Regulation of the IGF1 signaling pathway is involved in idiopathic pulmonary fibrosis induced by alveolar epithelial cell senescence and core fucosylation.

Wei Sun,Qian Zhang,Zuojun Xu,Xiaoyan Jing,Ping Wang,Qun Luo,Shu Xia,Na Wang,Xiaoyu Yang,Jian Guo,Hui Huang

doi:10.18632/aging.203335

Abstract

Idiopathic pulmonary fibrosis (IPF) mainly occurs in elderly people over the age of sixty. IPF pathogenesis is associated with alveolar epithelial cells (AECs) senescence. Activation of PI3K/AKT signaling induced by insulin-like growth factor 1 (IGF1) participates in AEC senescence and IPF by releasing CTGF, TGF-β1, and MMP9. Our previous study demonstrated that core fucosylation (CF) modification, catalyzed by a specific core fucosyltransferase (FUT8) can regulate the activation of multiple signaling pathways, and inhibiting CF can alleviate pulmonary fibrosis in mice induced by bleomycin. However, whether CF is involved in IGF1-mediated AEC senescence in IPF remains unclear. In this study, we found that the IGF1/PI3K/AKT signaling pathway was activated in IPF lung tissue. Meanwhile, CF was present in senescent AECs. We also showed that IGF1 could induce AECs senescence with enhanced CF in vivo and in vitro. Inhibiting CF alleviated AECs senescence and pulmonary fibrosis induced by IGF1. In addition, activation of IGF1/PI3K/AKT signaling depends on CF. In conclusion, this study confirmed that CF is an important target regulating the IGF1 signaling pathway in AEC senescence and IPF, which might be a candidate target to treat IPF in the future.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a refractory disease with unknown etiology, and the survival time after diagnosis is less than 3 years [1]
Hematoxylin and eosin (HE) and Masson staining showed that alveolar structure was destroyed and blue stained collagen fibers appeared in the interstitium of the lung parenchyma from patients with IPF compared with that in normal lung tissues (Figure 2A)
These results indicated that IPF is associated with alveolar epithelial cells (AECs) senescence, and AECs senescence is accompanied by core fucosylation (CF)

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a refractory disease with unknown etiology, and the survival time after diagnosis is less than 3 years [1]. Cell senescence occurs by inducing the overexpression of P21 and P16 (cyclin dependent kinase inhibitor 1A and cyclin dependent kinase inhibitor 2A, respectively), both of which are key proteins of senescence [8, 12, 13]. Profibrotic cytokines such as connective tissue growth factor (CTGF), transforming growth factor-β (TGF-β), and matrix metalloproteinases (MMPs), are associated with AECs senescence [14,15,16]. Considering the important role of the IGF1/PI3K/AKT signaling pathway in inducing AECs senescence in pulmonary fibrosis, determining the mechanisms that regulate this signaling pathway is imperative

Methods

Results

Conclusion