FOXO4-D-Retro-Inverso targets extracellular matrix production in fibroblasts and ameliorates bleomycin-induced pulmonary fibrosis in mice

Abstract

Pulmonary fibrosis (PF) occurs in various end stages of lung disease, and it is characterized by persistent scarring of the lung parenchyma with excessive deposition of extracellular matrix (ECM), leading to degressive quality of life and earlier mortality. FOXO4-D-Retro-Inverso (FOXO4-DRI), a synthesis peptide as a specific FOXO4 blocker, selectively induced dissociation of the FOXO4-p53 complex and nuclear exclusion of p53. Simultaneously, the p53 signaling pathway has been reported to activate in fibroblasts isolated from IPF fibrotic lung tissues and the p53 mutants cooperate with other factors that have the ability to disturb the synthesis of ECM. Yet, whether FOXO4-DRI influences the nuclear exclusion of p53 and then obstructs PF progress is still unknown. In this research, we explored the effect of FOXO4-DRI on bleomycin (BLM)-induced PF mouse model and activated fibroblasts model. The animal group of FOXO4-DRI therapeutic administration shows a milder pathologic change and less collagen deposition compared with the BLM-induced group. We also found the FOXO4-DRI resets the distribution of intranuclear p53 and concurrently decreased the total ECM proteins content. After further validation, FOXO4-DRI may well be a promising therapeutic approach to treating pulmonary fibrosis.

Keywords: Bleomycin; Extracellular matrix; FOXO4-DRI; Pulmonary fibrosis; p53.