Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor-γ, reduces the development of nonseptic shock induced by zymosan in mice*

Abstract

Objective 

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid, and thyroid hormone receptors. The PPAR-γ receptor subtype appears to play a pivotal role in the regulation of cellular proliferation and inflammation. Rosiglitazone (Avandia) is a PPAR-γ agonist (the most potent PPAR-γ agonist of the thiazolidinedione antidiabetics). In the present study, we investigated the effects of rosiglitazone on the development of nonseptic shock caused by zymosan in mice.

Design 

Experimental study.

Setting 

University laboratory.

Subjects 

Male CD mice.

Interventions 

We investigated the effects of rosiglitazone (3 mg/kg) on the development of nonseptic shock caused by zymosan (500 mg/kg, administered intraperitoneally as a suspension in saline) in mice.

Measurements and Main Results 

Organ failure and systemic inflammation in rats were assessed 18 hrs after administration of zymosan and/or rosiglitazone and monitored for 12 days (for loss of body weight and mortality rate). Treatment of mice with rosiglitazone (3 mg/kg intraperitoneally, 1 and 6 hrs after zymosan) attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by zymosan. Rosiglitazone also attenuated the lung, liver, and pancreatic injury and renal dysfunction caused by zymosan as well as the increase in myeloperoxidase activity and malondialdehyde concentrations caused by zymosan in the lung and intestine. Immunohistochemical analysis for inducible nitric oxide synthase, nitrotyrosine, and poly(adenosine diphosphate-ribose) revealed positive staining in lung and intestine tissues obtained from zymosan-treated mice. The degree of staining for nitrotyrosine, inducible nitric oxide synthase, and poly(adenosine diphosphate-ribose) was markedly reduced in tissue sections obtained from zymosan-treated mice that received rosiglitazone.

To elucidate whether the protective effects of rosiglitazone are related to activation of the PPAR-γ receptor, we also investigated the effect of a PPAR-γ antagonist, GW 9662, on the protective effects of rosiglitazone. GW 9662 (1 mg/kg administered intraperitoneally 30 mins before treatment with rosiglitazone) significantly antagonized the effect of the PPAR-γ agonist and thus abolished the protective effect.

Conclusions 

This study provides evidence, for the first time, that rosiglitazone attenuates the degree of zymosan-induced nonseptic shock in mice.