Suppression of intestinal ischemia-reperfusion injury by a specific peroxisome proliferator-activated receptor-γ ligand, pioglitazone, in rats

Abstract

Neutrophil activation and tumor necrosis factor-α (TNF-α) induction play a critical role in ischemia-reperfusion-induced intestinal inflammation. Peroxisome proliferator-activated receptor-γ (PPAR-γ), a member of the nuclear hormone receptor superfamily, has recently been implicated as a regulator of inflammatory responses. The aim of the present study was to determine whether pioglitazone, a specific PPAR-γ ligand, can ameliorate reperfusion-induced intestinal injury in rats, and whether the agent can inhibit the increase in neutrophil accumulation associated with TNF-α expression. Intestinal damage was induced in male Sprague-Dawley rats by clamping the superior mesenteric artery for 30 min followed by reperfusion. Reperfusion after 30 min ischemia resulted in an increase in luminal protein concentrations with levels reaching a maximum after 60 min of reperfusion. In contrast, pretreatment with pioglitazone 2 h before ischemia inhibited the increase in luminal protein concentrations after 60 min reperfusion in a dose-dependent manner (1-30 mg/kg). The increase in tissue-associated myeloperoxidase activity, an index of neutrophil infiltration, after reperfusion was significantly inhibited by pretreatment with pioglitazone. Pioglitazone also inhibited increases in intestinal TNF-α protein and mRNA expression determined by ELISA and RT-PCR, respectively. In conclusion, activation of PPAR-γ may represent a novel approach to the treatment of intestinal inflammation induced by ischemia-reperfusion.