Amelioration of TNBS-induced colon inflammation in rats by phospholipase [A.sub.2] inhibitor

The pathophysiology of infiammatory bowel disease (IBD) involves the production of diverse lipid mediators, namely eicosanoids, lysophospholipids, and platelet-activating factor, in which phospholipase [A.sub.2] (PL[A.sub.2]) is the key enzyme. Accordingly, it has been postulated that control of lipid mediator production by inhibition of PL[A.sub.2] would be useful for the treatment of IBD. This hypothesis was tested in the present study by examining the therapeutic effect of a novel extracellular PL[A.sub.2] inhibitor (ExPLI), composed of carboxymethylcellulose-linked phosphatidylethanolamine (CMPE), on trinitrobenzenesulfonic acid-induced colitis. Intraperitoneal administration of CMPE suppressed the colitis as measured by mortality rate, intestinal permeability, plasma PL[A.sub.2] activity, intestinal myeloperoxidase activity, and histological morphometry. Current therapeutic approaches for inflammatory conditions focus on the selective control of a lipid mediator(s) (e.g., prostaglandins or leukotrienes). The present study supports the concept that inclusive control of lipid mediator production by PL[A.sub.2] inhibition is a plausible approach to the treatment of colitis and introduces the ExPLIs as a prototype of a novel NSAID for the treatment of intestinal inflammation. inflammatory bowel disease; colitis; nonsteroidal anti-inflammatory drugs