Abstract
Lung fibrosis is one of the serious complications of bleomycin use in cancer therapy. The aim of this study was to investigate the effect of pre-treatment versus post-treatment with empagliflozin on pulmonary fibrosis induced by bleomycin. One hundred male C57BL/6 mice were divided into 5 equal groups as follows: control group; bleomycin group; bleomycin + carboxymethyl cellulose group; bleomycin group pretreated with empagliflozin and a group treated with empagliflozin after 15 days from starting bleomycin injection. The survival rate, lung weight/body weight ratio, lung tissue hydroxyproline, malondialdehyde, glutathione reductase, superoxide dismutase, nuclear factor (Erythroid-derived 2)-like 2 (Nrf2), heme oxygenase-1 (HO-1) and toll-like receptor 4 (TLR4) were assessed. Also, bronchoalveolar lavage fluid (BALF) was analyzed for total and differential leucocytic count, lactate dehydrogenase, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta 1 (TGF-beta 1). The pulmonary tissues were subjected to histopathological, immunohistochemical and electron microscopic study. Empagliflozin induced significant decrease in lung weight/body weight ratio, BALF lactate dehydrogenase, total leucocytic count, IL-6, TNF-alpha, TLR4 and TGF-beta 1 associated with significant decrease in lung tissue oxidative stress and hydroxyproline and significant increase in the survival rate and tissue Nrf2/HO-1 content compared to bleomycin group. This was accompanied with significant improvement of the histopathological, immunohistochemical and electron microscopic picture compared to bleomycin group. These effects were significant in mice pretreated with empagliflozin compared to the group that received empagliflozin 15 days after starting bleomycin injection. In conclusion, empagliflozin may be used prophylactically to prevent pulmonary fibrosis induced by bleomycin.