Nox4-Brd4 interaction induced lung fibroblast-mediated lung fibrosis

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K17226
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Juntendo University
• Principal Investigator: Kanemaru Ryota 順天堂大学, 大学院医学研究科, 助教 (70869156)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 肺線維芽細胞 / BRD4 / NOX4

Outline of Final Research Achievements

Previous studies have shown that bromodomain-containing protein 4 (Brd4), a kind of the bromodomain and extraterminal family of proteins that function as epigenetic gene regulator, plays an important role in lung fibrosis and Brd4 inhibitor suppressed lung fibrosis of mice induced by bleomycin. The recent paper suggested that Brd4 inhibition in lung fibroblasts downregulate Nox4 gene expression, but its details was not clarified. Brd4 inhibitors suppressed TGF-β1-induced collagen gel contraction, chemotaxis and αSMA , fibronectin through the down-regulation of Nox4 in lung fibroblast. Nox4 inhibitor suppressed lung fibrosis and 4-HNE, a stable marker for oxidative stress in the BLM induced fibrotic lung. Brd4/ Nox4 inhibition might be as an effective strategy for the treatment of fibrotic lung.

Free Research Field

呼吸器疾患、間質性肺疾患

Academic Significance and Societal Importance of the Research Achievements

肺線維症の線維化メカニズムの基礎的研究から創出される革新的な新規薬剤への開発へとつながることが多いに期待される。本研究は、実際のヒト肺線維症患者の肺線維芽細胞を用いて検証する説得性と、肺線維芽細胞及び無レオマイシン誘発肺線維症を用いた直接的な線維化メカニズムの解明により、BRD4のNOX4を介した線維化を制御する重要な治療標的となりうることを証明した。本研究の成果は更なる抗線維化作用をもつ新規薬剤の開発へ直結する、医学的貢献度の高い研究である。