Etanercept reduces acute tissue injury and mortality associated to zymosan-induced multiple organ dysfunction syndrome

Giuseppe Malleo, Emanuela Mazzon, Tiziana Genovese, Rosanna Di Paola, Carmelo Muià, Rocco Caminiti, Emanuela Esposito, Paolo Di Bella, Salvatore Cuzzocrea

Research output: Contribution to journalArticle

Abstract

It has been well demonstrated that TNF-α 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-α-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-α attenuated pancreas and ileum injury (histology), the increase in myeloperoxidase activity in the ileum and in the lung, and the formation of TNF-α and IL-1β. Immunohistochemical analysis for TNF-α, transforming growth factor β, 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-α 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.

Original languageEnglish
Pages (from-to)560-571
Number of pages12
JournalShock
Volume29
Issue number5
DOIs
Publication statusPublished - May 2008

    Fingerprint

Keywords

  • Apoptosis
  • Biological therapy
  • Inflammation
  • Knockout mice
  • MODS
  • Neutrophil infiltration
  • Zymosan

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Physiology

Cite this

Malleo, G., Mazzon, E., Genovese, T., Paola, R. D., Muià, C., Caminiti, R., Esposito, E., Bella, P. D., & Cuzzocrea, S. (2008). Etanercept reduces acute tissue injury and mortality associated to zymosan-induced multiple organ dysfunction syndrome. Shock, 29(5), 560-571. https://doi.org/10.1097/SHK.0b013e3181507234