Amelioration of bleomycininduced pulmonary fibrosis of rats by an aldose reductase inhibitor, epalrestat

Abstract

Aldose reductase (AR) is known to play a crucial role in the mediation of diabetic and cardiovascular complications. Recently, several studies have demonstrated that allergeninduced airway remodeling and ovalbumininduced asthma is mediated by AR. Epalrestat is an aldose reductase inhibitor that is currently available for the treatment of diabetic neuropathy. Whether AR is involved in pathogenesis of pulmonary fibrosis and whether epalrestat attenuates pulmonary fibrosis remains unknown. Pulmonary fibrosis was induced by intratracheal instillation of bleomycin (5 mg/kg) in rats. Primary pulmonary fibroblasts were cultured to investigate the proliferation by BrdU incorporation method and flow cytometry. The expression of AR, TGF-β1α-SMA and collagen I was analyzed by immunohistochemisty, realtime PCR or western blot. In vivo, epalrestat treatment significantly ameliorated the bleomycinmediated histological fibrosis alterations and blocked collagen deposition concomitantly with reversing bleomycininduced expression upregulation of TGF-β1, AR, α SMA and collagen I (both mRNA and protein). In vitro, epalrestat remarkably attenuated proliferation of pulmonary fibroblasts and expression of αSMA and collagen I induced by TGFβ1and this inhibitory effect of epalrestat was accompanied by inhibiting AR expression. Knockdown of AR gene expression reversed TGF-β1induced proliferation of fibroblasts, upregulation of α-SMA and collagen I expression. These findings suggest that AR plays an important role in bleomycininduced pulmonary fibrosis, and epalrestat inhibited the progression of bleomycininduced pulmonary fibrosis is mediated via inhibiting of AR expression.