Inflammation - Dr. Nazar M.Taher PDF

By Dr. Nazar M.Taher Head, Department of Pathology Ninevah Medical College Dr.Nazar Jawhar  Objectives of the coarse: At the the end of this coarse the student should be able to: -Understand the inflammatory process and its rule in body defense. -Know types of i...

By Dr. Nazar M.Taher Head, Department of Pathology Ninevah Medical College Dr.Nazar Jawhar  Objectives of the coarse: At the the end of this coarse the student should be able to: -Understand the inflammatory process and its rule in body defense. -Know types of inflammation & the mechanism underly each one. -Know chemical mediators& its mechanism of action -Know granulomatous inflammation, its cause &morphology -Understand process of healing & the factors that affect it. Dr.Nazar Jawhar  DEFINITION: It is the reaction of a tissue & its microcirculation to a pathogenic insult. It is characterized by elaboration of inflammatory mediators and movement of fluid & leukocytes from the blood into extravascular tissues. This response eliminates the cause of the injury (foreign particles, microorganisms, and antigens) & altered cells, and paves the way for the return to normal structure and function. It is essentially a protective mechanism Dr.Nazar Jawhar  Inflammation serves to destroy, dilute, or wall off the injurious stimuli & sets into motion series of events that try to heal & reconstitute the damaged tissue. Without inflammation, wounds and infections would never heal. Despite it’s beneficial effects, inflammation may cause harm, especially if the reaction is very strong, prolonged, or inappropriate (directed against self-antigens or against usually harmless environmental antigens) e.g. in arthritis, life threatening hypersensitivity reaction, fibrous adhesion. Dr.Nazar Jawhar ❖ The cells and molecules of host defense normally circulate in the blood, and the goal of the inflammatory reaction is to bring them to the site of infection or tissue damage and set them into action. ❖ When inflammation is terminated? ❖ Inflammatory responses are mediated by chemical substances (cytokines), derived from plasma & cells. ❖Anti-inflammatory drugs! Dr.Nazar Jawhar Many tissues & cells are involved in inflammatory reaction including: 1- Circulating cells & proteins: 2- Blood vessel wall: 3- Extracellular matrix & cells. Dr.Nazar Jawhar The steps of the inflammatory response can be remembered as the five Rs: (1) Recognition of the injurious agent (2) Recruitment of leukocytes (3) Removal of the agent (4) Regulation (control) of the response (5) Resolution (repair).  TYPES OF INFLAMMATION: - Acute inflammation: - Chronic inflammation: - Overlap Dr.Nazar Jawhar -Classical signs of inflammation are 5: * * * * * - Occur as consequences of mediator elaboration and leukocyte-mediated damage Dr.Nazar Jawhar - Stimuli that can trigger acute inflammation include: ❖ ❖ ❖ ❖ Dr.Nazar Jawhar Acute inflammation has two major components a vascular response & a cellular reaction : VASCULAR RESPONSE: Blood vessels (microcirculation) undergo series of changes including: - Vasodilation - increased vascular permeability Dr.Nazar Jawhar  1- VASODILATION: - Alterations in vessel caliber causing increased blood flow, resulting in heat & redness characteristically seen in acute inflammation. - Mechanism: results from the action of several chemical mediators Dr.Nazar Jawhar  2- Increased vascular permeability: ❑ Structural changes in the microcirculation that permits the out flow of fluid &proteins into the interstitial tissue resulting in edema ( swelling). Dr.Nazar Jawhar Fluid exchange occurs normally between intravascular and extravascular spaces, with the endothelium forming a permeability barrier. Endothelial cells are connected to each other by tight junctions and separated from the tissue by a limiting basement membrane Disruption of this barrier function is a hallmark of acute inflammation. One of the earliest responses to tissue injury occurs at the level of capillaries and postcapillary venules. Specific inflammatory mediators are produced at the site of injury and act directly upon blood vessels to increase vascular permeability. Vascular leakage is caused by endothelial cell contraction, endothelial cell retraction, and alterations in transcytosis. Endothelial cells are also damaged, either directly or indirectly by leukocyte-mediated damage. The loss of the permeability barrier may be extensive