間質性肺疾患の病態解明を目指した臨床・基礎研究

Clinical and basic research to elucidate the pathogenesis of interstitial lung disease

抄録

　間質性肺疾患の病態には動的ストレスや環境，加齢などの要因が複雑に関与し多彩な病態を示すため，疾患分類や層別化が明確ではなく，治療法も十分に確立していない．私共は，関連施設を含めた豊富な臨床症例を基盤に画像解析などの技術を用いた臨床研究からiPS細胞（induced pluripotent stem cells）研究をはじめとする基礎研究まで多面的に展開することにより，その病態解明と治療法の開発に取り組んできた．

　シェーグレン症候群関連間質性肺炎やサルコイドーシス，特発性胸膜肺実質線維弾性症（pleuroparenchymal fibroelastosis：PPFE）といった希少難病を対象として臨床，画像，病理学的な検討を行い，その疫学や肺の線維化病態の重要性を明らかにした．また，独自開発したソフトウェアや人工知能，数理モデルを用いた共同研究によって間質性肺炎の胸部CT画像定量化技術を開発し，客観的で再現性のある胸部CTの評価方法を確立した．さらに，特発性肺線維症や皮膚筋炎関連間質性肺疾患の予後予測に有用な血清・気管支肺胞洗浄液のバイオマーカーを同定した．これらの研究成果は，難治性間質性肺疾患の病態解明や創薬ターゲットの創出に寄与することが期待される．

　基礎研究の面では，世界に先駆けてiPS細胞から肺胞上皮を分化誘導し，長期培養する技術を開発した．その技術を用いて遺伝性間質性肺炎のひとつであるHermansky-Pudlak症候群の病態を解明した．また，家族性肺線維症から疾患iPS細胞を樹立し，間質性肺炎の病態解明と創薬研究を展開している．さらに，基礎研究で得られたシーズや臨床研究で確立した画像定量化技術を応用して，間質性肺炎と類似した画像を呈する新型コロナウイルス肺炎を対象とした新薬の多施設前向き臨床試験を進めており，今後は同薬剤を用いた間質性肺炎の急性増悪の臨床試験も予定している．

Abstract

　Because the pathogenesis of interstitial lung disease（ILD）is complex and diverse, involving factors such as dynamic stress, the environment, and aging, disease classification and stratification are not clear, and treatment methods have not been well established. Based on abundant clinical cases at affiliated hospitals, we have been conducting cooperative studies of clinical and basic research, applying CT image analysis and induced pluripotent stem cell（iPS cell）research technology to elucidate the pathophysiology and develop treatments for ILDs.

　Clinical, radiological, and pathological studies were conducted on rare intractable lung diseases such as Sjögren’s syndrome-related interstitial pneumonia, sarcoidosis, and idiopathic pleuroparenchymal fibroelastosis（PPFE）to clarify their epidemiology and the clinical relevance of lung fibrosis in these diseases. In addition, through the development of in-house software using mathematical models and industry-academia collaborative research applying artificial intelligence, we developed a technology for quantifying chest CT images of interstitial pneumonia and established an objective and reproducible evaluation method for chest CT. Furthermore, we identified biomarkers in serum and bronchoalveolar lavage fluid that are useful in predicting the prognosis of idiopathic pulmonary fibrosis and polymyositis/dermatomyositis-related ILDs. These research results are expected to contribute to the elucidation of the pathogenesis of intractable ILDs and the creation of new drug targets.

　In terms of basic research, we were the first in the world to develop a technology for efficient generation and long-term culture of alveolar epithelial cells from iPS cells. Applying this technology, we elucidated the pathogenesis of Hermansky-Pudlak syndrome, a form of hereditary interstitial pneumonia. We also established iPS cells from patients with familial pulmonary fibrosis to elucidate the pathogenesis of interstitial pneumonia and to conduct drug discovery research. Furthermore, by applying information obtained from basic research and image quantification technology established in clinical research, we are conducting a multicenter prospective clinical trial of a new drug for the novel coronavirus pneumonia that presents with chest CT images similar to ILDs. We are also planning to conduct clinical trials of the drug for acute exacerbations of interstitial pneumonia.