Eicosanoids Flashcards
What are the Eicosanoids?
Oxidation products of 20-carbon FA’s…..
predominantly of arachidonic acid.
Classical eicosanoids - prostanoids and leukotrienes (LT).
Non-classical include:
Endocannabinoids and Lipoxins, resolvins, isoprostanes.
What are the Prostanoids?
Prostaglandins (PG), Prostacyclins (PGI) and Thromboxanes (TX)…
How are leukotrienes synthesised?
Classical eicosanoids.
Arachidonic acid is converted to 5-HPETE by 5-Lipoxygenase.
5-HPETE forms LTA4 - the precursor to LTB4 or LTC4, LTD4 and LTE4….
LTC4, LTD4 and LTE4 are cysteinyl LTs which act via cysLT receptors.
LTB4 = chemotactic + neutrophil-depedent vascular permeability = via BLt1 receptor.
What are the actions of Leukotrienes?
Bronchoconstriction = LTC4 and LTD4
Oedema = LTC4 and LTD4 + LTB4
Chemotaxis = LTB4
Inflammation.
How are Leukotrienes related to bronchoconstriction and oedema?
LTC4 and LTD4 are very potent human bronchial SM contractor agonists
(1000 times more potent than histamine).
LTC4 and LTD4 stimulate vascular permeability INDEPENDENTLY to neutrophils.
LTB4 is released by neutrophils = neutrophil dependent vascular permeability
How are LTs related to Chemotaxis?
LTB4 = neutrophil-dependent vascular permeability.
And a potent chemotactic agent for recruiting inflammatory cells by acting on BLT1 receptors….
How are LTs implicated in RA?
LTs are present at high levels in synovial fluid of RA patients…
What are the various anti-LT therapies?
Zileuton - Inhibits 5-lipoxygenase.
Stops the conversion of arachidonic acid to 5-HPETE.
= Stops the formation of ALL LEUKOTRIENES….
Glucocorticoids inhibits PLA2 to reduce arachidonic acid synthesis from membrane phospholipids…
= Indirect inhibition.
Interestingly, no evidence to suggest statins decrease leukotriene synthesis.
Zafirlukast and Montelukaast block LTC4/LTD4 via cysLT receptor?
How are prostaglandins synthesised?
Under basal conditions the rate of synthesis of PGs is low, until inflammation.
Cyclo-oxygenase form PGH2 from arachidonic acid.
Tissue-specific isomerases then convert PGH2 to TxA2, or PGE2, PGI2 etc.
What are the various Prostanoid receptors?
TxA2 acts on TP receptors.
PGI2 acts on IP receptors.
PGE2 acts on EP1 - EP4 receptors
= all GPCRs..
What prostanoids initiate labour?
What prostanoids decrease Gastric acid production + enhance production of mucus?
PGF2a and PGE2 initiate labour!
PGE2.
What are the physiological functions of PGs?
Initiate labour - PGF2a and PGE2.
Inhibit gastric acid secretion + increase gastric mucus production = PGE2.
Inhibit platelet aggregation and cause vasodilation = PGI2 - Gs coupled = PKA…
Platelet aggregation and vasoconstriction = TXA2…
(dense granules release = Gq coupled)
The perception of pain!!!
What PGs are involved in vascular SM tone and platelets?
TxA2 acts on Gq coupled TP receptors to induce platelet aggregation and vasoconstriction.
PGI2 acts on Gs coupled IP receptors to induce vasodilation and inhibit aggregation of platelets
What are the pro-inflammatory actions of prostaglandins?
EP2 receptor has both pro and anti-inflammatory actions.
EP2 in vascular SM = Gs coupled = vasodilation.
= pro
EP2 in leukocytes = Gs coupled = inhibits function.
= anti
Via the same Gs-coupled EP2 receptor!!
How are PGs related to pain perception?
EP1 receptors are expressed on c fibre sensory nerves.
Ep1 receptor KO mice have reduce perception of pain!!!
Von frey pain perception test.
What is the role of the EP3 Receptor?
EP3 receptors are Gi linked = inhibit AC, reduce cAMP.
EP3 receptors are expressed on leukocytes and Mast cells.
- enhance function of leukocytes and Mast cells.
EP3 also enhances oedema formation.
EP3 involved in fever…
How are PGs related to fever?
Elevated hypothalamic thermostat - elevated metabolism + heat production to kill infection.
Prolonged/severe fever can be dangerous.
Hypothalamus regulates and produces PGE2.
EP3 particularly involved, Gi coupled.
Cereboventricular injections of PGE2 lead to fever.
What are the isoforms of Cyclo-oxygenase?
COX-1 is constitutively active - Housekeeping enzyme.
COX-1 converts Arachidonic acid to PGH2 - to form prostanoids.
COX-1 in normal function of GI tract + platelets.
COX-2 is induced - especially during inflammation.
COX-3 relevance in humans is contested.
How is COX-1 involved in housekeeping activity?
COX-1 is contstitutively active and involved in numerous homeostatic functions.
Gi tract, renal tract, platelet function + macrophage differentiation.
How can COX-2 be induced?
IL-1 and TNF, as well as Growth Factors, can +ve effect on COX-2.
Glucocorticoids have -ve effect on COX-2….
(depletion of arachidonic acid?
How does aspirin inhibit COX?
COX forms a hterodimer for catalytic activity.
Ser529 residues in catalytic site are irreversible acetylated by aspirin.
= obstruction of access of arachidonic acid.
= COX cannot synthesise PGH2.
= new enzyme needs to be synthesised..
Salicylate remains - which itself may have additional actions.
How does ibuprofen work?
A competitive inhibitor for arachidonate binding to COX.
What is COX-2 specificity?
Inhibiting COX-2 - not COX-1 - across the entire therapeutic dose range!
Diclofenac and Celecoxib.
What are the mixed NSAIDS?
Ibuprofen, aspirin and Naproxen
= Ibuprofen can competitively inhibit both COX-1 and COX-2
