMMATION

Mediators originate either from plasma or from cells. Plasma-derived mediators (eg. Complement proteins, kinins) are present in plasma in precursor forms that must be activated to acquire their biologic properties. Cells-derived mediators are normally sequestered in intracellular granules that need to be secreted (eg.histamine) or are synthesized de novo (prostaglandin, cytokines) The major cellular sources : platelets, neutrophils, macrophage, and mast cell.

CONTD
The production of active mediators is triggered by microbial product or by host proteins, such as the proteins of the complement, kinin, and coagulation system. Most mediator perform their biologic activity by initially binding to specific receptors on target cells. One mediator can stimulate the release of other mediators by target cells themselves. Mediators can act on one or few target cell types, have diverse targets, or may even have differing effects on different types of cells.

CONTD
Once activated and released from the cells, most of these mediators are short-lived. Most mediators have the potential to cause harmful effects.

VASOACTIVE AMINES
HISTAMINES Widely distributed in tissues The richest sources being the mast cells, also found in blood basophil and platelet. Cause dilation of the arteriols and increase the permeability of venules Acts on the microcirculation mainly via binding to H1 receptors on endothelial cells.

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SEROTONIN Vasoactive mediator with actions similar to those of histamine Present in platelets, enterochromaffin cells, and mast cell in rodent, but not humans Stimulated when platelets aggregate after contact with collagen, thrombin, ADP, and Ag-Ab complex. The platelet release reaction results in increased permeability during immunologic reaction

PLASMA PROTEIN COMPLEMENT SYSTEM Consists of 20 component proteins Found in greatest concentration in plasma Present as inactive forms in plasma and are numbered C1 through C9 The critical step of the biologic functions of complement : activation of the third component, C3 Cleavage of C3 can occur by one of 3 pathways : 1. The classical pathway 2. The alternative pathway 3. The lectin pathway

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KININ SYSTEM Generates vasoactive peptides from plasma proteins, called kininogens, by the action of spesific proteases called kallikreins. Activation of the kinin system results in the release of the vasoactive nonpeptide bradykinin. Bradykinin increases vascular permeability and causes contraction of smooth muscle, dilatation of blood vessels, and pain when injected into the skin.

CLOTTING SYSTEM The clotting system and inflammation are intimately connected processes. The clotting system is divided into 2 pathways that converge, culminating in the activation of thrombin and the formation of fibrin. The intrinsic clotting pathway is a series of plasma proteins that can be activated by Hegeman factor (factor XII). The protease thrombin provides the main link between the coagulation system and inflammation.

ARACHIDONIC ACID METABOLITS:

PROSTAGLANDINS, LEUKOTRIENES, AND LIPOXINS Arachidonic acid (AA) is a 20-carbon polyunsaturated fatty acid that is derived from dietary sources or by conversion from the essential fatty acid linoleic acid. AA metabolites are synthesized by two major classes of enzymes: cyclooxigenases and lipoxygenases

CYTOKINES AND CHEMOKINES

Cytokines are proteins produced by many cell types, that modulate the functions of other cell types. Have additional effects that play important roles in both acute and chronic inflammation Tumor necrosis factor (TNF) and Interleukin-1 (IL-1) are two of the major cytokines that mediate inflammation. Induce the systemic acute phase responses associated with infection or injury Fever, loss of apetite, slow wave sleep, release neutrophils into the circulation, others.

CONTD

Chemokines are family of small proteins that act primarily as chemoattractants for spesific types of leukocytes.

MORPHOLOGIC PATTERNS OF ACUTE

INFLAMMATION SEROUS INFLAMMATION Marked by the outpouring of a thin fluid that is derived from either the plasma or the secretions of mesothelial cells lining the peritoneal, pleural, and pericardial cavities e.g., Burn or viral infection

FIBRINOUS INFLAMMATION With more severe injuries and the resulting greater vascular permeability, larger molecules such as fibrinogen pass the vascular barrier, and fibrin is formed and deposited in the extracellular space. A fibrinous exudate is characteristic of inflammation in the lining of body cavities, such as the meninges, pericardium, and pleura.

SUPPURATIVE OR PURULENT INFLAMMATION Characterized by the production of large amounts of pus or purulent exudate consisting of neutrophils, necrotic cells, and edema fluid. Certain bacteria (e.g., staphylococci) produce this localized suppuration and are therefore referred to as pyogenic bacteria. A common example of an acute suppurative inflammation is acute appendicities. Abscesses are localized collections of purulent inflammatory tissue.

III. CHRONIC INFLAMMATION

Considered to be inflammation of prolonged duration (weeks or month) in which active inflammation, tissue destruction, and attempts at repair are proceeding silmutaneously. Causes of chronic inflammation : 1. Persistent infection : Tubercle bacili, treponema pallidum, virus, fungi. 2. Prolonged exposure to potentially toxic agents : silica (silicosis), plasma lipid (arteriosclerosis) 3. Autoimmunity : LE

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Chronic inflammation is characterized by : Infiltration with mononuclear cells, which include macrophage, lymphocyte, and plasma cells. Tissue destruction, induced by the persistent offending agent or by inflammatory cells. Attempts at healing by connective tissue replacement of damaged tissues, accomplished by proliferation of small blood vessels (angiogenesis) and, in particular, fibrosis.

GRANULOMATOUS INFLAMMATION A distinctive pattern of chronic inflammatory reaction characterized by focal accumulations of activated macrophages, which often develop an epithelial-like (epithelioid) appearance. A granuloma is a focus chronic inflammation consisting of a microscopic aggregation of macrophage that are transformed into epitheliumlike cells surrounded by a collar of mononuclear leukocytes, principally lymphocytes and occasionalyplasma cells.

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There are 2 types of granuloma : Foreign body granuloma Immune granuloma

LYMPHATIC INFLAMMATION The nodal enlargement is usually caused by hyperplasia of the lymphoid folicles, this constellation of nodal histologic changes is termed reactive , or inflammatory, lymphadenitis.

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