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Acute inflammation Physiological response Vascular responses Flow Hemodynamic responses Permeability Fluid exudation Cellular events Emigration

igration Causes Microbial infections Hypersensitivity reactions Physical agents Irritant and corrosive chemicals Tissue necrosis Sequence of events A. Vascular responses 1. Transient vasoconstriction 2. Vasodilation Early: vasoactive amines histamine, serotonin Later: prostaglandins, nitric oxide 3. Increased blood vessel permeability Primary site: venules Leakage protein deficiency plasma(transudation) or protein-rich plasma Endothelial cells contractions (transudation) Site: Venules Immediate, transient By histamine, bradykinins, leukotrienes Junctional retraction (transudation) Site: Venules Slower, prolonged (4-5 hrs after stimulus, persist for>24hrs) By cytokines, e.g. TNF, IL-1 Direct injury (exudation) Sites: arterioles, capillaries, and venules

B.

Immediate sustained, and delayed prolonged leakage Leukocytes dependent injury (exudation) Site: mostly venules Pulmonary capillaries Late response Chemical mediators affecting endothelial cells Plasma escape Rapid exodus of protein-rich plasma: Exudation Result: dilute, isolate, and confine stimulus 4. Blood flow stagnation Blood leukocytes contact the endothelial cells Cellular responses Leukocyte recruitment and activation to ingest and kill microbes neutrophils(early) and monocytes(later) [affected by chemical mediators] 1. Margination and pavementing Slow flowaxial core collapsesblood cells contact surface of endothelial cells Neutrophils and monocytes sticky and then lined up along the interior-lining surface 2. Rolling Nueotropils: express sialyl-lewis X-modified glycoprotein, L-selectin Endothelial cells: express E- and P-selectin , CD-34 sialyl-lewis X-modified glycoprotein binds E- and P-selectins L-selectin binds CD-34 binding rolling the selectins expression are stimulated by cytokines like histamine, thrombin, TNF, IL-1 by macrophages 3. Firm adhesion Leukocytes: express integrins Activated by chemokines into a higher affinity form with ICAM-1 Endothelial cells: express ICAM-1 Ligand for integrins Increased expression by cytokines(TNF and IL-1) Binding neutrophil adhesion on lining of vessel 4. Transmigration

C.

Neutrophils crawl along the lining (chemotaxins) Squeeze through the open junction between endothelial cells Mediated by CD31 trapped between outer endothelial surface and basement membrane Secrete collagenases to pass through basement membrane Leave blood vessel to enter the injured tissue

Exudation Accumulations of neutrophils, monocytes/macrophages Phagocytosis Macrophages Presenting antigenic substances to activate other cells Anitibodies Destroy or making antigens vulnerable to neutrophils and macrophages Blood clotting proteins Form blood clot, composed of a meshwork of fibrin Chemical mediators for chemotaxis Leukocytes migrate along path of increasing conc. of chemotaxins Stimulate cell movement, cell activation, secretion and degranulation Phagocytosis Non-specific Immune phagocytosis Recognition and attachment Engulfment Phagosome/lysosome fusion

D.

Chemical mediators of acute inflammation Plasma factors 4 enzymatic cascade systems Complement system Classic(antibody dependent), alternative, common pathway C5b67, C5a: chemotactic C3a, C4a, C5a: anaphylatoxins triggering mast cell degranulation C3b, C4B: opsonin phagocytosis Kinin system Bradykinin:vascular smooth muscle realaxation, increase permeabilityedema and pain Coagulation factor system fibrin Fibrinolytic system plasmin Inter-related Cell-derived Pre-formed mediators in secretory granules Vasoactive amine: histamine, serotonin Lysosomal enzymes Newly synthesized Eicosanoids: leukotrienes, prostaglandins Platelet-activiting factors Increase vascular permeability by degranulating mast cell Cause platelets aggregation Stimulates histamine release Cytokines Pro-inflammatory: IL-1, TNF (by monocytes and macrophages) Anti-inflammatory: IL-1, IL-10, IL-13 Central role: control direction, amplitude, duration of immune responses Control remodeling of tissue Microscopic features Dilated/congested capillarie/venules Neutrophils Specific for acute inflammation

Distended tissue spaces Suggesting exudation of plasma Fibrin Few monocytes/macrophages Consequences Hours or days Resolution- removals of stimuli and repair Increased local blood flow Altered microvascular permeability Edema is reversed with lymphatic drainage Fibrin deposits Broken down by plasmin Lymphatic removal Neutropils die locally and replaced by macrophages Discharged lysosomal contents drained with lymphatics Macrophages ingest most of the cell debris and dead neutrophils Large areas of cell necrosisscar formation