SMAC Mimetic as potential anti-fibrotic therapy in an in vivo model of Bleomycin-induced Pulmonary Fibrosis

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by the accumulation of myofibroblast, leading to respiratory failure and death. Members of the inhibitor of apoptosis protein (IAP) family, such as cIAP1, promote myofibroblast accumulation by antagonizing caspases activity. SMAC is an IAP-binding protein released during apoptosis to block IAP functions. Inhibition of IAPs by SMAC mimetic might be a strategy for the treatment of IPF. Aim: To investigate the anti-fibrotic effect by the inhibition of IAP family in the in vivo model of pulmonary fibrosis. Methods: The induction of pulmonary fibrosis in vivo was carried out on mice by oropharyngeal aspiration of bleomycin (BLM). Oral administration of the SMAC mimetic (BI891065) was performed for 2 weeks. Lung tissue was collected after 21 days of the BLM administration. Histopathology, RT-qPCR, western blot and immunofluorescence (IF) analysis were performed. Results: Treatment with SMAC mimetic (BI891065) attenuated fibrosis progression with a significant decrease in the Ashcroft score and promoted improved ambulatory behavior of the BLM-treated group of mice. SMAC mimetic decreased protein expression of markers of fibrosis such as fibronectin and alpha smooth muscle actin in lung tissue. In addition, IF data showed that cIAP1 expression increased in BLM-treated group. As expected, SMAC mimetic treatment attenuated cIAP1 expression. Interestingly, apoptosis via caspase activity increased in the lungs of mice treated with SMAC mimetic. Conclusion: Our results suggest that the inhibition of cIAP1 by SMAC mimetic treatment ameliorates pulmonary fibrosis by promoting myofibroblast apoptosis.