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Inflammation is a complex reaction to injurious agents

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. Repair process 를 동반한다 . : regeneration , scarring

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Inflammation is a complex reaction to injurious agents

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  1. 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 • Repair process를 동반한다. : regeneration , scarring • 기본적으로 생체의 protective response 이다. • 두개의 주된 요소 • vascular reaction, cellular reaction

  2. Innate Immunity : defense mechanisms that do not require a prolonged period of induction because they do not rely on the clonal expansion of antigen-specific lymphocytes Adaptive immunity: the immune response of antigen-specific lymphocytes to antigen, including the development of immunological memory. Generated by clonal selection of lymphocytes

  3. 1) cause of inflammation ; almost all causes of cell injury, infections (bacterial, viral, parasitic) & microbial toxins trauma (blunt and penetrating) physical agents (burns, frostbite, radiation) chemicals (toxins, caustic substances) tissue necrosis (from any cause) foreign bodies (splinters, dirt, sutures) immunologicreactions (also called hypersensitivity reactions)

  4. 2) Characteristics of acute inflammation a. relatively short duration b. exudation of fluid and plasma proteins (edema) and the emigration of leukocytes, predominantly neutrophils c. Regardless of the nature of injurious agent, acute inflammation is more or less stereotypic.

  5. Three major components of acute inflammation 1. Alteration in vascular caliber that lead to an increase in blood flow 2. Structural change in the microvasculature that permit the plasma proteins and leukocytes to leave the circulation 3. Emigration of the leukocytes from the microcirculation and their accumulation in the focus of injury

  6. I. Vascular changes • Changes in vascular flow and caliber • Vasodilation • sometimes followed by transient constriction of arterioles • arterioles -- opening of new microvascularbed in the area • increased blood flow -- heat and redness • hallmark of the early hemodynamicchanges in acute inflammation • induced by histamine, nitric oxide on vascular smooth muscle • 2) slowing of the circulation • -followed by increased permeability of the microvasculature • with outpouring of protein-rich fluid & concentration of RBC • in small blood vessels, • -increased viscosity of the blood : "stasis" • 3) leukocytemargination – emigration • Increased vascular permeability (Vascular leakage)

  7. Increased vascular permeability (Vascular leakage) : the hallmark of acute inflammation mechanisms 1) Gap due to endothelial cell contraction --> widening of intercellularjunction or intercellulargaps - histamine, bradykinin, leukotriens에 의해 "immediate transient response“ (reversible, short-lived) - site: venules20 - 60 mm in diameter Cytoskeletal& junctional reorganization (endothelial retraction) - cytokines(IL-1, TNF, IFN-g ) - delayed (4 to 6 hrs) & long-lived (24 hrsor more)

  8. 2) Direct endothelial injury resulting in endothelial necrosis & detachment "immediate sustained response" -all levels of the microcirculationare affected including venules, capillaries and arterioles - injury by severe burns or lyticbacterial infection 3) Delayed prolonged leakage delay; 2 - 12 hrs, duration; 수 시간내지 수 일 site: venules& capillaries 원인; mild-to-moderate thermal injury X- or UVirradiation bacterial toxins 4) Leukocyte-mediated endothelial injury : mostly venule, pulmonary, glomerular capillaries 5) increased transcytosis : vesiculovacuolar organelle, VEGF 6) Leakage from new blood vessels

  9. II. Cellular events: leukocyticextravasation, chemotaxis and phagocytosis 순서;1. Margination 2. Rolling 3. Activation of leukocytes 4. Firm adhesion to endothelium 5. Transmigration(diapedesis) 6. migration in interstitial tissues toward a chemotactic stimulus

  10. Adhesion receptors 1) selectins 특징; extracellularN-terminal domain related to sugar binding mammalian lectins a. E-selectin(CD62E, ELAM-1); endothelium b. P-selectin(CD62P, GMP140); endothelium, platelets E&P selectins binds to sialylated forms of oligosacharides (sialylated Lewis X) c. L-selectin(CD62L, LAM-1); bind to mucin-like glycoprotein (GlyCAM-1 & CD34) 2) Immunoglobulinfamily molecules------ iii. Integrins a. ICAM-1 ------ b integrins; LFA-1(CD11a/CD18), MAC-1(CD11b/CD18) b. VCAM-1 ----- a4b1integrins; VLA-4, a4b7

  11. 3) Integrins transmembrane heterodimeric glycoproteins a, b chains expressed on many cell types binds ligands on endothelial cells, other leukocytes the extracellular matrix a. ICAM-1 ------ b integrins; LFA-1(CD11a/CD18), MAC-1(CD11b/CD18) b. VCAM-1 ----- a4b1integrins; VLA-4, a4b7 4) Mucin-like glycoproteins heparan sulfate bind to CD44

