Targeting Inhibitor of Apoptosis Proteins Protects from Bleomycin-Induced Lung Fibrosis
Abstract
The accumulation of apoptosis-resistant fibroblasts is a key characteristic of pulmonary fibrosis. We hypothesized that disrupting the inhibitor of apoptosis protein (IAP) family could help mitigate lung fibrosis. Our initial findings demonstrate that transforming growth factor-β1 (TGF-β1) and bleomycin increase the levels of X-linked IAP (XIAP) and cellular IAPs (cIAP-1 and cIAP-2) in murine lungs and mesenchymal cells. When we functionally blocked XIAP and cIAPs using AT-406, an orally bioavailable Smac mimetic, we found it abolished bleomycin-induced lung fibrosis when administered both preventively and therapeutically. To determine if the reduction in fibrosis was primarily due to XIAP inhibition, we compared the fibrotic response between XIAP-deficient mice (XIAP(-/y)) and their littermate controls, finding no significant differences. There were no changes in the total number of inflammatory cells in either wild-type mice treated with AT-406 or in XIAP(-/y) mice. AT-406 treatment reduced CCL12 and IFN-γ levels, while XIAP(-/y) mice showed increased IL-1β expression. Interestingly, XIAP(-/y) mesenchymal cells demonstrated heightened resistance to Fas-mediated apoptosis. However, functional inhibition of cIAPs with AT-406 restored Fas-mediated apoptosis sensitivity in XIAP(-/y) mesenchymal cells in vitro, and increased apoptosis of mesenchymal cells in vivo. This suggests that the enhanced resistance to apoptosis in XIAP(-/y) mesenchymal cells was due to elevated cIAP expression. In conclusion, our findings indicate that: (1) IAPs play a AT406 significant role in the development of lung fibrosis; (2) a congenital deficiency of XIAP can be compensated by other IAPs; and (3) broad inhibition of IAPs could be a promising therapeutic strategy for lung fibrosis by promoting mesenchymal cell apoptosis.