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basic chemical mediator

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basic chemical mediator

  1. 1. 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
  2. 2. CLASSIC MEDIATORS &THEIR SOURCES
  3. 3. 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
  4. 4. HISTAMINE • Mast Cells, basophils • POWERFUL Vasodilator • Vasoactive “amine”
  5. 5. SEROTONIN • (5HT, 5-Hydroxy-Tryptamine) • Platelets and Entero Chromaffin Cells • Also vasodilatation, but more indirect • Evokes N.O. synthetase (a ligase) from argenine
  6. 6. COMPLEMENT SYSTEM • >20 components, in circulating plasma • Multiple sites of action: –Leukocyte chemotaxis and activation, –Opsonization, –Vasodilation (mast cell stimulation) –Membrane Attack Complex (MAC)
  7. 7. Complement System
  8. 8. KININ SYSTEM • BRADYKININ is KEY component, 9 aa’s • ALSO from circulating plasma • ACTIONS –Increased permeability –Smooth muscle contraction, NON vascular – PainPain
  9. 9. CLOTTING FACTORS • From circulating plasma • Coagulation, i.e., production of fibrin • Fibrinolysis –Endothelial activation, –Leukocyte recruitment
  10. 10. EICOSANOIDS (ARACHIDONIC ACID DERIVATIVES) • Part of cell membranes • ProstaglandinsProstaglandins (incl. Thromboxanes) • LeukotrienesLeukotrienes • LipoxinsLipoxins (new) MULTIPLE ACTIONS AT MANY LEVELS
  11. 11. Prostaglandins •Pain •Fever •Clotting
  12. 12. Leukotrienes •Chemotaxis •Vasoconstriction •Increased Permeability
  13. 13. Lipoxins • INHIBIT chemotaxis • Vasodilatation • Counteract actions of leukotrienes
  14. 14. AA Metabolites
  15. 15. Platelet-Activating Factor (PAF) • Phospholipid • From MANY cells, like eicosanoids • ACTIVATE PLATELETS, powerfully – Vasodilation, – Increased vascular permeability, – Leukocyte adhesion, – Chemotaxis, – Degranulation, – Oxidative burst
  16. 16. 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
  17. 17. Major effects of tumor necrosis factor (TNF) and interleukin 1 (IL-1) in inflammation Also; attractants for PMNs
  18. 18. NITRIC OXIDE • Produced from the action of nitric oxide synthetase from arginine –Potent vasodilator –Vascular smooth muscle relaxation; –killing of microbes
  19. 19. LYSOSOMAL CONSTITUENTS • PRIMARY • Also called AZUROPHILIC, or NON-specific • Myeloperoxidase • Lysozyme (Bact.) • Acid Hydrolases • SECONDARY • Also called SPECIFIC • Lactoferrin • Lysozyme • Alkaline Phosphatase • Collagenase
  20. 20. FREE RADICALS • O2–• (SUPEROXIDE) • H2O2(PEROXIDE) • OH- (HYDROXYLRADICAL) –Phagocytosis: –H2O2 +MPO+ Cl• = HOCl• (hypochlorous radical)
  21. 21. NEUROPEPTIDES • Produced in CNS (neurons) • SUBSTANCE P • NEUROKININ A –As vasoactive amines initiate inflammatory responses; –Regulate vessel tone, and modulate vascular permeability

Editor's Notes

  • These are the common features of ALL “chemical mediators” in acute inflammation. This is the shovelling part!
  • How many of the 4 cardinal signs of inflammation can histamine cause, by virtue of its being a powerful vasodilator? 3-4?
  • Serotonin is widely and primarily thought as being a neurotransmitter involved in the full spectrum of emotional responses, but its role in acute inflammation is just as powerful.
  • Complement fixation is the end stage of a cascade of multiple chemical events, similar to coagulation, which ultimately result in lysis of cell membranes, hopefully, membranes of bad cells.
  • Bradykinin is a potent endothelium-dependent vasodilator, causes contraction of non-vascular smooth muscle, increases vascular permeability and also is involved in the mechanism of pain.
  • Coagulation is also a cascade, like complement fixation.
  • Three classic eicosanoids, new classes are also being discovered. ALL are derivatives from arachidonic acid. Eicosanoids can also be directly attributed to causing the 4 cardinal signs of inflammation. http://en.wikipedia.org/wiki/Eicosanoid
    The problem with Eicosanoids is that you NEVER get the BIG picture: Here’s the BIG PICTURE NOW!
  • When you think of the three main things that ASPIRIN does, you can remember the three main properties of the prostaglandins.
  • Click back to the previous slide on LEOKITRIENES and realize that LIPOXINS generally do the OPPOSITE of what LEUKOTRIENES do.
  • It is produced in response to specific stimuli by a variety of cell types, including neutrophils, basophils, platelets, and endothelial cells. From wiki:Platelet-activating factor, also known as a PAF, PAF-acether or AGEPC (acetyl-glyceryl-ether-phosphorylcholine) is a potentphospholipid activator and mediator of many leukocyte functions, including platelet aggregation and degranulation, inflammation, and anaphylaxis. It is also involved in changes to vascular permeability, the oxidative burst, chemotaxis of leukocytes, as well as augmentation of arachidonic acid metabolism in phagocytes.
  • There are gazillions of cytokines/chemokines. The two most classical and famous ones are TNF-alpha and Interleukin-1.
    TNF-alpha, also called tumor necrosis factor, or cachectin, is a substance that is destructive of human tissues, and is a key player in “cachexia”.
    Interleukin-1 was the first of many interleukins discovered and generally propagates the inflammatory response at many levels and also has a significant effect on T-cells.
  • Which drug INCREASES the effect of nitric oxide? Hint: you get spam ads for it 10 times a day in your spam, even if you are a female.
  • MPO produces hypochlorous acid and tyrosyl radical are cytotoxic, so they are used by the neutrophil to kill bacteria and other pathogens. It is what makes pus look greenish yellow.
    Lactoferrin (LF), also known as lactotransferrin (LTF), is a globular multifunctional protein with antimicrobial activity (bacteriocide, fungicide)
    Lysozymes, also known as muramidase or N-acetylmuramide glycanhydrolase, are a family of enzymes (EC 3.2.1.17) which damage bacterial cell walls by causing hydrolysis.
  • Free radical are generated through a variety of enzymatic pathways as one of the main killing mechanisms of microbes. Free radicals themselves are just as toxic to human cells as they are microbes. Ultimately, they all affect the NADPH system.
  • Substance P is an 11 amino acid polypeptide tied into many things including mood disorders, anxiety, stress, reinforcement, respiration rate, neurotoxicity, nausea, emesis, and pain. The Neurokinins are also peptide neurotransmitters involved in many things.
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