Specific inhibition of iNOS decreases the intestinal mucosal peroxynitritelevel and improves the barrier function after thermal injury

Failure of GI tract mucosa to act as a barrier against bacterial translocat ion (BT) has been proposed as a potential source of sepsis and subsequent m ultiple organ failure post thermal injury. Nitric oxide (NO) is an inorgani c radical produced by NO synthase (NOS) from L-arginine. Gut mucosal consti tutive NOS (cNOS) provides protection for itself. In contrast to cNOS, indu cible NOS (iNOS) releases far greater amounts of NO, promotes oxidative rea ctions and is responsible for tissue injury. Peroxynitrite formed by the ra pid reaction between superoxide and NO, is a toxic substance that contribut es to tissue injury in a number of biological systems. This study was desig ned to investigate the effect of iNOS specific inhibitor S-methylisothioure a (SMT) on the postburn intestinal mucosal barrier function and the possibl e mechanism of SMT's action. Female SPF Sprague-Dawley rats underwent 35% t otal body surface area (TBSA) or sham burn. Either SMT or the same volume o f saline was given (5 mg/kg, i.p. q 12 h) for 2 days to assess the effect o f iNOS inhibition. On postburn day 2, the intestinal mucosal cNOS and iNOS activity were assayed by using Griess' reagent, the mesenteric lymph node ( MLN), spleen and liver were collected and cultured for BT assay and the cel lular localization of nitrotyrosine, a marker for peroxynitrite activity, w as examined by immunostaining. After thermal injury in rats, administration of SMT for 2 days decreased the intestinal mucosal iNOS activity/tNOS acti vity ratio and the BT incidence. Nitrotyrosine immunostaining of the intest inal mucosa showed a decrease in the SMT-treated group. These findings sugg est that SMT, a specific inhibitor for iNOS improves the barrier function a fter burn by suppression of the intestinal mucosal iNOS activity. The decre ase in NO production resulted in decreased formation of peroxynitrite and s ubsequently decreased damage of mucosal tissue. (C) 1998 Elsevier Science L td for ISBI. All rights reserved.