Anti-inflammatory action of arachidonoyl lysophosphatidylcholine or 15-hydroperoxy derivative in zymosan A-induced peritonitis

Arachidonic acid, released from PLA(2) hydrolysis of phosphatidylcholine, is converted to pro-inflammatory or anti-inflammatory mediators. Although lysophosphatidylcholine (lysoPC), another product, is known to be pro-inflammatory, the role of polyunsaturated lysoPCs is not clear. Here, we examined the role of arachidonoyl-lysoPC and its lipoxygenation product in inflammation. First, when the effect of arachidonoyl-lysoPC, administrated i.v., on zymosan A-induced plasma leakage in mice was examined, arachidonoyl-lysoPC was found to prevent zymosan A-induced plasma leakage remarkably. As the interval time between lysoPC administration and zymosan A challenge was extended, the suppression of plasma leakage was augmented, suggesting that a metabolism of arachidonoyl-lysoPC may be implicated in anti-inflammatory action. Additionally, 4-methyl-2-(4-methylpiperazinyl)pyrimido[4,5-b] benzothiazine, an inhibitor of 15-lipoxygenase, was found to diminish the suppressive action of arachidonyl-lysoPC, indicating that 15-HPETE-lysoPC may be a metabolite responsible for anti-inflammatory action of arachidonoyl-lysoPC. In support of this, 15-HPETE-lysoPC (ED50, 32 mu g/kg) exhibited a greater anti-inflammatory action than arachidonoyl-lysoPC. Further, mechanistic analysis indicates that anti-inflammatory action of 15-HPETE-lysoPC was related largely to the formation of lipoxin, and to less extent to the inhibition of LTC biosynthesis, but not to PGE formation. Further, i.p. administration of arachidonoyl-lysoPC or 15-HPETE-lysoPC also exhibited a dose-dependent effect, although less efficient than i.v. injection. Additionally, the time-dependent suppression was more remarkable for 15-HPETE-lysoPC than arachidonoyl-lysoPC, suggestive of different mechanisms for anti-inflammatory action in peritoneum. Taken together, it is proposed that arachidonoyl-lysoPC and its oxidation product may belong to endogenous lipids displaying anti-inflammatory effects in vivo. (C) 2009 Elsevier Inc. All rights reserved.