Effects of Saxagliptin Against Bleomycin-Induced Pulmonary Injury in Rats: Modulation of Inflammatory, Fibrotic, and Apoptotic Pathways

Bleomycin is an important chemotherapeutic agent that has been widely used in the treatment of various malignancies, including testicular germ cell tumors and Hodgkin lymphoma. However, its clinical use is limited due to pulmonary toxicity, such as pneumonitis, which can lead to irreversible pulmonary fibrosis. Saxagliptin, a dipeptidyl peptidase-4 inhibitor, possesses biological activities beyond its antidiabetic effects. The aim of this study was to explore the impact of saxagliptin on reducing bleomycin-induced pulmonary injury in rats and its relation to pro-inflammatory, apoptotic, and fibrotic mediators. Twenty-four adult male albino rats were evenly divided into four groups: Group I was the control (2% DMSO); Group II was administered 2.5 IU/kg bleomycin; Groups III and IV were treated with 5 mg/kg and 10 mg/kg saxagliptin, respectively. Pro-inflammatory cytokines (IL-6 and TNF-α), an apoptotic marker (caspase-3), and fibrotic markers (TGF-β and Smad-3) were measured, and lung tissues were examined histologically. Results showed that saxagliptin treatment decreased inflammatory cytokines, apoptotic markers, and fibrosis-related mediators compared to the bleomycin-only group (except for TGF-β, which remained upregulated). Histological examination of the lungs showed marked structural injury in the bleomycin group, mild improvement after treatment with low-dose saxagliptin, and near-normal pulmonary architecture after treatment with high-dose saxagliptin. Conclusion: Saxagliptin exerted protective effects against bleomycin-induced lung injury through anti-inflammatory, anti-apoptotic, and antifibrotic actions, supporting its potential use as a therapeutic approach for pulmonary fibrosis.