Suppression of murine endotoxic shock by sPLA(2) inhibitor, indoxam, through group IIA sPLA(2)-independent mechanisms

Endotoxic shock is a systemic inflammatory process, involving a variety of proinflammatory mediators. Two types of secretory phospholipase A(2) (sPLA( 2)) have been implicated in this process. Group IB sPLA(2) (PLA(2)-IB) bind s to the PLA(2) receptor (PLA(2)R), and PLA(2)R-deficient mice exhibit resi stance to endotoxin-induced lethality with reduced plasma levels of proinfl ammatory cytokines, such as TNF-alpha. Group IIA sPLA2 (PLA(2)-IIA) is foun d in many tissues and cell types, and local and systemic levels are elevate d under numerous inflammatory conditions including sepsis. In this study, w e investigated the effect of it specific sPLA(2) inhibitor, indoxam, on mur ine endotoxic shock. Indoxam suppressed the elevation of plasma TNF-alpha w ith a similar potency in PLA(2)-IIA-expressing and PLA(2)-IIA-deficient mic e after LPS challenge. In PLA(2)-IIA-deficient mice, indoxam also suppresse d the elevation of plasma IL-1 beta, IL-6 and NO, and prolonged survival af ter LPS challenge. Indoxam was found to block the PLA(2)-IB binding to muri ne PLA(2)R with a high potency (K-i = 30 nM). The inhibitory effects of ind oxam on the LPS-induced elevation of plasma TNF-alpha levels could not be o bserved in mice deficient in PLA(2)R. These findings suggest that indoxam b locks the production of proinflammatory cytokines during endotoxemia throug h PLA(2)-IIA-independent mechanisms, possibly via blockade of the PLA(2)R f unction. (C) 1999 Published by Elsevier Science B.V. All rights reserved.