Pathogenesis of Acute Inflammation PDF

21 PATHOGENESIS OF ACUTE INFLAMMATION ILOs By the end of this lecture, students will be able to 1. Evaluate process of Leukocyte recruitment to sites of inflammation under effect of certain cytokines. 2. Outline role of neutrophils and macrophages in clearance of the offending a...

21 PATHOGENESIS OF ACUTE INFLAMMATION ILOs By the end of this lecture, students will be able to 1. Evaluate process of Leukocyte recruitment to sites of inflammation under effect of certain cytokines. 2. Outline role of neutrophils and macrophages in clearance of the offending agent. 3. Classify types of acute Inflammation according to etiology, pathogenesis, and morphology. 4. Correlate subtypes of acute inflammation to corresponding clinical conditions. Leukocyte Recruitment to Sites of Inflammation: Neutrophils and macrophages are recruited to recognize invading pathogens and necrotic debris, eliminate them, and produce growth factors to facilitate repair. The type of leukocyte that emigrates into a site of injury depends on the original stimulus and the duration of the inflammatory response: ❖ Bacterial infections tend to initially recruit neutrophils. ❖ Viral infections recruit lymphocytes ❖ Allergic reactions have increased eosinophils ❖ Hypersensitivity reactions induce a mixed infiltrate. ❖ Necrosis will initially induce a neutrophilic recruitment that predominate during the first 6 to 24 hours, then are replaced by monocytes after 24 to 48 hours. Leukocytes move from vessel lumen to tissue interstitium in a multistep process: 1. Margination, rolling, and adhesion of leukocytes to the endothelium 2. Transmigration across the endothelium 3. Migration in interstitial tissues toward a chemotactic stimulus (Chemotaxis) 4. After emigration, neutrophils are also short-lived; they undergo apoptosis after 24 to 48 hours, whereas monocytes survive longer. Leukocyte rolling and adhesion to endothelium Occurs under the effect of progressive stasis of blood. Rolling, adhesion, and transmigration occur by interactions between complementary adhesion molecules on leukocytes and endothelium. The major adhesion molecule pairs are; Selectins; mediate rolling and the initial weak interactions between leukocytes and endothelium. Integrins; mediate the firm adhesion between leukocytes and endothelium. Expression of these adhesion molecules is enhanced by secreted proteins called cytokines including (tumor necrosis factor (TNF), and interleukin (IL-1)). Leukocyte transmigration through endothelium Page 1 of 5  After being arrested on the endothelial surface, leukocytes migrate through the vessel wall primarily by squeezing between cells at intercellular junctions. Extravasation of leukocytes occurs mainly in postcapillary venules, the site at which there is maximal retraction of endothelial cells. Further movement of leukocytes is driven by chemokines produced in extravascular tissues, which stimulate leukocytes to travel along a chemical gradient. After traversing the endothelium, leukocytes pierce the basement membrane by secreting collagenases, and they enter the extravascular tissue. Typically, the vessel wall is not injured during leukocyte transmigration. Chemotaxis of Leukocytes Chemotaxis is defined as locomotion along a chemical gradient. It means unidirectional movement of inflammatory cells towards site of injury. After emigrating through interendothelial junctions and traversing the basement membrane, leukocytes move toward sites of injury along gradients of chemotactic agents (chemotaxis). Mechanism; Chemotactic agents bind to specific leukocyte receptors; these trigger the polymerization of actin at the leading edge of the cell and facilitate cell movement in the direction of the locally produced chemoattractant. Leukocytes move by extending pseudopods that bind the extracellular matrix (ECM) and then pull the cell forward (front wheel drive). Chemotactic agents include: 1. Exogenous bacterial products 2. Endogenous mediators, such as: ❑ Complement fragments (particularly C5a) ❑ Arachidonic acid (AA) metabolites (particularly LT B4) ❑ Chemokines (e.g., interleukin-8). Phagocytosis and Clearance of the Offending Agent Phagocytosis involves three sequential steps: 1. Recognition