inflammation is a complex reaction to injurious agents

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

1) Repair process 를 동반한다 . : regeneration , scarring

2) 기본적으로 생체의 protective response 이다 .

3) 두개의 주된 요소

vascular reaction, cellular reaction

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

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)

immunologic reactions (also called hypersensitivity reactions)

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.

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

I. Vascular changes

Changes in vascular flow and caliber

1) Vasodilation sometimes followed by transient constriction of arterioles arterioles -- opening of new microvascular bed in the area increased blood flow -- heat and redness hallmark of the early hemodynamic changes in acute inflammation induced by histamine, nitric oxide on vascular smooth muscle2) 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) leukocyte margination – emigration

Increased vascular permeability (Vascular leakage)

Increased vascular permeability (Vascular leakage): the hallmark of acute inflammation

mechanisms

1) Gap due to endothelial cell contraction --> widening of intercellular junction or intercellular gaps - histamine, bradykinin, leukotriens 에 의해 "immediate transient response“ (reversible, short-lived) - site: venules 20 - 60 m in diameter Cytoskeletal & junctional reorganization (endothelial retraction) - cytokines (IL-1, TNF, IFN-) - delayed (4 to 6 hrs) & long-lived (24 hrs or more)

2) Direct endothelial injury resulting in endothelial necrosis & detachment "immediate sustained response" -all levels of the microcirculation are affected including venules, capillaries and arterioles - injury by severe burns or lytic bacterial infection3) Delayed prolonged leakage

delay; 2 - 12 hrs, duration; 수 시간내지 수 일site: venules & capillaries원인 ; mild-to-moderate thermal injury

X- or UV irradiation bacterial toxins

4) Leukocyte-mediated endothelial injury : mostly venule, pulmonary, glomerular capillaries5) increased transcytosis : vesiculovacuolar organelle, VEGF6) Leakage from new blood vessels

II. Cellular events: leukocytic extravasation, chemotaxis and phagocytosis

순서 ;1. Margination 2. Rolling

3. Activation of leukocytes 4. Firm adhesion to endothelium5. Transmigration(diapedesis)6. migration in interstitial tissues

toward a chemotactic stimulus

Adhesion receptors

1) selectins 특징 ; extracellular N-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) Immunoglobulin family molecules ------ iii. Integrins a. ICAM-1 ------ integrins; LFA-1(CD11a/CD18), MAC-1(CD11b/CD18) b. VCAM-1 ----- 1 integrins; VLA-4, 7

3) Integrins transmembrane heterodimeric glycoproteins , chains expressed on many cell types binds ligands on endothelial cells, other leukocytes the extracellular matrix a. ICAM-1 ------ integrins; LFA-1(CD11a/CD18), MAC-1(CD11b/CD18) b. VCAM-1 ----- 1 integrins; VLA-4, 7

4) Mucin-like glycoproteins heparan sulfate bind to CD44

Endothelial molecules

P-selectin Sialyl-LewisX Rolling PSGL-1E-selectin Sialyl-LewisX Rolling, adhesion to endotheliumICAM-1 CD11/CD18 Adhesion, arrest, transmigration (LFA-1, Mac-1)VCAM-1 41(VLA4) Adhesion 47 (LPAM-1) GlyCam-1 L-selectin Lymphocyte homing to HEVCD31(PECAM) CD31 Leukocyte migration through endothelium

LeukocyteReceptors

Major roles

Endothelial/Leukocyte Adhesion Molecules

2) Chemotaxis & leukocyte activation

a) Chemotaxis the unidirectional migration of cells toward an attractant locomotion oriented along a chemical gradient neutrophils ------------> monocytes first 6-24 hrs in 24-48 hrs

a. short-lived neutrophils b. long-sustained monocyte emigration c. chemotactic factors

most significant chemotactic agents for neutrophils

a. exogenous agents : bacterial products (N-formyl- methionine terminal a.a., lipid in nature)

b. endogenous chemical mediators - components of the complement system (C5a) - products of the lipoxygenase pathway (leukotrien B4) - cytokines : IL-8 family

the mechanisms of chemotactanta. binding of chemotactic agents to specific receptorsb. pseudopod (lamellipod)

Phagocytosis

1) Recognition and attachment

2) Engulfment

3) Killing or Degradation

1. Recognition and attachment opsonins; - Fc fragment of IgG - C3b (opsonic fragment of C3) - carbohydrate-binding protein (lectins) of plasma (collectin) bind to microbial cell wallcorresponding receptors of leukocytes Fc R --- Fc of IgG CR1, CR2, CR3 --- C3b and C3bi C1q---- collectin CR3/Mac-1 : binds to the extracellular matrix(fibronectin,laminin)

2. Engulfment

3. Killing or degradation two categories of bactericidal mechanisms i) oxygen-dependent bactericidal mechanism (a burst in oxygen consumption, glycogenolysis, increased glucose oxidation via HMP shunt, production of reactive oxygen intermediates, ROI)

NADPH oxidase: a. cytosolic phosphoproteinsb. membrane cytochrome protein components (cytochrome b-558)

oxidase 2O2 + NADPH ---------> 2O2- + NADP+ + H+ 2O2-·+ 2H+ ----> H2O2 + O2

a. the H2O2-myeloperoxidase(MPO)-halide system : the most efficient bacteriacidal system in neutrophils (Myeloperoxidase-dependent killing)b. MPO-independent killing superoxide, hydroxyl radicals, singletoxygen

ii) oxygen-independent mechanisms bactericidal permeability increasing protein (BPI)

lysozyme lactoferrin major basic protein (MBP) acid hydrolase (azurophilic granules)

5. Defects in leukocyte function a. defects in number of circulating cells b. defects in adhesion genetic deficiencies in leukocyte adhesion molecules (LAD type 1,2) LAD type1 : recurrent bacterial infections and impaired wound healing deficiency of chain of CD11/CD18 integrins --abnormal neutrophil adhesion, spreading, phagocytosis and 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 chemotactic factor generation iii. serum chemotactic inhibitor iv. inhibitors of leukocyte locomotion

d. defects in phagocytosis Chediak-Higashi syndrome : defective degranulation, delayed microbial killing -neutropils having giant granules due to aberrant organelle fusion-reduced transfer of lysosomal enzyme to phagocytic vacuoles (causing susceptibility to infection), -melanocytes (leading to albinism), -cells of the nervous system (associated with nerve defect)-platelete (generating bleeding disorder)e. defects in microbicidal activity i. impaired H2O2 production ii. MPO deficiency iii. severe deficiency of leukocyte G6PD chronic granulomatous disease : genetic defects in the genes encoding several components of NADPH oxidase

f. mixed defects

Morphologic Patterns of Acute Inflammation

1. Serous inflammation2. Fibrinous inflammation3. Suppurative or purulent inflammation4. Ulcers

Serous inflammation

Fibrinous Pericarditis

Suppurative or purulent inflammation

Ulcer

Chronic InflammationDefinition; Inflammation of prolonged duration in which activeinflammation, tissue destruction, and attempt at repair are proceedingSimultaneously

Causes of chronic inflammation1. Persistent infection2. Prolonged exposure to potentially toxic agents, either exogenous or endogenous3. Autoimmunity

Morphologic features1. Infiltration with mononuclear cells (macrophages, lymphocytes, plasma cells)2. Tissue destruction3. Healing by connective tissue replacement of damaged tissues

Acute bronchopneumoniaChronic inflammation in the lung