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

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.

Fisetin Alleviated Bleomycin-Induced Pulmonary Fibrosis Partly by Rescuing Alveolar Epithelial Cells From Senescence

“…Prior studies have shown that BLM treatment can effectively induce cellular senescence in alveolar epithelial cells ( Aoshiba et al, 2003 ). Cyclin-dependent kinase inhibitors p16 and p21, as well as SA-β-Gal activity are often used to confirm the appearance of senescence ( Aoshiba et al, 2013 ; Qiu et al, 2019 ). As shown in Figure 2 , both p16 and p21 gene expressions were apparently up-regulated in BLM-induced fibrotic mouse lungs, p21 protein was also significantly increased compared with the control group.…”

“…To further explore the effects of FIS on inflammatory reaction, several common cytokines were analyzed by ELISA, which have also been suggested to be part of the SASP ( Aoshiba et al, 2013 ; Qiu et al, 2019 ). In Figure 3 , the levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), profibrogenic cytokine (TGF-β) and metalloproteinase-9 (MMP-9) in the BALF of BLM-induced mice were significantly higher than those in healthy mice.…”

“…To build the model of alveolar epithelial cell senescence and select the optimal concentration of BLM, A549 cells were stimulated with different doses of BLM for 3 days ( Qiu et al, 2019 ). Next, we observed the roles of FIS and AMPK in alveolar epithelial cell senescence.…”

“…Bleomycin (BLM)-induced PF is the most frequently used animal model. Treatment with BLM can also induce alveolar epithelial cell senescence in vitro and in vivo ( Aoshiba et al, 2003 ; Qiu et al, 2019 ). In this study, BLM was used to reproduce PF in mice and induce alveolar epithelial cell senescence to investigate the effect and mechanism of FIS in experimental PF.…”

A new human adipocyte model with PTEN haploinsufficiency

“…PTEN's role in senescence seems to be cell-type specific and can be enhancing or suppressing. While an upregulation of PTEN in alveolar epithelial cells caused senescence-associated fibrosis [36], PTEN overexpression in glioblastoma neurospheres led to increased senescence [37]. A recent study in a mouse model with conditional PTEN knockout in adipose tissue depots showed a phenotype of adipose tissue redistribution with massive expansion of the PTEN knockout depot and reduced fat mass in other adipose tissue depots.…”