Prostaglandins and platelet activation

Induction of synthesis of various lipid-based inflammatory mediators, including some prostaglandins and platelet-activating factor, by macrophages and other cells. Many of these promote sustained vasodilation and increased vascular leakage. 

Mast cell degranulation in response to allergens results in release of mediators such as histamine eosinophil, and neutrophil chemotactic factors leukotrienes C4, D4, and E4 prostaglandins and platelet-activating factor (PAF). Histamine is capable of inducing smooth muscle constriction and bronchospasm and may play a role in mucosal edema and mucus secretion. 

In addition to their effects on leukocyte function, glucocorticoids influence the inflammatory response by reducing the prostaglandin, leukotriene, and platelet-activating factor synthesis that results from activation of phospholipase - Finally, glucocorticoids reduce expression... 

Davi, G., G. Ciabattoni, A. Consoli, A. Mezzetti, A. Falco, S. Santarone, E. Pennese, E. Vita-colonna, T. Bucciarelli, F. Costantini, F. Capani, and C. Patrono. 1999. In vivo formation of 8-iso-prostaglandin f2alpha and platelet activation in diabetes mellitus effects of improved metabolic control and vitamin E supplementation. Circulation 99 224-229. 

Glucocorticoids inhibit pathways that normally lead to production of prostaglandins, leukotrienes and platelet activating factor. These mediators would normally contribute to increased vascular permeability and subsequent changes including oedema, leucocyte migration, fibrin deposition. 

Concerning mediators of immediate hypersensitivity, the most important include histamine, leukotriene e.g., SRS-A (slow-reacting substance of anaphylaxis, ECF-A (eosinophil chemotactic factor of anaphylaxis), PAF (platelet-activating factor), and serotonin. There are also three classes of lipid mediators that are synthesized by activated mast cells through reactions initiated by the actions of phospholipase A2. These are prostaglandins, leukotrienes, and platelet-activating factors (PAF). 

Besides histamine release, mast cell degranulation releases interleukins, proteases, and other enzymes that activate the production of other mediators of inflammation. Several classes of important mediators, including arachidonic acid and its metaholites (i.e., prostaglandins, leukotrienes, and platelet-activating factor), are derived from cell membrane phospholipids. 

Immunosuppressive agents, alone or in combination, are commonly used to alter the immune processes that are responsible for the glomerulonephritides. Corticosteroids, in addition to their immunosuppressive effecL also possess anti-inflammatory activities. They reduce the production and/or release of many substances that mediate the inflammatory process, such as prostaglandins, leukotrienes, platelet-activating factors, tumor necrosis factors (TNFs), and interleukin-1 (IL-1). Movement of leukocytes and macrophages to the site of inflammation is also inhibited. The immunosuppressive effects of corticosteroids are mediated through the inhibition of the release... 

Thrombin is by far the most efficient stimulus in releasing arachidonic acid from platelets and consequently has been the most studied. Collagen is also able to release substantial amounts of arachidonic acid by a mechanism that seems to depend on positive feedback by formed prostaglandin endoperoxides but most other platelet agonists, such as ADP, serotonin and platelet activating factor, are weak inducers of arachidonic acid release. 

The synthetic utihty of the above transformations stems from the fact that many monoesters obtained as a result of hydrolysis may be converted to pharmaceutically important intermediates. For example, the optically active glycerol derivative (27) is a key intermediate in the production of P-blockers. Akyl derivative (25) may be converted into (5)-paraconic acid [4694-66-0] ((5)-5-oxo-3-tetrahydrofurancarboxyhc acid) that is a starting material for the synthesis of (3R)-A-factor. The unsaturated chiral cycHc monoacetate (31) is an optically active synthon for prostaglandins, and the monoester (29) is used for the synthesis of platelet activating factor (PAF) antagonists. 

Few areas of organic medicinal chemistry in recent memory have had so many closely spaced pulses of intense research activity as the prostaglandins. Following closely on the heels of the discovery of the classical monocyclic prostaglandins (prostaglandin El, F2, A2, etc.), with their powerful associated activities, for example, oxytocic, blood pressure regulating, and inflammatory, was the discovery of the bicyclic analogues (the thromboxanes, prostacyclin) with their profound effects on hemodynamics and platelet function. More recently, the non-... 

Histamine Serotonin Platelet-activating factor (PAF) Eicosanoids (various prostaglandins and leukotrienes) C3a, C4a, and C5a from the complement system Bradykinin and fibrin split products from the coagulation system... 

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