Inflammation and the Acute Inflammatory Response Flashcards
Inflammation is basically
Rxn of vascularized tissue to injury
Types of edema
Exudate - inflammatory edema…high protein content, specific gravity > 1.020…from increase in blood vessel permeability that is characteristic of inflammation **contains cellular and chemical mediators critical to inflammation
Transudate - low protein content and specfic gravity < 1.012…filtrate of plasma caused by increase in hydrostatic pressure or decrease in plasma oncotic pressure…no association with vascular permeability
Vascular flow change - acute inflammation
Vasodilation…increased blood flow to affected tissue
Vascular permeability - acute inflammation
Increases in microvasculature…escape of exudate to injured tissue…blood remaining in vessels is concentrated and moves slows
2 mechanisms to increase vascular permeability
Endothelial cell contraction (retraction)
Leukocyte mediated endothelial injury
Retraction
Mainly in venules
Endothelial cells shorten, leading to widening of junctions…exudate through gaps
Rapid
Mediated by lots of chemical mediators
Leukocyte mediated endothelial injury
Mostly in venules
Leukocytes adhere to endothelial cells and become activate…release toxic substances that cause endothelial injury and detachment of cells from inner wall of blood vessels
Delayed onset
Adhesion
When stasis occurs, leukocytes within blood stream move toward inner wall of blood vessels (margination)
Rolling leads to adhesion
Adhesion molecules are mediators that bind…selectins involved in rolling, integrins promote firm adhesion
Modulation of adhesion molecules necessary to promote binding to one another
Redistribtuion of adhesion molecules from within cytoplasm to cell surface where they are available for binding example
P-selectin normally bound to Weibel-Palade bodies in endothelial cytoplasm…chemical mediators cause migration to endothelial membrane
Induction of adhesion molecule synthesis example
E-selectin…not found within endothelial cells unless induced by chemical mediator of inflammation…not immediately available
Increase in binding affinity of adhesion molecules example
LFA-1/ICAm-1 interaction…leukocyte activation leads to conformational changes of adhesion molecules
Transmigration across endothelium
Diapedesis
Leuko squeezes through gaps and into tissues…homophilic adhesion to PECAM-1 …**neutrophil is predominant cell that transmigrates in acute
Two types of chemoattractants
Exogenous - from bacteria
Endogenous - produced by injured host
Mechanism of chemotractant inducement of movement
Chemoattractant binds receptor on leukocyte membrane…activates intracellular phospholipase C which triggers series of events increased intracellular calcium…causes cross linked of actin…forms pseudopod and moves in direction of density gradient…process of pseudopod formation occurs repeatedly until it reaches sources
Phagocytosis steps
Recognition and attachment
Engulfment
Killing
Recognition - phago
Enhanced by coating of object with opsonins (fragment of IgG and compllement C3b)…opsonins bind to leukocyte
Engulfment - phago
FOrms phagosome…lysosomes fuse to form phagolysosome
Killing and degradation options
Oxygen dependent killing - consumption of oxygen in phagolysosome causes oxidative burst…involves peroxide-myeloperoxidase-halide system which is covalent insertion of halide into bacterial molecules
Oxygen independent killing - involves other substances in lysosomes that don’t need oxygen (BPI, lysozyme, lactoferrin)
Acid hydrolases degrade
Vasoactive amines
Histamine and serotonin
Histamine
Preformed and immediately available
Found in mast cells
Dilations of arterioles, increase vascular permeability, redistribute P-selectin
Causes some tissue damage
Serotonin
Found iwhtin platelet granules…preformed and similar to histamine
Complement system
Lyses microorganisms by generating membrane attack complex
C3a and C5a cause vasodilation and increase permeability…also help release histamine from mast cells
C5a - potent chemoattactant and stimulates movement of leukocytes
C3b - opsonin
Kinin system
When factor 12 (Hageman factor) of clotting system comes in contact with injured tissue, becomes activated and activates cascade
Bradykinin- increases vascular permeability…contributor to pain
Kallikrein - activates Hageman factor and produces more brady kinin…also chemoattractant
Clotting system
Triggered by factor 12
Produces thrombin…binds to protease activated receptors (PARs) on membranes of cells…redistribtuing of P-selectin and production of prostaglandins
AA metabolites
Phospholipases that have been activated will release AA into cells…metabolized by 1 of 2 pathways
Cyclooxygenase pathway
Produces prostaglandins
Prostacyclin
PGI2
Vasodilation…inhibits aggregation
Thromboxane A
Vasoconstriction and promotes aggregation
PGD2 and PGE2
Vasodilation and increased permeability of post-cap venules…PGD2 is chemoattractant for neutrophils
Prostaglandins can cause
Pain ad fever
Lipooxygenase pathway
Produces leukotrienes and lipoxins
Leukotriene B4
Chemoattractant
Leukotriends C4,D4, and E4
Increase permeability
Vasoconstriction
Bronchospasm
Lipoxins A4 and B4
INhibit neutrophil chemotaxis and ability of neutrophil to adher to endothelium…terminates
Cytokines
Synthesizes by activated leukocytes
Interluekin 1
Similar to TNF
Promote leukocyte adhesion
Promote synthesis of prostaglandins and others
Cause fever, loss of app, increased sleep
Interleukin 8
Member of chemokines (powerful chemo attractant)…chemotaxis for neutrophils
Nitric oxide
SOluble gas released by endothelial and macrophages
Vasodilator
Interacts with Oxygen free rads to produce antimic substances
Inhiits some of cellular events of inflammation and keeps response under control
