Source: International Congress 2014 – Cell biology 2014
Disease area: Interstitial lung diseases

Abstract

Introduction: Accumulation of profibrotic myofibroblasts is a crucial step for fibrotic remodeling in idiopathic pulmonary fibrosis (IPF), and transforming growth factor (TGF)-bhas a key regulatory role in myofibroblast differentiation. Reactive oxygen species (ROS) has been proposed to be involved in the mechanism for TGF-b-induced myofibroblast differentiation. Metformin is a biguanide antidiabetic medication and its pharmacological action is mediated through the activation of AMPK, which regulates not only energy homeostasis but also stress responses including ROS. Hence, we hypothesized that metformin may modulate TGF-b-induced myofibroblast differentiation through the regulation of ROS production. Methods: Using human lung fibroblast (LFB), western blotting (WB) of alpha-smooth muscle actin (SMA) was performed to evaluate TGF-b-induced myofibroblast differentiation in the presence and absence of metformin. AMPK activation was detected by showing phosphorylation via WB. AMPK was inhibited by siRNA-mediated knockdown. CM-H2DCFDA was used to evaluate intracellular ROS production. Results: TGF-b induced myofibroblast differentiation, which was clearly inhibited by metformin treatment. AMPK inhibition illustrates that metformin-mediated activation of AMPK was responsible for suppression of TGF-b-induced myofibroblast differentiation. Intriguingly, metformin also suppressed TGF-b-induced NADPH oxidase 4 (NOX4) expression and ROS production via AMPK activation.Conclusion:Metformin suppresses NOX4 expression and ROS production via AMPK activation, resulting in inhibition of TGF-b-induced myofibroblast differentiation. Therefore, metformin may also be used for the treatment of IPF.

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N. Takasaka, J. Araya, Y. Kurita, K. Kobayashi, S. Ito, H. Wakui, Y. Yoshii, S. Minagawa, J. Kojima, H. Hara, T. Numata, K. Shimizu, M. Kawaishi, Y. Kaneko, K. Nakayama, K. Kuwano (Tokyo, Japan). Metformin inhibits TGF-b-induced myofibroblast differentiation through AMPK activation. Eur Respir J 2014; 44: Suppl. 58, 3854

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