Prostaglandins Flashcards
2013.02.13 prostaglandins • See Slide 11 • See Slide 14 • See Slide 21 • See Slide 44
2013.02.13 prostaglandins • See Slide 11 • See Slide 14 • See Slide 21 • See Slide 44
What are the precursors to Prostaglandins, Leukotrieines, and Thromboxanes?
• unsaturated membrane fatty acids, the 20-carbon eicosaenoic acids aka eicosanoids.
What cells produce eicosanoids?
- Virtually all cells and tissues produce eicosanoids
* the specific types produced vary widely from cell-type to cell-type.
Explain the general cycle of synthesis, release, localization, and degradation of eicosanoids.
- synthesized and released in response to inflammatory, mechanical, neurological, or hormonal stimuli.
- Rapidly degraded by dehydrogenase enzymes, most effectively in the lung.
- Eicosanoids have very short half-lives and thus, eicosanoids are “local” autocrine or paracrine hormones.
NOMENCLATURE & MECHANISM OF ACTION OF EICOSANOIDS
• Letters designate ring structure;
• Numbers denote # of double bonds–important for receptor binding and function;
• Receptors, usually G-protein coupled, are specific for each different eicosanoid;
e.g. DP1 and DP2 are receptors for Prostaglandin D.
EP1, EP2, EP3 and EP4 are four distinct receptors for E prostaglandins.
NOMENCLATURE & MECHANISM OF ACTION OF EICOSANOIDS
• Letters designate ring structure;
• Numbers denote # of double bonds–important for receptor binding and function;
• Receptors, usually G-protein coupled, are specific for each different eicosanoid;
e.g. DP1 and DP2 are receptors for Prostaglandin D.
EP1, EP2, EP3 and EP4 are four distinct receptors for E prostaglandins.
What is the precursors to eicosanoids? What is the primary precursor?
- arachidonic (eicosatetraenoic) acid.
- fatty acids cleaved from membrane phospholipids following activation of phospholipases (e.g. PLA2) are rapidly converted to eicosanoids.
What causes the release of eicosanoids?
- Inflammatory, mechanical, neurological, or hormonal stimuli activate the phospholipase A2 family to release membrane fatty acids (eicosaenoic acids).
- Also…
- —injury (exposed collagen; thrombin; damaged cells)
- —heat (thermal injury)
- —hormones (angiotensin; vasopressin, cytokines …)
- —Ag-Ab complexes, activated complement
- —bacteria, LPS (endotoxin)
What is Cyclooxygenase?
What is Prostaglandin H Synthase I and II?
What eicosanoids are formed by these enzymes?
- Prostaglandins and thromboxanes (prostanoids) are formed via the cyclooxygenase (COX) pathways
- prostaglandin H synthase I (PGHS-1 = COX-1) and PGHS-2 (COX-2).
What eicosanoid is formed via…
5-lipoxygenase?
5-, 12-, 15- lipoxygenase?
- Leukotrienes are produced via the enzyme 5-lipoxygenase.
* Lipoxins are products of 5-, 12-, and 15-lipoxygenases.
Explain the inflammatory pathway with regard to eicosanoid production.
• IL-1, TNF, LPS ==> COX-2 ==> phospholipase A2 (PLA2) ==> eicosanoid production at sites of inflammation.
How do eicosanoids affect pain sensation?
• Eicosanoids are hyperalgesic–do not produce pain directly but increase tissue sensitivity to other stimuli. E-prostaglandins induce hyperalgesia via EP4.
How do eicasanoids affect edema?
• Eicosanoids enhance edema caused by bradykinin, histamine and the C5a anaphylatoxin.
How do eicosanoids affect chemotaxis? Which one is noted?
• Eicosanoids contribute to leukocyte activation and chemotaxis. e.g. LTB4 is chemotactic for both T cells and PMNs.
What is the effect of PGE2 (E-prostaglandin) on inflammation?
• PGE2 induces all cardinal signs of inflammation when injected into an animal or person (rubor, calor, dolor, tumor)
Which eicosanoids are part of asthma?
• Cysteinyl leukotrienes (cysLTs; LTC4, D4, E4) induce many of the abnormalities seen in both acute and chronic asthma.
What effects do cysteinyl leukotrienes have on asthma?
- -Induce smooth muscle contraction and protracted bronchoconstriction;
- -Promote of microvascular permeability, bronchovascular leakage & mucous secretion;
- -Promote leukocyte infiltration and production of pro-inflammatory cytokines.
What inhibits eicosanoid production? (long list)
- anti-inflammatory NSAIDs, coxibs (COX-2 inhibitors) and glucocorticoids.
- 5-lipoxygenase inhibitors and leukotriene receptor antagonists (anti-asthma drugs).
- Lipoxins, resolvins & protectins counter the inflammatory effects of leukotrienes.
How do glucocorticoids affect eicosaniods?
- induce synthesis of annexin-1 which blocks cPLA2
- inhibit synthesis of COX-2 (but not COX-1)
- induce MAPK phosphatase 1
- inhibiting production of inflammatory cytokines that stimulate PG production.
- Thus, GCs can inhibit production of prostaglandins, thromboxanes and leukotrienes.
How do NSAIDs affect eicosanoids?
- block cyclooxygenases 1 and 2 (COX-1 and COX-2);
* But do not inhibit and may lead to enhanced leukotriene production.
How do 5-lipoxygenase inhibitors affect eicosanoids?
• block production of leukotrienes.
