The Role of TGF-β in Bleomycin Induced Pulmonary Fibrosis

Abstract

Bleomycin sulfate, a combination of two analogues of bleomycin, bleomycin A2 and B2 is an antineoplastic antibiotic used as a chemotherapeutic agent for a number of malignancies. Bleomycin has several functional domains but its most critical action, which is oxidative damage to DNA, is located in the N-terminal domain that binds to oxygen and then to DNA by intercalation. The clinical use of bleomycin is limited by the potential pulmonary toxicity and fibrosis associated with bleomycin. In animal models of bleomycin induced pulmonary fibrosis (BPF), TGF-β1, a potent fibrogenic cytokine is elevated in the alveolar macrophages, epithelial cells, endothelial cells, and interstitial fibroblasts after bleomycin administration. The release of transforming growth factor-β (TGF-β1) in an active form by alveolar macrophages and conversion of biologically latent-TGF-β1 to an active conformation by alveolar epithelial cells (AECs) are critical to the inflammatory and fibrotic sequelae of bleomycin lung toxicity (BLT). A number of agents can abrogate BLT in animal models by decreasing the release of active TGF-β1 or reducing the expression or effects of TGF-β1. In humans, the mainstay of management of BLT remains prevention by using a reduced dose of bleomycin and high dose corticosteroids in the event of BLT.