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65 Cards in this Set
- Front
- Back
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What are eicosanoids?
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The signaling molecules synthesized from 20-carbon polyunsaturated fatty acids (PUFAs, eicosanoic acids)
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What are the members of the eicosanoid family?
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1. Prostaglandins
2. Prostacyclins 3. Thromboxanes 4. Leukotrienes |
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What are the precursors of the eisonanoids?
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1. Dihomogammalinolenic acid
2. Arachidonic acid 3. Eicosapentaenoic acid |
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What catalyzes the first step in forming eicosanoids?
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Phospholipase A2 (PLA2)
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What is released as a biproduct of the reaction catalyzed by phospholipase A2 (PLA2)?
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Fatty acids esterified to the sn2 position of the membrane phospholipid.
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What generates fatty acids for eicosanoid synthesis?
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Non-pancreatic secretory PLA2s
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What is the regulated enzyme in eicosanoid synthesis?
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cytosolic phospholipase A2
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What does cytosolic PLA2 release as a biproduct?
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arachidonic acid (AA) from membrane phospholipids
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What physiologic stimuli activates cytosolic PLA2?
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1. adrenalin (epinephrine)
2. Bardykinin, ANG II 3. Vasopressin (aldosterone) 4. certain Ag-Ab complexes |
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What non-physiologic stimuli activates cytosolic PLA2?
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1. mechanical tissue damage
2. ischemia 3. venoms 4. Tumor promoters such as the phorbol esters |
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What are the products of membrane phospholipid catabolism by PLA2?
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Lysophosphatidate and Arachidonate
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What do the eicosanoid cascades ("arachidonate cascades") begin w/?
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Eicosanoic acid
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What does the cyclic or cycloxygenase pathway synthesize in the eicosanoid cascade?
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1. prostaglandins
2. prostacyclins 3. thromboxanes |
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What does the linear/lipoxygenase pathway synthesize?
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1. leukotrienes
2. hydroxyeicosanoates |
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What catalyzes the first step in the lipoxygenation pathway?
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5-lipoxygenase
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What catalyzes the first step in the cyclooxygenation pathway?
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Prostaglandin endoperoxide H synthase (PGHS)
aka "cyclooxygenase or COX" |
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What are the products of the cycloxygenase pathway chemically related to?
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Prostanoic acid
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What are the catalytic activities of PGHS/COX?
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two catalytic activities:
1. Arachidonic acid -> prostaglandin G2 *catalyzed by cyclooxygenase w/ O2* 2. Prostaglandin G2 -> Prostaglandin H2 *catalyzed by peroxidase w/ glutathione* |
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What are the three beginning eicosanoic acids?
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1. GLA (dihomogammalinolenic acid)
2. Arachidonic acid (AA) 3. Eicosapentaenoic acid (EPA) |
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What does GLA preferentially become? what catalyzes the rxn?
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Becomes prostaglandin F1-alpha, catalyzed by PGH1
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What does AA preferentially become? what catalyzes the rxn?
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prostaglanding F2-alpha, catalyzed by PGH2
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What does EPA preferentially become? what catalyzes the rxn?
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Prostaglanding F3-alpha, catalyzed by PGH3
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What does the lipoxygenase br of the eicosanoid casacde lead to?
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1. HPETE (hydroperoxyeicosatetraenoic acid)
2. HETE (hydroxyeicosatetraenoic acid) 3. leukotrienes |
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What are the members of the leukotriene family?
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1. LTB4 - a dihydroxyacid
2. LTC4, LDT4 & LTE4 - the cysteinyl-leukotrienes |
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What is the function of the leukotrienes?
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mediators of the allergic response and of inflammation.
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What is the action of eicosanoids?
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They are regulatory molecules:
1. Autocrine - action in or on the cells that synthesize them 2. Paracrine - action on nearby cells |
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What affect do eicosanoids have on platelets?
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They activate platelets and participate in plug formation
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What do platelets bind to at the site of endothelial injury?
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Collagen
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What does binding of platelets expose?
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Thrombin receptors (proteinase activated receptors, PAR)
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How does thrombin activate platelets?
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Receptor-bound thrombin activates platelets by cleaving a short polypeptide from the receptor extracellular segment.
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What happens to platelets when they are activated?
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1. they change their shape
2. release a battery of substances 3. become sticky (goopy!) 4. form a platelet plug. (*splork*) |
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What follows PAR1 activation?
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A rapid burst of signaling before the resceptor is desensitized/cleared from the surface. (BOOM!)
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How is PAR-1 activated, chemically?
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PAR-1 is cleaved by thrombin on a strand that hangs outside of the membrane. Thrombin cleaves PAR1 b/e arginine 41 and serine 42 to expose a new N-terminus that serves as a tethered ligand.
