Core fucosylation regulates alveolar epithelial cells senescence through activating of transforming growth factor-β pathway in pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF), a fatal disorder associated with aging, has a terrible prognosis. However, the potential causes of IPF remain a riddle. In this study, we designed to explore whether the modification of the core fucosylation (CF) can ameliorate pulmonary fibrosis by targeting alveolar epithelial cells (AECs) senescence. First, we verified that cellular senescence occurs in the bleomycin-induced lung fibrosis mice models and CF modifications accompanying senescent AECs in pulmonary fibrosis. Next, both gain- and loss- of function research on CF were performed to elucidate its role in promoting AECs senescence and triggering pulmonary fibrosis in vitro. Notably, using alveolar epithelial cell-specific FUT8 conditional knockout mouse models, however, inhibition of cellular senescence by deleting the FUT8 gene could attenuate pulmonary fibrosis in vivo. Finally, blocking the CF modification of transforming growth factor -β type I receptor (TGF-βR I) could reduce the activation of downstream transforming growth factor -β (TGF-β) pathways in AECs senescence both in vivo and in vitro. This study reveals that CF is a crucial interventional target for the treatment of pulmonary fibrosis. Blocking CF modification contributes importantly to inhibiting AECs senescence resulting in pulmonary fibrosis lessen.