CHEMICAL MEDIATORS• From plasma or cellsFrom plasma or cells• Have “triggering” stimuliHave “triggering” stimuli• Usually have specific targetsUsually have specific targets• Can cause a “cascade” of reactionCan cause a “cascade” of reaction• Are short livedAre short lived

CLASSIC MEDIATORS &THEIR SOURCES

CLASSIC MEDIATORS• Vasoactive amines:– Histamine, serotonin

• Complement products• Kinins• Clotting factors• Arachidonic Acid

Metabolites: Eicosanoids• Nitric oxide

• Platelet activating factor (paf)

• Cytokines/Chemokines• Lysosome constituents• Free radicals• Neuropeptides

HISTAMINE•Mast Cells, basophils• POWERFUL Vasodilator• Vasoactive “amine”

SEROTONIN• (5HT, 5-Hydroxy-Tryptamine)• Platelets and Entero Chromaffin Cells• Also vasodilatation, but more indirect• Evokes N.O. synthetase (a ligase) from

argenine

COMPLEMENT SYSTEM• >20 components, in circulating plasma• Multiple sites of action:–Leukocyte chemotaxis and activation, –Opsonization, –Vasodilation (mast cell stimulation)–Membrane Attack Complex (MAC)

Complement System

KININ SYSTEM• BRADYKININ is KEY component, 9 aa’s• ALSO from circulating plasma• ACTIONS– Increased permeability– Smooth muscle contraction, NON vascular– PainPain

CLOTTING FACTORS• From circulating plasma• Coagulation, i.e., production of fibrin• Fibrinolysis–Endothelial activation, –Leukocyte recruitment

EICOSANOIDS(ARACHIDONIC ACID DERIVATIVES)

• Part of cell membranes• ProstaglandinsProstaglandins (incl.

Thromboxanes)• LeukotrienesLeukotrienes• LipoxinsLipoxins (new)

MULTIPLE ACTIONS AT MANY LEVELS

Prostaglandins

•Pain• Fever•Clotting

Leukotrienes

•Chemotaxis•Vasoconstriction• Increased Permeability

Lipoxins

• INHIBIT chemotaxis• Vasodilatation• Counteract actions of

leukotrienes

AA Metabolites

Platelet-Activating Factor(PAF)

• Phospholipid• From MANY cells, like eicosanoids• ACTIVATE PLATELETS, powerfully–Vasodilation, – Increased vascular permeability, – Leukocyte adhesion, – Chemotaxis, –Degranulation, –Oxidative burst

CYTOKINES/CHEMOKINES• CYTOKINES are PROTEINS produced by :– MANY cells, – But usually LYMPHOCYTES & MACROPHAGES,

• Numerous roles in acute and chronic inflammation

–Major cytokines: TNFα, IL-1

Major effects of tumor necrosis factor (TNF) and interleukin 1 (IL-1) in inflammation

Also; attractants for PMNs

NITRIC OXIDE• Produced from the action of

nitric oxide synthetase from arginine–Potent vasodilator–Vascular smooth muscle

relaxation; –killing of microbes

LYSOSOMAL CONSTITUENTS• PRIMARY• Also called

AZUROPHILIC, or NON-specific

• Myeloperoxidase• Lysozyme (Bact.)• Acid Hydrolases

• SECONDARY• Also called SPECIFIC

• Lactoferrin• Lysozyme• Alkaline Phosphatase• Collagenase

FREE RADICALS• O2–• (SUPEROXIDE)

• H2O2(PEROXIDE)

• OH- (HYDROXYL RADICAL)

–Phagocytosis:

–H2O2 +MPO+ Cl • = HOCl• (hypochlorous radical)

NEUROPEPTIDES• Produced in CNS (neurons)• SUBSTANCE P• NEUROKININ A–As vasoactive amines initiate

inflammatory responses; –Regulate vessel tone, and modulate

vascular permeability