Role of irbesartan in protection against pulmonary toxicity induced by bleomycin in rats

Abstract

Bleomycin (BLM) is an anti-neoplastic, antibiotic drug that produces dose and time dependant pulmonary fibrosis. Recent studies reported some mechanisms of irbesartan in attenuating lung and skin fibrosis in mice. Therefore, the current study was conducted to examine the effect of irbesartan focusing on angiogenesis and plasminogen activator inhibitor-1(PAI-1) expression as possible mechanisms in protection against BLM-induced lung fibrosis in rats. The effect of irbesartan on the serum and tissue levels of growth factors and mRNA expression of PAI-1 were studied. Oral administration of irbesartan (10, 20 and 40 mg/kg/day) to rats for 21 days, starting from the first day of bleomycin injection (10 mg/kg/day/10 days, i.p.) attenuated the severity of BLM-induced pulmonary fibrosis, enhanced the histopathological features of the lungs, reduced serum transforming growth factor-β1 (TGF-β1) compared to BLM group without any improvement in the survival percentage. In addition, immunohistochemical staining revealed lower expression of angiotensin-II type 1 receptor (AT1) and α-smooth muscle actin (α-SMA) in lung tissues after treatment with irbesartan (20 and 40mg/kg) compared to BLM-treated group. Importantly, irbesartan (10, 20 and 40mg/kg) suppressed the expression of PAI-1 gene in lung tissues while increased both serum level and immunohistochemical staining of vascular endothelial growth factor (VEGF) compared to BLM-treated group. So that, the present study concluded that the ameliorating effect of irbesartan against BLM-induced pulmonary fibrosis in rats involves increasing angiogenesis, reduction of PAI-1 gene expression and modulation of growth factors.