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Involvement of ER stress, PI3K/AKT activation, and lung fibroblast proliferation
in bleomycin-induced pulmonary fibrosis
#MMPMID29079731
Hsu HS
; Liu CC
; Lin JH
; Hsu TW
; Hsu JW
; Su K
; Hung SC
Sci Rep
2017[Oct]; 7
(1
): 14272
PMID29079731
show ga
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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