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Involvement of ER stress, PI3K/AKT activation, and lung fibroblast proliferation in bleomycin-induced pulmonary fibrosis.

Involvement of ER stress, PI3K/AKT activation, and lung fibroblast proliferation in bleomycin-induced pulmonary fibrosis.
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Hsu HS, Liu CC, Lin JH, Hsu TW, Hsu JW, Su K, Hung SC,


Hsu HS, Liu CC, Lin JH, Hsu TW, Hsu JW, Su K, Hung SC, (click to view)

Hsu HS, Liu CC, Lin JH, Hsu TW, Hsu JW, Su K, Hung SC,

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Scientific reports 2017 10 277(1) 14272 doi 10.1038/s41598-017-14612-5
Abstract

Pulmonary fibrosis is characterized by fibroblast proliferation and extracellular matrix remodelling, leading to respiratory insufficiency. The mechanisms underlying this progressive and devastating disease remain unclear. Conditions that can impair the function of the endoplasmic reticulum (ER) cause accumulation of unfolded or misfolded proteins, resulting in ER stress and activation of the unfolded protein response (UPR). ER stress has been implicated in many conditions including cancer, diabetes, obesity, and inflammation. It is also involved in lung fibrosis, through myofibroblastic differentiation of fibroblasts; however, the precise role of ER stress in lung fibrosis is unknown. The current study aimed to investigate the underlying mechanisms of ER stress inhibitors in the treatment of bleomycin-induced lung fibrosis. We demonstrated that bleomycin can activate ER stress associated proteins, including GRP78, CHOP, and ATF-4, both in vitro and in vivo. PI3K/AKT acts upstream of ER stress to affect lung fibroblast proliferation, resulting in bleomycin-induced pulmonary fibrosis. Treatment with ER stress inhibitors or a PI3K inhibitor caused a reduction in fibroblast proliferation and improved pulmonary function. The relationship between PI3K/AKT/mTOR and ER stress in pulmonary fibrosis, and the application of PI3K inhibitors and ER stress inhibitors in the treatment of pulmonary fibrosis require further investigation.

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