  12. Endothelial/Leukocyte Adhesion Molecules Endothelial molecules Leukocyte Receptors Major roles P-selectin Sialyl-LewisX Rolling PSGL-1 E-selectin Sialyl-LewisX Rolling, adhesion to endothelium ICAM-1 CD11/CD18 Adhesion, arrest, transmigration (LFA-1, Mac-1) VCAM-1 a4b1(VLA4) Adhesion a4b7 (LPAM-1) GlyCam-1 L-selectin Lymphocyte homing to HEV CD31(PECAM) CD31 Leukocyte migration through endothelium

  13. 2) Chemotaxis& leukocyteactivation a) Chemotaxis the unidirectional migration of cells toward an attractant locomotion oriented along a chemical gradient neutrophils ------------> monocytes first 6-24 hrsin 24-48 hrs a. short-lived neutrophils b. long-sustained monocyteemigration c. chemotacticfactors

  14. most significant chemotacticagents for neutrophils a. exogenousagents :bacterial products (N-formyl- methionineterminal a.a., lipid in nature) b. endogenous chemical mediators - components of the complement system (C5a) - products of the lipoxygenasepathway (leukotrienB4) - cytokines: IL-8 family the mechanisms of chemotactant a. binding of chemotacticagents to specific receptors b. pseudopod(lamellipod)

  15. Phagocytosis 1) Recognition and attachment 2) Engulfment 3) Killing or Degradation

  16. 1. Recognition and attachment opsonins; - Fcfragment of IgG - C3b (opsonicfragment of C3) - carbohydrate-binding protein (lectins) of plasma (collectin) bind to microbial cell wall corresponding receptors of leukocytes FcR --- Fcof IgG CR1, CR2, CR3 --- C3b and C3bi C1q---- collectin CR3/Mac-1 : binds to the extracellularmatrix(fibronectin,laminin) 2. Engulfment

  17. 3. Killing or degradation two categories of bactericidal mechanisms i) oxygen-dependent bactericidal mechanism (a burst in oxygen consumption, glycogenolysis, increased glucose oxidation via HMPshunt, production of reactive oxygen intermediates, ROI) NADPHoxidase: a. cytosolicphosphoproteins b. membrane cytochromeprotein components (cytochromeb-558) oxidase 2O2 + NADPH---------> 2O2- + NADP+ + H+ 2O2-·+ 2H+----> H2O2 + O2

  18. a. the H2O2-myeloperoxidase(MPO)-halidesystem : the most efficient bacteriacidalsystem in neutrophils (Myeloperoxidase-dependent killing) b. MPO-independent killing superoxide, hydroxylradicals, singletoxygen ii) oxygen-independent mechanisms bactericidal permeability increasing protein (BPI) lysozyme lactoferrin major basic protein (MBP) acid hydrolase(azurophilicgranules)

  19. 5. Defects in leukocytefunction a. defects in number of circulating cells b. defects in adhesion genetic deficiencies in leukocyteadhesion molecules (LAD type 1,2) LAD type1 : recurrent bacterial infections and impairedwound healing deficiency of b chain of CD11/CD18 integrins --abnormal neutrophiladhesion, spreading, phagocytosisand generation of the oxidative burst LAD type 2 : defect in fucosyl transferase required for synthesis of a sialyl-Lewis X c. defects in migration and chemotaxis i. intrinsic abnormality of leukocytes ii. defect in chemotacticfactor generation iii. serum chemotacticinhibitor iv. inhibitors of leukocytelocomotion

  20. d. defects in phagocytosis Chediak-Higashisyndrome : defective degranulation, delayed microbial killing -neutropilshaving giant granules due to aberrantorganellefusion -reduced transfer of lysosomalenzyme to phagocyticvacuoles(causing susceptibility to infection), -melanocytes(leading to albinism), -cells of the nervous system (associated with nerve defect) -platelete(generating bleeding disorder) e. defects in microbicidalactivity i. impaired H2O2production ii. MPOdeficiency iii. severe deficiency of leukocyteG6PD chronic granulomatous disease : genetic defects in the genes encoding several components of NADPH oxidase f. mixed defects

  21. Morphologic Patterns of Acute Inflammation • Serous inflammation • Fibrinous inflammation • Suppurative or purulent inflammation • Ulcers

  22. Serous inflammation

  23. Fibrinous Pericarditis

  24. Suppurative or purulent inflammation

  25. Ulcer

  26. Chronic Inflammation • Definition; Inflammation of prolonged duration in which active • inflammation, tissue destruction, and attempt at repair are proceeding • Simultaneously • Causes of chronic inflammation • Persistent infection • Prolonged exposure to potentially toxic agents, either exogenous • or endogenous • Autoimmunity • Morphologic features • Infiltration with mononuclear cells • (macrophages, lymphocytes, plasma cells) • 2. Tissue destruction • 3. Healing by connective tissue replacement of damaged tissues

  27. Acute bronchopneumonia Chronic inflammation in the lung

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