EICOSANOIDS (prostaglandins, thromboxanes, leukotrienes) - PowerPoint PPT Presentation

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EICOSANOIDS (prostaglandins, thromboxanes, leukotrienes)

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EICOSANOIDS (prostaglandins, thromboxanes, leukotrienes) Eicosanoids Eicosaniods Derived from 20-crabon polyunsaturated fatty acids Paracrine or autocrine messengers ... – PowerPoint PPT presentation

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Title: EICOSANOIDS (prostaglandins, thromboxanes, leukotrienes)


1
EICOSANOIDS(prostaglandins, thromboxanes,
leukotrienes)
2
Eicosanoids
  • Major classes of eicosanoids.
  • Precursors of eicosanoids.
  • Major pathways of eicosanoid synthesis
    (cyclooxygenase and lipoxygenase).
  • Important functions of eicosanoids.
  • Important inhibitors of eicosanoid synthesis

3
Eicosaniods
  • Derived from 20-crabon polyunsaturated fatty
    acids
  • Paracrine or autocrine messengers molecules
  • Short half-lives (10 secs 5 mins) so that
    functions are usually limited to actions on
    nearby cells.
  • Bind to specific cell surface G-protein coupled
    receptors, and generally increase cAMP levels.
    May also bind to nuclear receptors and alter gene
    transcription.
  • Wide variety of functions

4
Major Classes of Eicosanoids
  • Prostaglandins
  • Thromboxanes
  • Prostacyclins
  • Leukotrienes
  • HETES

5
Effects of Eicosaniods
  • Induction of inflammation
  • Mediation of pain signals
  • Induction of fever
  • Smooth muscle contraction (including uterus)
  • Smooth muscle relaxation
  • Protection of stomach lining
  • Simulation of platelet aggregation
  • Inhibition of platelet aggregation
  • Sodium and water retention

6
Precursors of Eicosanoids
  • Arachidonic acid (?6)
  • Eicosatrienoic acid (g-linolenic acid, ?6)
  • Eicosapentaenoic Acid (?3)

7
  • Dietary Linoleic Acid (C18 ?9,12) (from plant
    oils)

8
Arachidonic acid release from membrane lipids
Phosphatidyl choline
Phosphatidylinositol bisphosphate
9
Pathways for Arachidonic Acid Metabolism
  • Arachidonic acid

10
Prostaglandins Structural Features
  • PGA, PGD, PGE, PGF, PGG, PGH, PGI
  • Depending on the functional groups present at X
    and Y
  • PGF 1, 2 or 3
  • Depending on the number of double bonds present
    in the linear hydrocarbon chain

11
PGF 1, 2 or 3
12
Thromboxane A2 (TXA2) - structure
13
CYCLO-OXYGENASE PATHWAY PG and TX synthesis
2GSH
2GSSG
14
Some Functions of Prostaglandins
  • PGI2, PGE2, PGD2
  • ? Vasodilation, cAMP
  • ? Platelet and leukocyte aggregation, IL1 and
    IL2, T-cell proliferation, lymphocyte migration
  • PGF2a
  • ? Vasoconstriction, Bronchoconstriction, smooth
    muscle contraction
  • TXA2
  • ? Vasoconstriction, Platelet aggregation,
    lymphocyte proliferation, bronchoconstriction

15
Lipoxygenase pathway
16
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17
Some Functions of Leukotrienes
  • LTB4
  • ? Vascular permeability, T-cell proliferation,
    leukocyte aggregation, IL -1, IL-2, IFN-g
  • LTC4 and LTD4
  • ? Bronchoconstriction, Vascular permeability,
    IFN-g

18
Leukotrienes and allergies
  • Leukotrienes are a hundred times more potent than
    histamine
  • Histamine provided a rapid response to an
    allergen
  • In the later stages leukotrienes are principally
    responsible for
  • inflammation, smooth muscle constriction,
    constriction of the airways and mucous secretion
    form mucosal epithelium

19
Anti inflammatory Drugs inhibit Eicosanoid
Synthesis
20
Mechanism of Aspirin Action
21
  • COX-1 is constitutively expressed in nearly all
    tissues responsible for normal physiological
    functions
  • Little or no COX-2 is present in normal resting
    cells. COX-2 is induced by inflammatory stimuli
    (cytokines, bacterial lipopolysaccharides).
  • 20 of patients on long term NSAID treatment
    develop gastric ulcers
  • It was postulated that inhibitors selective for
    COX-2 should relieve pain and inflammation
    without gastric complications

22
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23
Aspirin and cardiovascular disease
  • Low dose aspirin has an anti -thromobogenic
    effect and lowers the risk of heart attacks and
    strokes.
  • It inhibits the formation of TXA2 in platelets,
    by inhibition of COX-1 which cannot be overcome
    because platelets have no nucleus.
  • Endothelial cells have a nucleus and synthesis
    more COX-1 enzyme needed for the normal
    prostaglandin functions

24
Omega-6/omega-3 fatty acid balance
  • w6 and w3 are not interconvertible in humans
    (mammals).
  • Diets rich in w3 fatty acids result in high
    content of these fatty acids in membrane
    phospholipids
  • Recommended ratio 1-4 1 (w6 w3)
  • Typical western diet 14-25 1 (w6 w3)

25
Omega-6/omega-3 fatty acid balance
A diet rich in omega-6 FAs shifts the
physiological state to one that is
proinflammatory, prothrombotic and proaggregatory
leading to heart disease in susceptible
individuals
26
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27
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