Source: International Congress 2014 – Novel approaches in transcriptomics and epigenomics in inflammatory lung diseases and lung cancer
Disease area: Interstitial lung diseases

Abstract

Introduction:Contractile myofibroblast accumulation has been implicated in pathological lung remodeling. We have reported the involvement of insufficient autophagy, a process of lysosomal self-degradation, in myofibroblast differentiation. Insufficient mitophagy, the selective autophagic degradation of mitochondria, results in increased reactive oxygen species (ROS) production. ROS is involved in the process of myofibroblast differentiation through the modulation of cell signaling pathways. Methods:To explore the regulatory role of mitophagy in ROS production and its involvement in myofibroblast differentiation, human lung fibroblasts were used in vitro. Transfection of PINK1 and Parkin siRNA were performed to inhibit mitophagy. DCFH-DA and MitoSOX Red were used to evaluate ROS production, and NAC and MitoTEMPO were employed for inhibition of ROS. Wortmannin and AG1296 were used to inhibit PI3K-Akt pathway and PDGF receptor (PDGFR) tyrosine kinase, respectively. Results:Inhibition of mitophagy via PINK1 and Parkin knockdown increased mitochondrial ROS production and induced myofibroblast differentiation, which was inhibited by treatment with anti-oxidants. Mitophagy inhibition activated PI3K-Akt pathway, and both wortmannin and Akt1/2 kinase inhibitor abrogated myofibroblast differentiation. PDGFR-mediated signaling was partly responsible for myofibrobalst differentiation in the setting of insufficient mitophagy, as elucidated by anti-oxidants and AG1296 treatments. Conclusion:These findings suggest insufficient mitophagy-induced ROS production with subsequent PDGFR-PI3K-Akt activation is a potent underlying mechanism for myofibroblast differentiation in the pathogenic sequence of fibrotic lung disorders.

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K. Kobayashi, J. Araya, H. Hara, Y. Kurita, S. Ito, N. Takasaka, S. Fujii, S. Minagawa, J. Kojima, T. Numata, K. Shimizu, M. Kawaishi, Y. Kaneko, T. Morikawa, K. Nakayama, K. Kuwano (Tokyo, Japan). Mitophagic regulation of myofibroblast differentiation in lung fibroblasts. Eur Respir J 2014; 44: Suppl. 58, 401

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