and leakage of fluid and cells into the extravascular space, termed edema Mechanisms for increased vascular permeability: Dr.Nazar Jawhar As the microvasculature becomes more permeable, protein-rich fluid moves into the extravascular tissues. This causes the red blood cells to become more concentrated, thereby increasing blood viscosity and slowing the circulation. These changes are reflected microscopically by numerous dilated small vessels packed with erythrocytes and slowly flowing blood, a process called stasis. Several definitions are important for understanding the consequences of inflammation: ❖ Edema is accumulation of fluid within the extravascular compartment & interstitial tissues. ❖ Effusion is excess fluid in body cavities, e.g., peritoneum or pleura. ❖ Transudate is edema fluid with low protein content (specific gravity < 1.015). ❖ Exudate is edema fluid with a high protein concentration (specific gravity > 1.015), which frequently contains inflammatory cells. Exudates are observed early in acute inflammatory reactions and are produced by mild injuries, such as sunburn or traumatic blisters. ❖ Serous exudate is characterized by the absence of a prominent cellular response and has a yellow, straw-like color. ❖ Serosanguineous refers to a serous exudate that contains red blood cells & has a red tinge. ❖ Fibrinous exudate contains large amounts of fibrin as a result of activation of the coagulation system. ❖ Purulent exudate is one that contains prominent cellular components & debris (pus). As stasis develops, leukocytes (principally neutrophils) begin to accumulate along the vascular endothelial surface, a process called margination. This is the first step in the journey of the leukocytes through the vascular wall into the interstitial tissue  LEUKOCYTE CELLULAR EVENTS: Immigration of leukocytes from microcirculation & accumulation at the site of injury. It is divided into the following steps: 1. Margination 2. Adhesion & rolling 3. Transmigration (diapedsis) 4. Chemotaxis: 5. Activation, phagocytosis & degranulation: Dr.Nazar Jawhar  Margination: the process of leukocyte accumulation at the periphery of vessels (what is laminar flow?). Adhesion to endothelium; rolling along the vessel wall; firm adhesion to the endothelium Dr.Nazar Jawhar ❖ Both rolling & adhesion are mediated by binding of complementary adhesion molecules on leukocytes & endothelial surface like lock & key. ❖ Chemical mediators affect these processes by modulating surface expression of these adhesion molecules, example TNF, IL-1. Dr.Nazar Jawhar ❖ There are few major families of adhesion molecules: - Selectin (E, P & L) on endothelial cells (EC), for rolling. - Integrin on PNL, for firm adhesion. - Ig like ICAM & VCAM on EC. - CD31 (PECAM-1) for transmigration - Others as glycoproteins. Dr.Nazar Jawhar ❖ These molecules are modulated by three mechanisms to induce rolling and adhesion: - Redistribution of adhesion molecule to surface of EC. - Induction of adhesion molecule - Increase avidity of binding as in integrin on PNL. Dr.Nazar Jawhar Transmigration (diapedsis) between endothelial cells piercing the basement membrane. Leukocytes move by extending pseudopods that anchor to the ECM and then pull the cell in the direction of the extension Dr.Nazar Jawhar ❖Chemotaxis: (directional movement in interstitial tissues toward a chemotactic stimulus). After extravasation, neutrophils emigrate toward the site of injury. This movement is mediated and directed by chemical agents (chemotactic) which include exogenous factors (as bacterial products) and endogenous factors (as C5a, Lt-B4, IL-8). ❖ Such factors also cause leukocytes activation (production of arachidonic acid metabolites & release of lysosomal enzymes). Dr.Nazar Jawhar ❖Recognition of microbes and dead tissue: Leukocytes express several receptors that recognize external stimuli as: Receptors for microbial products as Toll-like receptors (TLRs) that recognized different bacterial components as LPS. G protein-coupled receptors: also recognize short bacterial peptides. Receptors for opsonin Receptores for cytokines as INF-gamma Dr.Nazar Jawhar Phagocytosis: The ultimate effect of recruitment of PNL is to phagocytose microbes with subsequent killing. Phagocytosis is facilitated by host proteins called opsonins that coat microbes and target them for phagocytosis (a process called opsonization), e.g IgG & C3b. Killing and degredation of