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.