title: Etanercept reduces acute tissue injury and mortality associated to zymosan-induced multiple organ dysfunction syndrome.
abstract: 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.
authors.affiliation: Department of Clinical, Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Messina, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Malleo
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mazzon
authors.forename: Tiziana
authors.initials: T
authors.lastname: Genovese
authors.forename: Rosanna
authors.initials: R
authors.lastname: Di Paola
authors.forename: Carmelo
authors.initials: C
authors.lastname: Muià
authors.forename: Rocco
authors.initials: R
authors.lastname: Caminiti
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
authors.forename: Paolo
authors.initials: P
authors.lastname: Di Bella
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000068800:Etanercept; D053222:Fas Ligand Protein / Q000378:metabolism; D007074:Immunoglobulin G / Q000494:pharmacology*; D007249:Inflammation; D051379:Mice; D018345:Mice, Knockout; D009102:Multiple Organ Failure / Q000188:drug therapy* / Q000401:mortality*; D010538:Peritonitis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D015054:Zymosan / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C494827:Bax protein, mouse; D053222:Fas Ligand Protein; D007074:Immunoglobulin G; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D051028:bcl-2-Associated X Protein; D015054:Zymosan; D000068800:Etanercept