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Acute inflammation(pathology)

  1. 1. Dr. Nausheen Henna Assistant Professor Pathology M.Phil; FCPS
  2. 2. Inflammation  Beneficial host response to foreign invaders and necrotic tissue  The main components: ◦ Vascular reaction and a cellular response;  Steps of the inflammatory response (5Rs):  Recognition of the injurious agent,  Recruitment of leukocytes,  Removal of the agent,  Regulation (control) of the response, and  Resolution (repair).
  3. 3. External manifestations  Cardinal signs: ◦ Heat (calor), ◦ Redness (rubor), ◦ Swelling (tumor), ◦ Pain (dolor) and ◦ Loss of function (functio laesa).
  4. 4. Effect of Inflammation  Either ◦ Elimination of the noxious stimulus followed by decline of the reaction & ◦ Repair of the damaged tissue, or ◦ Persistent injury resulting in chronic inflammation.
  5. 5. ACUTE INFLAMMATION Acute inflammation is a rapid response to injury or microbes and other foreign substances that is designed to deliver leukocytes and plasma proteins to sites of injury.
  6. 6. Stimuli for Acute Inflammation Infections Trauma Physical and chemical agents Tissue necrosis : Ischemia Foreign bodies Immune reactions (hypersensitivity reactions)
  7. 7. Two major components ◦ Vascular changes:  Vasodilatation  Increased vascular permeability ◦ Cellular events:  Cellular recruitment and activation. The principal leukocytes in acute inflammation are neutrophils (polymorph nuclear leukocytes).
  8. 8. Vascular changes
  9. 9. Vascular Changes  Changes in Vascular Caliber and Flow ◦ Begin rapidly after infection or injury  Depending on the nature and severity of the original inflammatory stimulus. ◦ Transient vasoconstriction (lasting only for seconds), ◦ Arteriolar vasodilation occurs,  Locally increased blood flow &  Engorgement of the down-stream capillary beds.
  10. 10. Microvasculature permeable RBC become more concentrated Slowing of the circulation ChemotaxisMargination Stasis Protein-rich fluid moves out EV tissues Increasing blood viscosity
  11. 11. Increased vascular permeability  Endothelial cell contraction leading to intercellular gaps in postcapillary venules  Endothelial injury  Leukocyte-mediated endothelial injury  Increased transcytosis of proteins via an intracellular vesicular pathway augments venular permeability (VEGF)  Angiogenesis.
  12. 12. Endothelial cell contraction **leading to intercellular gaps in postcapillary venules Reversible process Histamine, bradykinin, leukotrienes, and many other chemical mediators.
  13. 13. ◦ Occurs rapidly after binding of mediators to specific receptors, is usually short-lived (15-30 minutes), and is called the immediate transient response. ◦ Changes in the cytoskeleton,  cytokines such as TNF and IL-1. ◦ This reaction may take 4 to 6 hours to develop after the initial trigger and persist for 24 hours or more.
  14. 14. Endothelial injury  Vascular leakage by causing endothelial cell necrosis and detachment.  Direct injury to endothelial cells is usually seen after severe injuries (e.g., burns and some infections).  Immediate sustained response: leakage begins immediately after the injury and persists for several hours (or days) until the damaged vessels are thrombosed or repaired.
  15. 15.  Direct injury to endothelial cells may also induce a delayed prolonged leakage that begins after a delay of 2 to 12 hours, lasts for several hours or even days, and involves venules and capillaries.  Examples include mild to moderate thermal injury, certain bacterial toxins, and x- or ultravoilet irradiation  In a thermal burn, leakage results from chemically mediated endothelial contraction as well as from direct injury and leukocyte-mediated endothelial damage.
  16. 16. Responses of Lymphatic Vessels  In inflammation, lymph flow is increased and helps  Drain edema fluid from the EV space.  Equilibrates with EV fluid.  In severe inflammatory reactions, especially to microbes, the lymphatics may transport the offending agent.  Lymphangitis &lymphadenitis.  Inflamed LN are often enlarged, because of hyperplasia of the lymphoid follicles and increased numbers of lymphocytes and phagocytic cells lining the sinuses of the lymph nodes…. RLH  Red streaks near a skin wound is a telltale sign of an infection in the wound.
