Abstract Text: Idiopathic pulmonary fibrosis (IPF) is a chronic and refractory interstitial lung disease with no effective treatment other than lung transplantation. Although there are two approved drugs for IPF, pirfenidone and nintedanib, they were not able to completely cure the disease. Therefore, there is an urgent need to develop of a new therapeutic agent for IPF. To find effective drug for IPF, we chose a drug repositioning strategy. In this study, we investigated the effect of a xanthine derivative, theophylline that has long been used for the treatment of asthma, on pulmonary fibrosis. Administration of theophylline attenuated the fibrotic changes of lung tissues and improved mechanical pulmonary functions in a bleomycin (BLM)-induced pulmonary fibrosis. A variety of studies have reported the importance of Th17 cells and IL-17 in IPF. IL-17 was detected in the sera of BLM-treated mice as well as patients with IPF, and lung fibrosis was inhibited by IL-17A antibody. Theophylline treatment suppressed IL-17 production through inhibiting cytokines controlling Th17 differentiation; TGF-β, IL-6, IL-1β and IL-23. Inhibition of IL-6 and IL-1β by theophylline is mediated by suppressing BLM-induced ROS production and NF-κB activation in epithelial cells. We further demonstrated that theophylline inhibited TGF-β-induced epithelial-to-mesenchymal transition in epithelial cells through suppressing phosphorylation of Smad2/3 and AKT. Taken together, these results demonstrated that theophylline exhibits the potent anti-fibrotic effect on pulmonary fibrosis by inhibiting Th17 differentiation and TGF-β signaling, and thus suggest that theophylline may be a potential new therapeutic agent for IPF.
