Functional Analysis of Pulmonary Fibrosis Pulmonary Fibroblasts for Novel Antifibrotic Drug Development.

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K17647
• 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: Koyama Ryo 順天堂大学, 医学部, 准教授 (10365611)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: 特発性肺線維症 / 肺線維芽細胞 / トランスフォーミング増殖因子β(TGF-β)

Outline of Final Research Achievements

Lysophosphatidic acid (LPA), generated extracellularly by the action of autotaxin through LPA receptors (LPARs) to induce pro-fbrotic signaling in patients with idiopathic pulmonary fibrosis. We hypothesized that the autotaxin/LPA axis-induced changes in human lung fibroblasts play an important role in the lung fibrosis. The ability of fibroblasts to mediate TGF-β1 or LPA inducing migration and contraction of three-dimensional type I collagen gels was assessed in the presence of GLPG1690 and BMS-986020.
GLPG1690 and BMS-986020 significantly suppressed TGF-β1 and LPA inducing collagen gel contraction, migration and the expression of α-SMA and fibronectin through Rho/ROCK signal (p<0.05). The response to TGF-β1 and LPA-stimulating collagen gel contraction and migration were greater in lung fibrosis fibroblasts than in normal lung fibroblasts. Autotaxin/LPA axis is the key therapeutic target to suppress Rho/ROCK signal mediated lung fibrosis in lung fibroblasts.

Free Research Field

間質性肺炎、肺がん、呼吸器疾患

Academic Significance and Societal Importance of the Research Achievements

肺線維症の線維化のメカニズムの基礎的研究から創出される、新たな知見がこの未だ有効な治療法のない肺線維症患者のための革新的な新規薬剤への開発へとつながることが十分に期待される。本研究は、実際のヒト肺線維症の肺線維芽細胞を用いて検証する説得性と、肺線維芽細胞を介する直接的な線維化メカニズムの解明により、Rho/ROCK経路を介したオートタキシン/リゾホスファチジン酸経路の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。本研究成果は更なる新規抗線維化薬の開発へ直結する、極めて医学的貢献度の高い研究である。