  17. 17. CELLULAR EVENTS 1. Leukocyte Recruitment Neutrophils predominate in the early (6-24 hrs) inflammatory infiltrate and are later replaced by macrophages in 24- 48 hrs. 1. Leukocyte Activation
  18. 18. Leukocyte Recruitment: Margination, adhesion to endothelium, and rolling along the vessel wall; Firm adhesion to the endothelium; Transmigration between endothelial cells; and migration in interstitial tissues toward a chemotactic stimulus. Chemotaxis
  19. 19. Histamine, thrombin & PAF TNF & IL-1 Collagenase ß1-integrin& CD44
  20. 20.  Chemotaxis: o Exo and endo substances  Bacterial products, particularly peptides with N-formylmethionine termini;  Cytokines (chemokine)  Complement system, particularly C5a; and  Products of the lipoxygenase pathway of arachidonic acid (AA) metabolism, particularly LTB4.
  21. 21. Leukocyte Activation Stimuli for activation Microbes, Products of necrotic cells, and Several mediators. Leukocytes express on their surface different kinds of receptors that sense the presence of microbes.
  22. 22. Leukocyte Activation Phagocytosis  Recognition and attachment of the particle to the ingesting leukocyte;  Engulfment, with subsequent formation of a phagocytic vacuole; and  Killing and degradation of the ingested material.
  23. 23. Fibronectin, fibrinogen, MBL, CRP
  24. 24. Mannose receptor & scavenger receptor
  25. 25. Bactericidal Mechanism Oxygen dependent:  Myeloperoxidase Oxygen independent:  Bactericidal permeability increasing protein (BPI), PL activation  Lysozyme,  Lactoferrin,  Major basic protein,  Defensins,  Neutrophil granules contain many enzymes, such as elastase. All contribute to microbial killing.
  26. 26. Leukocyte induced injury Regurgitation during feeding Frustrated phagocytosis Cytotoxic release
  27. 27. Acute Chronic Acute respiratory distress syndrome Arthritis Acute transplant rejection Asthma Asthma Atherosclerosis Glomerulonephritis Chronic lung disease Reperfusion injury Chronic rejection Septic shock Vasculitis Leukocyte induced injury
  28. 28. Defects in leukocyte adhesion Genetic deficiencies in leukocyte adhesion molecules (LAD types 1 and 2). LAD 1 is characterized by recurrent bacterial infections and impaired wound healing. LAD 2 is clinically milder than LAD 1 but is also characterized by recurrent bacterial infections.
  29. 29. Defects in phagolysosome function Chédiak-Higashi syndrome Autosomal recessive Characterized by  Neutropenia,  Defective degranulation,  Delayed microbial killing.  The neutrophils (and other leukocytes) have giant granules,  Reduced transfer of lysosomal enzymes to phagocytic vacuoles in phagocytes (causing susceptibility to infections)
  30. 30.  Abnormalities in melanocytes (leading to albinism),  Cells of the CNS (associated with nerve defects), and  Platelets (generating bleeding disorders).  The secretion of granule proteins by cytotoxic T cells is also affected, accounting for part of the immunodeficiency seen in the disorder.
  31. 31. Defects in microbicidal activity Chronic granulomatous disease: Recurrent bacterial infection. Inherited defects in the genes encoding several components of NADPH oxidase, which generates superoxide. The most common variants are an X-linked defect in one of the plasma membrane-bound components (gp91phox) and Autosomal recessive defects in the genes encoding two of the cytoplasmic components (p47phox and p67phox).
  32. 32. TERMINATION OF THE ACUTE INFLAMMATORY RESPONSE Short lived mediators, Stop signals, Switch in the production of pro-inflammatory leukotrienes to anti-inflammatory lipoxins from AA, Liberation of an anti-inflammatory cytokine, Transforming growth factor-β (TGF-β), from macrophages and other cells, Neural impulses (cholinergic discharge) that inhibit the production of TNF in macrophages.