FUMONISIN B1 REDUCES THE DEVELOPMENT OF MULTIPLE ORGAN FAILURE INDUCED BY ZYMOSAN IN MICE.

Ceramide is a major proapoptotic mediator released in response to numerous stimuli, including oxidative stress and cytokines. The role of ceramide in the pathophysiology of inflammation is just emerging, and the potential relevance of this pathway in nonseptic shock is not known. The aim of this study was to investigate the effects of fumonisin B1 (FB1), a specific inhibitor of ceramide synthase, on the development of nonseptic shock in mice caused by zymosan. CD1 mice received either zymosan (500 mg/kg, administered i.p. as a suspension in saline) or vehicle (0.25 mL per mouse saline). Fumonisin B1 (3 mg/kg, i.p.) was administered 1 and 6 h after zymosan administration. Organ failure and systemic inflammation in mice were assessed 18 h after administration of zymosan and/or FB1. Treatment of mice with FB1 attenuated peritoneal exudate formation and the migration of polymorphonuclear cells caused by zymosan. Fumonisin B1 also attenuated plasma markers of lung, liver and pancreatic injury, and renal dysfunction caused by zymosan and the increase in myeloperoxidase activity in the intestine caused by zymosan. Immunohistochemical analyses for the presence of ceramide and nitrotyrosine revealed positive staining in intestinal tissue obtained from zymosan-injected mice. The degree of staining for ceramide and nitrotyrosine was markedly reduced in tissue sections obtained from zymosan-injected mice that had received FB1. In addition, administration of zymosan caused a severe illness in the mice characterized by a systemic toxicity, significant loss of body weight, and 80% mortality within 12 days. Treatment with FB1 significantly reduced systemic toxicity, weight loss, and mortality caused by zymosan. This study provides evidence that FB1 attenuates the degree of zymosan-induced nonseptic shock in mice.