microbes: Such killing is achieved by 2 factors: Generation of free radicals (reactive O2 species- oxidative burst and reactive nitrogen species) and lysosomal enzyme Killing and degredation of microbes: Such killing is achieved by 2 factors: Generation of free radicals (reactive O2 species- oxidative burst and reactive nitrogen species) and lysosomal enzyme Dr.Nazar Jawhar Dr.Nazar Jawhar  LEUKOCYTE-INDUCED TISSUE INJURY During phagocytosis lysosomal enzymes may leak into the interstitial tissue causing injury (as in acute gout, acute respiratory distress syndrome,…). WHY NEUTROPHILS PREDOMINATE IN ACUTE INFLAMMATION? Dr.Nazar Jawhar  DEFECTS IN LEUKOCYTES FUNCTIONS: Since leukocytes play a vital role in acute inflammation, then both acquired & genetic defects in leukocyte function increases vulnerability to infection. ❑ GENETIC DEFECTS: Defects in leukocyte adhesion: e.g LAD-1 syndrome, genetic deficiency of integrin, reducing endothelial adhesion. Defects in phagolysosome function: e.g Chediak Higashi disease HOW? Defects in microbicidal activity: As in chronic granulomatous diseases ❑ ACQUIRED DEFECTS:Dr.Nazar example Jawhar  Acquired defects: Disease defect Bone marrow suppression: Production of leukocytes tumors, radiation, and chemotherapy Thermal injury, diabetes, Chemotaxis malignancy, sepsis, immunodeficiencies Hemodialysis, diabetes Adhesion mellitus Leukemia, anemia, sepsis, Phagocytosis and diabetes, neonates, microbicidal activity malnutrition CHEMICAL MEDIATORS OF ACUTE INFLAMMATION: These are chemical substances that play vital roles in the inflammatory process. Many mediators are known, and this knowledge has been used to design a large armamentarium of anti-inflammatory drugs. Dr.Nazar Jawhar  Sources of mediators: ❖ Cell derived mediators: produced locally by cells at the site of inflammation. ❖ Circulating in the plasma (typically synthesized by the liver) as inactive precursors that are activated during inflammation. Cell-derived mediators are normally sequestered in intracellular granules and are rapidly secreted upon cellular activation (e.g., histamine in mast cells) or are synthesized de novo in response to a stimulus (e.g., prostaglandins and cytokines) Dr.Nazar Jawhar SOURCES OF CHEMICAL MEDIATORS: Present as precursor i.e inactive form. Dr.Nazar Jawhar  EFFECTS OF CHEMICAL MEDIATORS: ❑ Production of chemical mediators is triggered by microbial products & damaged tissues. ❑ Chemical mediators perform their function by binding to a specific receptors on the target cells. ❑ One mediator can stimulate the release of other mediator from the target cell (2ry). ❑ Mediators can act on one or few target cells, & may have different effects on different types of cells. ❑ The action of chemical mediators is firmly controlled, once they perform their function they decay quickly or rapidly inactivated. Dr.Nazar Jawhar  EXAMPLES OF CHEMICAL MEDIATORS: ❑ Plasma proteins: - Complement system: - Kinin system: - Clotting system: Dr.Nazar Jawhar  Major Cell-derived Mediators Vasoactive amines: histamine, serotonin; main effects are vasodilation and increased vascular permeability Arachidonic acid metabolites: prostaglandins and leukotrienes; several forms, involved in vascular reactions, leukocyte chemotaxis, and other reactions Cytokines: proteins produced by many cell types; mediate multiple effects, mainly in leukocyte recruitment and migration; e.g TNF, IL-1, and chemokines Reactive oxygen species: role in microbial killing, tissue injury Nitric oxide: vasodilation, microbial killing Lysosomal enzymes: role in microbial killing, tissue injury Others: as PAF Role of mediators in different reactions of inflammation Prostaglandins, Vasodilation NO, Histamine Vasoactive amines, C3a & C5a, Increased vascular permeability Bradykinin Leukotienes C4,D4,E4, Other C5a, Chemotaxis & leukocyte Leukotrine B4, activation IL-1, TNF, others Fever IL-1,TNF, prostaglandins Prostaglandins, Pain bradykinin Lysosomal enzymes, O2 –derived Tissue damage free radicals & NO Dr.Nazar Jawhar Major effects of cytokines in inflammation Dr.Nazar Jawhar BENEFICIAL EFFECTS OF ACUTE INFLAMMATORY EXUDATE: Beside elimination of injurious stimuli & participation in the removal of necrotic tissues, inflammatory exudate is protective through: ❖ Dilution of toxins: ❖ Protective antibodies: ❖ Fibrin formation: ❖ Plasma mediator system: ❖ Cell nutrition: ❖ Promotion of immunity: Dr.Nazar Jawhar