Targeting ELK-1 transcription factor and mechanosensitive MDM4 receptor using an HCN channel blocker alleviates lung fibrosis

Abstract

Idiopathic pulmonary fibrosis is a progressive interstitial lung disease associated with poor prognosis and high mortality rate. It is a chronic irreversible lung disorder, mainly characterized by matrix stiffening. This study aims to investigate the therapeutic potential of targeting ELK-1 transcription factor and mechanosensitive MDM4 receptor using Ivabradine (IVA), an HCN channel blocker, in bleomycin (BLM)-induced pulmonary fibrosis (PF) rat model. Total, differential cell counts and LDH activity were assessed in bronchoalveolar lavage fluid. Pulmonary levels of MDA, GSH, IL-1β, α-SMA, COL1A1, ELK-1, MDM4, p-53, caspase-3, cleaved caspase-3, and CX3CL-1 were measured. Our study demonstrated that IVA induced a marked decrease in MDA and increase in GSH levels. Also, rats treated with IVA revealed a significant reduction in inflammation scores, LDH, IL-1β, α-SMA and COL1A1 levels. IVA-treated group showed a marked downregulation of MDM4 and ELK-1 along with significant upregulation of p-53, caspase-3, cleaved caspase-3, and CX3CL-1 levels when compared to BLM-induced PF group. In conclusion, these findings highlight the therapeutic potential of IVA in the treatment of pulmonary fibrosis. The antifibrotic effects of IVA in the bleomycin-induced rat model may be attributed to restoring redox balance, alleviation of aberrant inflammatory response, sensitizing lung myofibroblasts to apoptosis and promoting their clearance by macrophages.