Phospholipase inflammation mediation

Schaefer U, Schneider A, Rixen D, Neugebauer E (1998) Neutrophil adhesion to histamine stimulated cultured endothelial cells is primarily mediated via activation of phospholipase C and nitric oxide synthase isozymes. Inflamm Res 47(6) 256-264 Schaefer U, Schmitz V, Schneider A, Neugebauer E (1999) Histamine induced homologous and heterologous regulation of histamine receptor subtype mRNA expression in cultured endothelial ceUs. Shock 12(4) 309-315... 

Figure 8.9 Prostaglandins and leukotrienes are potent eicosanoid lipid mediators, derived from phospholipase-released arachidonic acids, that are involved in numerous homeostatic biological functions and inflammation. They are generated by cyclooxygenase isozymes and 5-lipoxygenase, respectively, and their biosynthesis and pharmacological actions are inhibited by clinically relevant nonsteroidal anti-inflammatory drugs.

Sponge-derived sesterterpenoids are potent anti-inflammatory metabolites which inhibit phospholipase A2 (Sipkema et ah, 2005a). In arachi-donic acid pathway of inflammatory response (Fig. 8.3), phospholipase A2 catalyzes the release of membrane-bound phospholipids to produce inflammatory mediators once stimulated by tissue injury. Manoalide (Fig. 8.4) is a best known sponge-derived anti-inflammatory sesterterpe-noid. Dysidotronic acid (Fig. 8.5), non-complex manoalide analogue, has been identified as an anti-inflammatory metabolite of the sponge Dysidea sp. The mechanism by which dysidotronic acid inhibit inflammation is much more selective and potent than manoalide. This sesquiterpenoid... 

Phospholipases are crucial enzymes in the arachidonic acid pathway and appear to be primarily responsible for the esterolytic action that releases arachidonic acid from phospholipids (209). Once released, this acid is converted into several mediators of inflammation. The PLA2 s are small (MW 14,000) stable proteins that require Ca2 + ions for the specific hydrolysis of the 2-acyl group of 3-sn-phospholipids. 

Arachidonic acid (20 4n - 6) is one of two major PUFA synthesized by the D6D/D5D pathway (Fig. 4). In many tissues and cell types, 20 4n - 6 is esterified to the sn-2 position of membrane PL, and is used for the eicosanoid-mediated signaling to perform specialized cell functions. Arachidonic acid esterified in PL is a storage form of this fatty acid and is hydrolyzed from the PL by phospholipases prior to enzymatic conversion into eicosanoids (Chapter 13). Eicosanoids are autocrine/paracrine hormones that mediate a variety of localized reactions, such as inflammation, homeostasis, and protection of digestive tract epithelium. D6D deficiency in humans leads to severe food intolerance and growth retardation (J. Nwankwo, 2003). These symptoms are reversed by arachidonic acid supplementation to the diet, which supports the essential role of eicosanoids in the protection of digestive tract mucosa in humans. 

Alclometasone is a topical glucocorticoid with antiinflammatory, antipruritic, and vasoconstrictive properties. It acts by inducing phospholipase A2 inhibitory proteins, thus controlling biosynthesis of potent mediators of inflammation. Alclometasone (0.05% ointment) is a topical adrenocorticoid with antiinflammatory properties that is indicated in inflammation of corticosteroid-responsive dermatoses. 

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