FOXO4 peptide targets myofibroblast ameliorates bleomycin-induced pulmonary fibrosis in mice through ECM-receptor interaction pathway

Abstract

Pulmonary fibrosis (PF) is a progressive interstitial lung disease with limited treatment options. The incidence and prevalence of PF is increasing with age, cell senescence has been proposed as a pathogenic driver, the clearance of senescent cells could improve lung function in PF. FOXO4-D-Retro-Inverso (FOXO4-DRI), a synthesis peptide, has been reported to selectively kill senescent cells in aged mice. However, it remains unknown if FOXO4-DRI could clear senescent cells in PF and reverse this disease. In this study, we explored the effect of FOXO4-DRI on bleomycin (BLM)-induced PF mouse model. We found that similar as the approved medication Pirfenidone, FOXO4-DRI decreased senescent cells, downregulated the expression of senescence-associated secretory phenotype (SASP) and attenuated BLM-induced morphological changes and collagen deposition. Furthermore, FOXO4-DRI could increase the percentage of type 2 alveolar epithelial cells (AEC2) and fibroblasts, and decrease the myofibroblasts in bleomycin (BLM)-induced PF mouse model. Compared with mouse and human lung fibroblast cell lines, FOXO4-DRI is inclined to kill TGF-β-induced myofibroblast in vitro. The inhibited effect of FOXO4-DRI on myofibroblast lead to a downregulation of extracellular matrix (ECM) receptor interaction pathway in BLM-induced PF. Above all, FOXO4-DRI ameliorates BLM-induced PF in mouse and may be served as a viable therapeutic option for PF.