It has been well demonstrated that
TNF-alpha is integral to the pathogenesis of
multiple organ dysfunction syndrome (
MODS). In this study, we investigate the effects of
etanercept (10 mg/kg, s.c.), a specific
TNF-alpha-soluble inhibitor, on the acute phase and late mortality in a murine model of
MODS of nonseptic origin induced by
zymosan (500 mg/kg, suspended in
saline solution, i.p.).
Etanercept was administered 1 h after the injection of
zymosan. Animals were killed after 18 h. In another set of experiments, mice were monitored for systemic toxicity, loss of
body weight, and mortality for 12 days.
Sham-treated and
TNF receptor 1 (TNFR1)-deficient animals were used as control. Treatment of mice with
Etanercept and
TNFR1 gene deletion decreased the peritoneal exudation and the migration of neutrophils caused by
zymosan. In addition, pharmacological and genetic neutralization of
TNF-alpha attenuated pancreas and ileum injury (histology), the increase in
myeloperoxidase activity in the ileum and in the lung, and the formation of
TNF-alpha and IL-1beta. Immunohistochemical analysis for
TNF-alpha,
transforming growth factor beta, and
vascular endothelial growth factor revealed a positive staining in pancreas and ileum sections. The degree of immunostaining was markedly reduced after
etanercept treatment and in
TNFR1 knockout mice. Furthermore,
TNF-alpha neutralization decreased the potent apoptotic stimulus induced by
zymosan. All of these findings ultimately led to an amelioration of organ functions at 18 h and to a better survival rate at 12 days. Therefore, we demonstrate that
etanercept reduces acute tissue injury and mortality associated to
MODS of nonseptic origin in mice.