and attachment of the particle to be ingested by the leukocyte by Phagocytic Receptors that recognizes microbes and not host cells. This is greatly enhanced when microbes are opsonized (coated) by specific proteins (opsonins) for which the phagocytes express high- affinity receptors. Examples of opsonins include IgG immunoglobulin and C3b. 2. Engulfment, with subsequent formation of a phagocytic vacuole (phagosome) that fuses with lysosomes, resulting in the discharge of lysosomal contents into the phagolysosome 3. Killing or degradation of the ingested material: by reactive oxygen species (ROS), reactive nitrogen species, mainly derived from nitric oxide (NO), and lysosomal enzymes. Role of neutrophils and macrophages in clearance of the offending agent: Neutrophils and monocytes contain granules packed with enzymes; lysozyme, myeloperoxidase, proteases and others, along with anti-microbial proteins that degrade microbes and dead tissues and may contribute to tissue damage. Page 2 of 5  ROS are produced within the phagolysosome. They include hydrogen peroxide which is converted to hypochlorite (by myeloperoxidase MPO in neutrophils) and hydroxyl radical; both of which are potent anti-microbial agents. Inducible nitric oxide synthase (iNOS) is expressed when macrophages are activated by cytokines (e.g., IFN-γ) or microbial products. iNOS induces the production of nitric oxide that reacts with superoxide to generate the highly reactive free radical peroxynitrite. Both nitrogen-derived free radicals and ROS attack and damage the lipids, proteins, and nucleic acids of microbes and host cells. Other functions of activated leukocytes: Activated leukocytes- especially macrophages also produce: Cytokines that can amplify or limit inflammatory reactions. Growth factors that stimulate endothelial cell and fibroblast proliferation and can drive collagen synthesis. Enzymes that remodel connective tissues. NOTE: In most forms of acute inflammation, neutrophils predominate in the inflammatory infiltrate during the first 6 to 24 hours since they are more numerous in the blood than other leukocytes, respond more rapidly to chemokines, and attach more firmly to the adhesion molecules that are rapidly induced on endothelial cells, such as selectins. After entering tissues, neutrophils are short-lived; they undergo apoptosis, disappear within 24 to 48 hours and are gradually replaced by monocyte-derived macrophages. Macrophages not only survive longer but also may proliferate in the tissues, and thus they become the dominant population in prolonged inflammatory reactions. Following recruitment of leukocytes, they are activated to undergo phagocytosis and intracellular killing. Termination of the Acute Inflammatory Response Inflammation declines in part because mediators are produced only transiently and typically have short half-lives. Inflammation is also regulated by stop signals that are activated. These include anti- inflammatory cytokines, such as transforming growth factor-β (TGF-β) and IL-10. The morphologic hallmarks of acute inflammatory reactions are: 1. Dilation of small blood vessels 2. Accumulation of leukocytes and fluid in the extravascular tissue. The vascular and cellular reactions account for the signs and symptoms of the inflammatory response: Increased blood flow to the injured area and increased vascular permeability lead to the accumulation of extravascular fluid rich in plasma proteins (edema) and account for the redness (rubor), warmth (calor), and swelling (tumor) that accompany acute inflammation. Page 3 of 5  Leukocytes that are recruited and activated by the offending agent and by endogenous mediators may release toxic metabolites and proteases extracellularly, causing tissue damage and loss of function (functio laesa). During the damage, and as a result of the liberation of prostaglandins, neuropeptides, and cytokines, one of the local symptoms is pain (dolor). However, depending on the severity of the reaction, its specific cause, the particular tissue and site involved, special morphologic patterns often provide valuable clues to the underlying cause. Serous inflammation: Etiology and pathogenesis: Exudation of cell poor fluid into spaces created by injury to surface epithelia