Protective effects of M40401, a selective superoxide dismutase mimetic, on zymosan-induced nonseptic shock

Objective: Zymosan enhances formation of reactive oxygen species, which contributes to the pathophysiology of organ failure during nonseptic shock. Here we have investigated the effects of M40401, a new superoxide dismutase mimetic, on the organ failure associated with nonseptic shock caused by zymosan in rats. Design: Experimental study. Setting: Laboratory. Subjects: Male Sprague-Dawley rats. Interventions: We investigated the effects of M40401 on the organ failure associated with nonseptic shock caused by zymosan (500 mg/kg, administered intraperitoneally as a suspension in saline) in rats. Measurements and Main Results: Organ failure and systemic inflammation in rats were assessed 18 hrs after administration of zymosan and/or M40401 and were monitored for 12 days (for loss of body weight and mortality). Treatment of rats with M40401 (10 mg/kg intraperitoneally, 1 and 6 hrs after zymosan) attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by zymosan. M40401 administration also attenuated the lung and intestinal injury (histology) as well as the increase in myeloperoxldase activity and malondialdehyde concentrations caused by zymosan In lung and intestine. Immunohistochemical analysis for nitrotyrosine and for poly(adenosine 5′-diphosphate-ribose) revealed positive staining in lung and intestine from zymosan-treated rats. The degree of staining for nitrotyrosine and poly(adenoslne 5′-diphosphate- ribose) was markedly reduced in tissue sections obtained from zymosan-treated rats administered with M40401. Conclusion: This study provides the first evidence that M40401 attenuates the degree of zymosan-induced nonseptic shock in the rat.