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2016 ; 17
(1
): 107
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Metformin attenuates lung fibrosis development via NOX4 suppression
#MMPMID27576730
Sato N
; Takasaka N
; Yoshida M
; Tsubouchi K
; Minagawa S
; Araya J
; Saito N
; Fujita Y
; Kurita Y
; Kobayashi K
; Ito S
; Hara H
; Kadota T
; Yanagisawa H
; Hashimoto M
; Utsumi H
; Wakui H
; Kojima J
; Numata T
; Kaneko Y
; Odaka M
; Morikawa T
; Nakayama K
; Kohrogi H
; Kuwano K
Respir Res
2016[Aug]; 17
(1
): 107
PMID27576730
show ga
BACKGROUND: Accumulation of profibrotic myofibroblasts in fibroblastic foci (FF)
is a crucial process for development of fibrosis during idiopathic pulmonary
fibrosis (IPF) pathogenesis, and transforming growth factor (TGF)-? plays a key
regulatory role in myofibroblast differentiation. Reactive oxygen species (ROS)
has been proposed to be involved in the mechanism for TGF-?-induced myofibroblast
differentiation. Metformin is a biguanide antidiabetic medication and its
pharmacological action is mediated through the activation of AMP-activated
protein kinase (AMPK), which regulates not only energy homeostasis but also
stress responses, including ROS. Therefore, we sought to investigate the
inhibitory role of metformin in lung fibrosis development via modulating TGF-?
signaling. METHODS: TGF-?-induced myofibroblast differentiation in lung
fibroblasts (LF) was used for in vitro models. The anti-fibrotic role of
metfromin was examined in a bleomycin (BLM)-induced lung fibrosis model. RESULTS:
We found that TGF-?-induced myofibroblast differentiation was clearly inhibited
by metformin treatment in LF. Metformin-mediated activation of AMPK was
responsible for inhibiting TGF-?-induced NOX4 expression. NOX4 knockdown and
N-acetylcysteine (NAC) treatment illustrated that NOX4-derived ROS generation was
critical for TGF-?-induced SMAD phosphorylation and myofibroblast
differentiation. BLM treatment induced development of lung fibrosis with
concomitantly enhanced NOX4 expression and SMAD phosphorylation, which was
efficiently inhibited by metformin. Increased NOX4 expression levels were also
observed in FF of IPF lungs and LF isolated from IPF patients. CONCLUSIONS: These
findings suggest that metformin can be a promising anti-fibrotic modality of
treatment for IPF affected by TGF-?.
|AMP-Activated Protein Kinases/metabolism
[MESH]
|Animals
[MESH]
|Bleomycin
[MESH]
|Cell Differentiation/drug effects
[MESH]
|Cells, Cultured
[MESH]
|Cytoprotection
[MESH]
|Disease Models, Animal
[MESH]
|Dose-Response Relationship, Drug
[MESH]
|Enzyme Activation
[MESH]
|Humans
[MESH]
|Idiopathic Pulmonary Fibrosis/enzymology/genetics/pathology/*prevention & control
[MESH]
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