Chemical Mediators of Inflammation
Vasoactive amines (histamine & serotonin)
Plasma proteins (complement, kinin, clotting systems)
Arachadonic acid metabolites (prostaglandins, leukotrienes, lipoxins)
Platelet activating factor
Cytokines (tumor necrosis factor and interleukin-1) & chemokin
Sources of chemical mediators
PLASMA: plasma-derived mediators are produced in the liver and are present in precursor (latent) forms that must be activated, usually by proteolytic cleavage. They can be activated by microbes and damaged tissue. Ex. factor XII activation and complement
Histamine
Histamine and serotonin are critical mediators of inflammatory responses because they are preformed (located in granules) and are released rapidly and early during inflammation.
Histamine(preformed)
Distribution: widely-distributed in tissues and found in
Serotonin
Preformed.
Distribution: platelets and enterochromaffin cells
Stimuli that trigger release: Platelet aggregation stimulated by (1) contact with collagen, thrombin, ADP, Ag-Ab complexes or (2) PAF (mast cell-derived)
Actions/Functions: (1)
increased vascul
Plasma proteins: complement system
Distribution: Complement proteins were present in the plasma as inactive proteins, numbered C1 through C9. When activated, many become proteolytically active enzymes that form a highly-ordered cascade to degrade other complement proteins and ultimately ac
Steps of complement activation
The early steps:
1. Classical pathway is triggered by fixation of C1 to antigen-antibody (IgG/IgM) complexes, which cleaves C2 and C4. A C4b2a complex functions as C3 convertase.
2. Alternative pathway: C3 contacts microbial surface molecules (e.g. endoto
Actions and Functions of Complement System & Regulation
1. C3a/C4a/C5a (anaphylotoxins) act on mast cells to induce histamine and increase vascular permeability
2. C5a activated lipoxygenase pathways in PMNs and monocytes. As a result, these cells release inflammatory mediators
3. C5a: leukocyte chemotaxis (PM
Disorders of Complement system
Result in increased susceptibility to infection (complement) or pathologic activation (regulator)
1. Deficiency of C3 results in increased susceptibility to infection and can be fatal unless treated.
2. Paroxysmal nocturnal hemoglobinuria is a disease lin
Plasma proteins: Kinin system
The kinin system generates vasoactive peptides from kininogens (plasma proteins), following cleavage by kallikreins.
Activation of the kinin system results in the release of bradykinin
Actions of bradykinin: (1) incereases vascular permeability, (2) cause
Plasma proteins: clotting system
The clotting, kinin, complement and fibrinolytic systems are intimately linked through the common initiation molecule, Factor XIIa.
A cascade of reactions occur to generate thrombin (Factor IIa).
Thrombin is a key link between the clotting system and infl
Generation of eicosanoids (arachidonic acid metabolites) and their roles in inflammation
Phospholipase cleaves off arachidonic acid.
Lipooxygenase takes arachidonic acid to leukotrienes and lipoxins. Lipoxin A4 and B4 cause vasodilation, inhibit neutrophil chemotaxis and stimulate monocyte adhesion. 5-HETE and Leukotriene B4 cause chemotaxis.
Inflammatory Actions of Eicosanoids
Action--Metabolite pairs
Vasocontriction--thromboxane A2, leukotrienes C4, D4, E4
Vasodilation--PGI2, PGE2, PGF2a, PGD2
Increased vascular permeability--Leukotrienes C4, D4, E4
Chemotaxis, leukocyte adhesion--leukotriene B4, HETE, lipoxins (opposes chemot
Cyclooxygenase Pathway
AA-->prostaglandins
COX-1 and COX-2 convert AA to prostaglandins.
While COX1 is constitutively expressed (e.g. homeostatic prostaglandins), COX2 is induced by inflammation and stimulates production of prostaglandins in inflammatory reactions.
NSAIDs (non-
Lipoxygenase Pathway
AA--->lipoxins and leukotrienes
Leukotrienes:
5-lipoxygenase converts AA to HETE, which is chemotactic for neutrophils.
HETE is then converted to a family to leukotrienes.
LTB4 is a potent chemoattractant and stimulates leukocyte aggregation and adhesion
Platelet Activating Factor (PAF)
PAF was originally found to be produced by antigen-stimulated, IgE sensitized basophils to stimulate platelet aggregation. It is now known to bind a single G-protein-coupled receptor on platelets, basophils, mast cells, PMN, monocytes, macrophages and end
TNF and IL1; NO
TNF and IL1 are major mediators of inflammation.
Key actions include: endothelial activation (adhesion molecules, cytokines, chemokines, eicosanoids, GFs, NO), trigger matrix remodeling, systemic acute phase response.
Help in wound healing--CHANGE ENDOTHE
Lysosomal Constituents of Leukocytes
Lysosomal granules withing neutrophils and monocytes are destructive organelles that contain enzymes to degrade bacteria, debris, extracellular matrix proteins and virulence factors.
Specific: small, empty into phagocytic vacuoles, release into extracellu
Oxygen-derived free radicals
Oxygen-derived free radicals are released extracellularly by leukocytes in response to microbes, chemokines, immune complexes or following a phagocytic challenge. Oxygen-derived free radicals destroy phagocytosed microbes.
Superoxide anion, hydrogen perox
Neuropeptides; Other
Neuropeptides play a role in the initiation and propagation of an inflammatory response. They are produced in the central and peripheral nervous systems.
Substance P and neurokinin A are two such molecules.
Substance P can transmit pain, increase vascular
Actions of Inflammatory Mediators
Mediator--source--vascular leakage--other effects
Histamine & serotonin--mast cells, platelets--+--increased permeability
Bradykinin--plasma substrate--+--pain, increased permeability
C3a--plasma protein via liver--+--opsonic fragment (C3b)
C5a--macrophag
Actions of Inflammatory Mediators, cont'd
Vasodilation: prostaglandins, NO, histamine are pro-inflammatory
Increased vascular permeability: vasoactive amines, C3a and C5a (thru liberating amines), bradykinin, leukotrienes C4, D4, E4, PAF, substance P are pro-inflammatory and lipoxins are anti-inf