A treatment strategy for pulmonary fibrosis targeting fibroblast adaptation to tissue acidosis

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08157
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Tokyo Medical University
• Principal Investigator: Aoshiba Kazutetsu 東京医科大学, 医学部, 教授 (60231776)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 肺線維症 / 間質性肺炎 / 線維芽細胞 / アシドーシス / 炭酸脱水素酵素 IX

Outline of Final Research Achievements

Recent studies have shown that fibrotic tissue particularly in the lung is acidic because of enhancement of glycolysis due to tissue hypoxia. This study was aimed to determine whether carbonic anhydrase IX, which regulates extracellular and intracellular pH, plays an important role in the survival and activation of fibroblasts in pulmonary fibrosis. We found that treatment of normal human fibroblasts with transforming growth factor β induced extracellular acidification by stimulating glycolysis. We also found that treatment of bleomycin-exposed mice with U-104, a selective inhibitor of carbonic anhydrase IX, improved lung tissue accumulation of collagen and lung tissue stiffness. These results suggest that CA IX is a therapeutic target for pulmonary fibrosis.

Free Research Field

呼吸器内科学

Academic Significance and Societal Importance of the Research Achievements

特発性肺線維症の治療成績は十分ではなく、新規治療薬の開発が望まれている。近年、線維化肺組織では解糖系が亢進して酸性化していることが報告されているが、本研究では肺線維芽細胞が線維化組織で生存、活性化するためには細胞内外のpHを調節するCarbonic anhydrase IX (CA IX)が重要な役割を果たしていることが示された。CA IXは肺線維症の新しい治療標的になると考えられた。