or into body cavities lined by the peritoneum, pleura, or pericardium. Typically, the fluid in serous inflammation is not infected by destructive organisms and does not contain large numbers of leukocytes. In body cavities the fluid may be derived from the plasma (as a result of increased vascular permeability) or from the secretions of mesothelial cells (as a result of local irritation); accumulation of fluid in these cavities is called an effusion. Examples: The skin blister resulting from a burn or viral infection Peritoneal, pleural and pericardial serous effusions. Morphology: Accumulation of serous fluid within or immediately beneath the damaged epidermis of the skin. Outcome: Resolution Fibrinous inflammation: Etiology and pathogenesis: A fibrinous exudate develops when the vascular leaks are large or there is a local procoagulant stimulus. With a large increase in vascular permeability, higher-molecular weight proteins such as fibrinogen pass out of the blood, and fibrin is formed and deposited in the extracellular space. Examples: A fibrinous exudate is characteristic of inflammation in the lining of body cavities, such as the meninges, pericardium, and pleura. Morphology: Histologically, fibrin appears as an eosinophilic meshwork of threads or sometimes as an amorphous coagulum. Outcome: Fibrinous exudates may be dissolved by fibrinolysis and cleared by macrophages. If the fibrin is not removed, with time, it may stimulate the ingrowth of fibroblasts and blood vessels and thus lead to scarring. Conversion of the fibrinous exudate to scar tissue (organization) within the pericardial sac leads to opaque fibrous thickening of the pericardium and epicardium in the area of exudation and, if the fibrosis is extensive, obliteration of the pericardial space. Purulent (Suppurative) Inflammation and Abscess Page 4 of 5 Pathogenesis: Purulent inflammation is characterized by the production of pus, an exudate consisting of neutrophils, the liquefied debris of necrotic cells, and edema fluid. Etiology: The most frequent cause of purulent (also called suppurative) inflammation is infection with bacteria that cause liquefactive tissue necrosis, such as staphylococci; these pathogens are referred to as pyogenic (pus-producing) bacteria. Example of an acute suppurative inflammation is acute appendicitis. Abscesses are localized collections of pus caused by suppuration buried in a tissue, an organ, or a confined space. They are produced by seeding of pyogenic bacteria into a tissue. Morphology: Abscesses are composed of several layers; central region that appears as a mass of liquefied necrotic leukocytes and tissue cells. An intermediate zone of preserved neutrophils around this necrotic focus, and an outer region showing vascular dilation and parenchymal and fibroblastic proliferation, indicating chronic inflammation and repair. Outcome: In time the abscess may become walled off and ultimately replaced by connective tissue (healing by fibrosis). When persistent or at critical locations (such as the brain), abscesses may have to be drained surgically. Ulcers: An ulcer is a local defect of the surface epithelium of an organ or tissue that is produced by the sloughing (shedding) of inflamed necrotic tissue. Pathogenesis and aetiology: Ulceration can occur only when tissue necrosis and resultant inflammation exist on or near a surface. Examples: (1) The mucosa of the mouth, stomach, intestines, or genitourinary tract. (2) The skin and subcutaneous tissue of the lower extremities in older persons who have circulatory disturbances that predispose to extensive ischemic necrosis. (3) Acute and chronic inflammation often coexist in ulcers, such as peptic ulcers of the stomach or duodenum and diabetic ulcers of the legs. Morphology: Acute stage; there is intense polymorphonuclear infiltration and vascular dilation in the margins of the defect. Chronic stage; the margins and base of the ulcer develop fibroblast proliferation, scarring, and the accumulation of lymphocytes, macrophages, and plasma cells. References: 1. Kumar, Abbas, Aster. Robbins Basic Pathology, 10th ed. Elsevier. 2. Mitchell, Kumar, Abbas, Aster. Pocket Companion to Robbins and Cotran Pathologic Basis of Disease, 9th ed. Elsevier. Page 5 of 5