Suppression of murine endotoxic shock by sPLA2 inhibitor, indoxam, through group IIA sPLA2-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) binds to the PLA(2) receptor (PLA(2)R), and PLA(2)R-deficient mice exhibit resistance to endotoxin-induced lethality with reduced plasma levels of proinflammatory cytokines, such as TNF-alpha. Group IIA sPLA2 (PLA(2)-IIA) is found in many tissues and cell types, and local and systemic levels are elevated under numerous inflammatory conditions including sepsis. In this study, we investigated the effect of it specific sPLA(2) inhibitor, indoxam, on murine endotoxic shock. Indoxam suppressed the elevation of plasma TNF-alpha with a similar potency in PLA(2)-IIA-expressing and PLA(2)-IIA-deficient mice after LPS challenge. In PLA(2)-IIA-deficient mice, indoxam also suppressed the elevation of plasma IL-1 beta, IL-6 and NO, and prolonged survival after LPS challenge. Indoxam was found to block the PLA(2)-IB binding to murine PLA(2)R with a high potency (K-i = 30 nM). The inhibitory effects of indoxam on the LPS-induced elevation of plasma TNF-alpha levels could not be observed in mice deficient in PLA(2)R. These findings suggest that indoxam blocks the production of proinflammatory cytokines during endotoxemia through PLA(2)-IIA-independent mechanisms, possibly via blockade of the PLA(2)R function. (C) 1999 Published by Elsevier Science B.V. All rights reserved.