The Effects of Sub-Chronic Treatment with Pioglitazone on the Septic Mice Mortality in the Model of Cecal Ligation and Puncture: Involvement of Nitric Oxide Pathway.

Sepsis is a systemic inflammatory response syndrome caused by an infection and remains as a major challenge in health care. Many studies have reported that pioglitazone may display anti-inflammatory effects. This study was designed to evaluate the effect of subchronic treatment with pioglitazone on high-grade septic mice survival and nitrergic system involvement. Diffused sepsis was induced by cecal ligation and puncture (CLP) surgery in male NMRI mice (20-30 g). Pioglitazone (5,10 and 20 mg/kg) was administered by gavage daily for 5 days prior to surgery. Nitric oxide involvement was assessed by sub-chronic administration of a non-selective nitric oxide synthase inhibitor, L-NAME and a selective inducible nitric oxide synthase inhibitor, aminoguanidine. TNF-α  and IL-1β plasma levels were measured by ELISA. Pioglitazone (10 and 20 mg/kg) significantly improved survival rate in septic mice. The chronic intraperitoneally co-administration of L-NAME (0.5 mg/kg, daily) or aminoguanidine (1 mg/kg, daily) with a daily dose of pioglitazone, 5 mg/kg, significantly increased the survival rate. This survival improving effect was accompanied by a significant reduction in pro-inflammatory cytokines TNF-α and IL-1β plasma levels. In conclusion, sub-chronic pioglitazone treatment can improve survival in mouse sepsis model by CLP. Inhibition of nitric oxide release, probably through inducible nitric oxide synthase at least in part is responsible for this effect. Suppression of TNF-α and IL-1β could be another mechanism in pioglitazone-induced survival improving effect in septic mice.