Investigation of the roles of alveolar macrophages in connective tissue disease-associated interstitial lung disease with progressive fibrosis

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K16304
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Fujii Wataru 京都府立医科大学, 医学部附属病院, 専攻医 (60755643)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 膠原病関連間質性肺疾患 / 進行性線維化を伴う間質性肺疾患 / 肺胞マクロファージ / 好中球 / 気管支肺胞洗浄液 / scRNA-seq

Outline of Final Research Achievements

Progressive fibrosing interstitial lung disease (PF-ILD) is a problem in interstitial lung diseases such as connective tissue disease-associated interstitial lung disease (CTD-ILD), despite appropriate treatment, but its pathogenesis is still unclear and there are no specific biomarkers. In this study, we found that the inflammatory cytokine IL-6 and the complement C3a, C4a and C5a levels were elevated in bronchoalveolar lavage fluid (BALF) of patients with CTD-ILD who fulfilled the PF-ILD definition. We also found by scRNA-seq that chemokine-positive alveolar macrophages and MMP9-positive neutrophils and immature neutrophils were increased in PF-ILD patients. These findings suggest that abnormalities in the innate immune system are involved in the pathogenesis of progressive pulmonary fibrosis.

Free Research Field

膠原病、間質性肺疾患、トランスクリプトーム

Academic Significance and Societal Importance of the Research Achievements

本研究によって膠原病関連間質性肺疾患(CTD-ILD)の中で免疫抑制治療にも関わらず進行性肺線維化をきたすPF-ILDの免疫学的特徴が明らかとなった。すなわち、PF-ILD患者BALF中でIL-6と補体成分C3a, C4a, C5aが上昇し、ケモカイン陽性肺胞マクロファージとMMP9陽性好中球、未成熟好中球が増加していた。これらの研究結果から肺胞マクロファージと好中球の相互作用と機能変化がPF-ILDの主たる病態であると考えられ、これら自然免疫系細胞サブセットや液性因子の変化がPF-ILDを予測するバイオマーカーや新たな治療標的候補となり得るか、今後前向き試験により検証を進める予定である。