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Loss of PTEN induceslung fibrosis viaalveolar epithelialcell senescencedepending on NF‐κBactivation Yaqiong TianHui LiTing Qiu2018 год

Loss of PTEN induces lung fibrosis via alveolar epithelial cell senescence depending on NF‐κB activation
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Аннотация: Abstract Idiopathic pulmonary fibrosis (IPF) is an aging‐associated disease with poor prognosis. Currently, there are no effective drugs for preventing the disease process. The mechanisms underlying the role of alveolar epithelial cell (AEC) senescence in the pathogenesis of IPF remain poorly understood. We aimed to explore whether PTEN/NF‐κB activated AEC senescence thus resulting in lung fibrosis. First, we investigated the association between the activation of PTEN/NF‐κB and cellular senescence in lung tissues from IPF patients. As a result, decreased PTEN, activated NF‐κB and increased senescent markers (P21 WAF1 , P16 ink4a , and SA‐β‐gal) were found in AECs in fibrotic lung tissues detected by immunohistochemistry (IHC) and immunofluorescence (IF). In vitro experiments showed increased expression levels of senescent markers and augmented senescence‐associated secretory phenotype (SASP) in AECs treated with bleomycin (Blm); however, PTEN was reduced significantly following IκB, IKK, and NF‐κB activation after stimulation with Blm in AECs. AEC senescence was accelerated by PTEN knockdown, whereas senescence was reversed via NF‐κB knockdown and the pharmacological inhibition (BMS‐345541) of the NF‐κB pathway. Interestingly, we observed increased collagen deposition in fibroblasts cultured with the supernatants collected from senescent AECs. Conversely, the deposition of collagen in fibroblasts was reduced with exposure to the supernatants collected from NF‐κB knockdown AECs. These findings indicated that senescent AECs controlled by the PTEN/NF‐κB pathway facilitated collagen accumulation in fibroblasts, resulting in lung fibrosis. In conclusion, our study supports the notion that as an initial step in IPF, the senescence process in AECs may be a potential therapeutic target, and the PTEN/NF‐κB pathway may be a promising candidate for intervention.
Год издания: 2018
Авторы: Yaqiong Tian, Hui Li, Ting Qiu, Jinghong Dai, Yingwei Zhang, Jingyu Chen, Hourong Cai
Издательство: Wiley
Источник: Aging Cell
Ключевые слова: Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis, Histiocytic Disorders and Treatments, Eosinophilic Disorders and Syndromes
Другие ссылки: Aging Cell (PDF)
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Europe PMC (PubMed Central) (PDF)
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PubMed Central (HTML)
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