PTEN loss regulates alveolar epithelial cell senescence in pulmonary fibrosis depending on Akt activation.

Ting Qiu,Jingyu Chen,Hui Li,Hourong Cai,Yaqiong Tian,Mengshu Cao,Xiaoqin Liu,Hui Ding,Jinghong Dai,Hongyan Wu,Yujuan Gao,Yingwei Zhang,Ji Zhang,Miao Ma

doi:10.18632/aging.102262

Abstract

Idiopathic pulmonary fibrosis (IPF) is an aging-associated disease with poor prognosis. The mechanisms underlying the role of alveolar epithelial cell (AEC) senescence in IPF remain poorly understood. We aimed to investigate if PTEN/Akt activates AEC senescence to induce pulmonary fibrosis. We investigated the association between PTEN/Akt and cellular senescence in lung tissues from IPF patients. As a result, decreased PTEN and activated Akt pathway were found in AECs in fibrotic lung tissues detected by immunohistochemistry (IHC) and immunofluorescence (IF). Increased expression levels of aging-associated markers (P21WAF1 and SA-β-gal) in AECs treated with bleomycin were found. AEC senescence was accelerated by PTEN knockdown and attenuated by PTEN overexpression. Bleomycin induced AEC senescence was reversed by Akt2 knockdown and the pharmacological inhibitors (LY294002 and MK2206) of the Akt pathway. Reducing Akt activation dramatically improved lung fibrosis in a fibrotic mice model. In addition, a co-immunoprecipitation (co-IP) assay demonstrated that PTEN physically associated with Akt. These indicated that senescent AECs modulated by the PTEN/Akt pathway promote lung fibrosis. In conclusion, our study demonstrated that as a trigger indicator in IPF, the senescence process in AECs should be a potential therapeutic target and that the PTEN/Akt pathway may be a promising candidate for intervention.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive, fibrosing interstitial pneumonia [1] with a median survival rate of 3.8 years after diagnosis [2]
Strongly positive SA-β-Gal staining was primarily located in alveolar epithelial cell (AEC) from lung tissues with IPF, whereas SA-β-Gal staining was barely observed in normal lung tissues (Figure 1C, 1D)
Western blotting confirmed P21WAF1 expression differences between IPF and normal lung tissues (Figure 1F, 1G). These data suggested that IPF is an aging-related disease as previous findings demonstrated and abnormal senescence occurs in AECs from IPF lung tissues

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive, fibrosing interstitial pneumonia [1] with a median survival rate of 3.8 years after diagnosis [2]. The incidence of IPF increases with age, and it is widely regarded as a disease of aging [3]. IPF patients under 50 years of age are rare [4]. Two-thirds of IPF patients are older than 60 years at the time of presentation with a mean age of 66 years at the time of diagnosis. The survival rate of IPF patients markedly decreases with age [5]. Different mechanisms associated with aging, including stem cell dysfunction [7], aging mediator overexpression [8], and mitochondrial superoxide [9], have been described to participate in the pathogenesis of IPF

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