Effects of calpain inhibitor I on multiple organ failure induced by zymosan in the rat

Objective: Zymosan enhances the formation of reactive oxygen species, which contributes to the pathophysiology of multiple organ failure. We investigated the effects of calpain inhibitor I (5, 10, or 20 mg/kg) on the multiple organ failure caused by zymosan (500 mg/kg, administered intraperitoneally as a suspension in saline) in rats. Setting: University research laboratory. Subjects: Male Sprague-Dawley rats. Interventions: Multiple organ failure in rats was assessed 18 hrs after administration of zymosan and/or calpain inhibitor I and was monitored for 12 days (for loss of body weight and mortality rate). Measurement and Main Results: Treatment of rats with calpain inhibitor I (5, 10, or 20 mg/kg intraperitoneally, 1 and 6 hrs after zymosan) attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by zymosan in a dose-dependent fashion. Calpain inhibitor I also attenuated the lung, liver, and intestinal injury (histology) as well as the increase in myeloperoxidase activity and malondialdehyde concentrations caused by zymosan in the lung, liver, and intestine. Immunohistochemical analysis for nitrotyrosine and for poly(adenosine-disphosphate-ribose) revealed positive staining in lung, liver, and intestine from zymosan-treated rats. The degree of staining for nitrotyrosine and poly(adenosine-disphosphate-ribose) was reduced markedly in tissue sections obtained from zymosan-treated rats administered calpain inhibitor I (20 mg/kg intraperitoneally). Furthermore, treatment of rats with calpain inhibitor I significantly reduced the expression of inducible nitric oxide synthase and cyclooxygenase-2 in lung, liver, and intestine. Conclusion: This study provides the first evidence that calpain inhibitor I attenuates the degree of zymosan-induced multiple organ failure in the rat.