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What substances do activated platelets secrete that activate additional platelets?
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1. ADP
2. Thromboxane A2 (TXA2) |
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What do activated platelets release?
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1. factors that activate other platelets
2. clotting factors leading to thrombus (clot) formation |
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What inhibits platelet aggregation?
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Prostacyclin I2 (PGI2) which is secreted by endothelial cells.
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What helps modulate the rate of thrombus formation?
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The opposing actions of TXA2 and PGI2
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What does aspirin (acetylsalicylate) do in the blood?
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Inhibits the cyclooxygenase (COX) activity of prostaglandin synthase, this accounts for the antithrombotic activity of aspirin.
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Why do populations that consume fish oil rich in N-3 highly unsaturated fatty acids (omega 3 HUFAs) have fewer strokes and heart attacks?
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1. EPA is converted to PGH more slowly than arachidonate
2. TXA3 is produced when EPA is the starting substrate 3. TXA3 is less effective than TXA2 as a platelet activator 4. This slows the formation of the platelet plug. |
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What is the difference b/e arachinoic acid (AA) and eicosapentaenoic acid (EPA)?
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AA has a faster conversion to TXA2, TXA2 is more effective at activating platelets than TXA3.
EPA has a slower conversion to TXA3, which is less effective at activating platelets that TXA2. |
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What are the classical markers of inflammation? and what causes them?
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1. Rubor: Redness. Due to vasodilation w/ inc. Q
2. Calor: heat: due to inc. vasodilation w/ inc. Q 3. Tumor: swelling. Due to edema, a consequence of increased vascular permeability 4. Dolor: Pain. Due to stimulation of nerve endings by chemical mediators of inflammation. |
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What drug inhibits PLA2?
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Adrenal corticosteroids such as cortisol
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What drug inhibits 5-lipoxygenase?
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Zyflo
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What drug inhibits prostaglanding synthase?
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Ibuprofen
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What drugs decrease the production of all products of the eicosanoid pathways?
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Adrenal corticosteroids (cortisol and prednisone)
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What drugs inhibit the COX portion of PGH2 synthase?
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NSAIDS like ibuprofen (Flurbiprofen which is a competitive inhibitor of COX)
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What is the difference b/e COX1 and COX2?
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They are isoenzymes, COX1 is constitutively expressed and COX2 is induced by inflammatory stimuli and cytokines
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What inhibits both COX1 and COX2 isoenzymes?
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NSAIDS (ibuprofen, motrin, advil and nuprin)
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What drugs selectively inhibit COX2?
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Celecoxib celebrex and refecoxib Vioxx
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What inhibits both COX1 and COX2 by inhibiting synthesis of prostaglandins and related substances when arachidonate and peroxides are low but not when they are present at substantial levels?
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Acetaminophen (Tylenol)
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What drug destroys the cyclooxygnation activity of both COX1 and COX2 by covalently inhibiting COX?
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Aspirin (acetylsalicylate)
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What does acetylated COX2 do?
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It is still an active enzyme and is able to convert arachidonate to 15-R-hydroxyeicosatetraenoic acid (15 RHETE)
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What is 15-RHETE? what does it do?
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An aspirin triggered lipoxin (ATL); ATL and other trihydroxlipoxins promote resolution of inflammation
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What drug promotes resolution of inflammation by stimulating production of 15-RHETE?
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Aspirin
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What does Zileuton (Zyflo) do?
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Inhibits 5-lipoxygenase, the first enzyme in the pathway leading to leukotrienes.
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What causes bronchospasm as a side-effect in the eicosanoid cascade?
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Leukotriene
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What dz is Zileuton used to treat?
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Asthma/bronchospasm as a consequence of leukotriene activation.
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What does Monteleucast (Singulair) do?
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Blocks cysteinyl-leukotriene receptors, used to treat asthma.
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What are the cysteinyl leukotrienes?
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LTC4, LTD4
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What is the function of the cysteinyl leukotrienes, LTC4 and LTD4?
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Cause vasoconstriction, bronchospasm and inc. vascular permeability.
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What eicosanoids have antiinflammatory properties?
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Arachidonic acid
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How does arachidonic acid act as a antiinflammatory?
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AA is converted to 15lipoxygenase and glutathione peroxidase which are converted to 15S-HETE.
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What converts AA to 15-R HETE?
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Aspirin acetylated COX2
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What are 15-R HETEs?
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Substances that travel to leukocytes where they are hydrolyzed to 15-LXA4 and 15-epiLXA4
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What antiinflammatory mediators are derived from AA and omega-3 polyunsaturated fatty acids?
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Resolvins
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