Metformin alleviates bleomycin-induced pulmonary fibrosis in rats: Pharmacological effects and molecular mechanisms

Background: Metformin, a commonly used oral antidiabetic agent, is known to possess pleiotropic antioxidant, anti-inflammatory and anti-fibrotic effects. In this study, we evaluated the effect of metformin on pulmonary fibrosis and the mechanism underlying its effect. Methods: Pulmonary fibrosis was induced experimentally with bleomycin (0.035 U/g, i.p.) given twice weekly for four weeks. Metformin (125, 250 and 500 mg/kg/day, p.o) was given seven days prior to first injection of bleomycin and continued till 28 days after starting bleomycin injection. Prednisolone (5 mg/kg/day, p.o) was the standard control. Results: Administration of bleomycin caused pulmonary fibrosis in rats as evidenced by characteristic structural changes in histopathology, increased inflammatory cells in bronchoalveolar lavage fluid, elevated lipid peroxidation marker, depleted endogenous antioxidants and increased inflammatory mediators (TNF-alpha, IL-6). There were also increased levels of TGF-beta, Smad2/3, ERK1/2, p38, JNK, fibronectin, hydroxyproline and type I collagen in bleomycin-control group. All these changes were ameliorated by high dose metformin. It restored structural, biochemical and molecular changes towards normal. This protective effect may be attributed to activation of AMPK by metformin, with consequent reduction in oxidative stress and TGF-beta. Moreover, this protective effect was superior to prednisolone as metformin had additional antioxidant and antifibrotic properties. Conclusion: These data suggest that metformin protects against bleomycin-induced pulmonary fibrosis through activation of AMPK and amelioration of TGF-beta signaling pathways.