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이종욱Jong-Uk Lee

순천향대학교 부천병원

Exp. Mol. Med., Feb 28 2024, | https://doi.org/10.1038/s12276-024-01170-w Role of lung ornithine aminotransferase in idiopathic pulmonary fibrosis: regulation of mitochondrial ROS generation and TGF-β1 activity

Jong-Uk Lee¹, Ki Sung Song¹, Jisu Hong¹, Hyesun Shin¹, Eunji Park¹, Junyeong Baek¹, Shinhee Park¹, Ae-Rin Baek¹, Junehyuk Lee¹, An Soo Jang¹, Do Jin Kim¹, Su Sie Chin², U-Jin Kim³, Sung Hwan Jeong⁴and Sung-Woo Park¹

¹Division of Allergy and Respiratory Medicine, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 14584 Gyeonggi-Do, South Korea.

²Department of Pathology, Soonchunhyang University Bucheon Hospital, Bucheon 14584 Gyeonggi-Do, South Korea.

³Department of Internal Medicine, Environmental Health Center Kangwon National University, Gangwondaehakgil, Chuncheon-si, Gangwon-do, South Korea.

⁴Department of Allergy, Pulmonary and Critical Care Medicine, Gachon University, Gil Medical Center, Incheon, South Korea.

Corresponding author : Correspondence to Sung-Woo Park.

Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant lung remodeling and the excessive accumulation of extracellular matrix (ECM) proteins. In a previous study, we found that the levels of ornithine aminotransferase (OAT), a principal enzyme in the proline metabolism pathway, were increased in the lungs of patients with IPF. However, the precise role played by OAT in the pathogenesis of IPF is not yet clear. The mechanism by which OAT affects fibrogenesis was assessed in vitro using OAT-overexpressing and OAT-knockdown lung fibroblasts. The therapeutic effects of OAT inhibition were assessed in the lungs of bleomycin-treated mice. OAT expression was increased in fibrotic areas, principally in interstitial fibroblasts, of lungs affected by IPF. OAT levels in the bronchoalveolar lavage fluid of IPF patients were inversely correlated with lung function. The survival rate was significantly lower in the group with an OAT level >75.659 ng/mL than in the group with an OAT level ≤75.659 ng/mL (HR, 29.53; p = 0.0008). OAT overexpression and knockdown increased and decreased ECM component production by lung fibroblasts, respectively. OAT knockdown also inhibited transforming growth factor-β1 (TGF)-β1 activity and TGF-β1 pathway signaling. OAT overexpression increased the generation of mitochondrial reactive oxygen species (ROS) by activating proline dehydrogenase. The OAT inhibitor L-canaline significantly attenuated bleomycin-induced lung injury and fibrosis. In conclusion, increased OAT levels in lungs affected by IPF contribute to the progression of fibrosis by promoting excessive mitochondrial ROS production, which in turn activates TGF-β1 signaling. OAT may be a useful target for treating patients with fibrotic lung diseases, including IPF.

논문정보

형식Research article
게재일2024년 02월 (BRIC 등록일 2024-03-04)
연구진국내 연구진
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