Volume 288,
Issue 2,
2024
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特報
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第60回(2023年度)ベルツ賞受賞論文1等賞
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Source:
医学のあゆみ 288巻2号, 148-161 (2024);
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Idiopathic pulmonary fibrosis(IPF)is a chronic and progressive lung fibrotic disease belonging to idiopathic interstitial pneumonias. The 5-year survival of IPF is poor to be 30 to 50%, and therefore novel therapy has been required. From the 2000s, the concept of basic pathogenesis of IPF changed from chronic inflammation to chronic injury of alveolar epithelial cells and the subsequent aberrant repair. Based on the concept, the development of antifibrotic, not anti-inflammatory, drugs has been expected. We aimed a drug repositioning with molecular-targeting agents for cancer to develop antifibrotic therapy. We firstly focused on growth factors including platelet-derived growth factor (PDGF)as a therapeutic target, and demonstrated that imatinib showing the inhibitory effects of PDGF receptor (PDGFR)inhibited pulmonary fibrosis in mice. By an industry-academia collaboration, we found TAS-115 showing the strong inhibitory effect on PDGFR as a novel antifibrotic agents. The exploratory phase Ⅱa trial with TAS-115 against IPF patients showed the promising antifibrotic effects to reduce the decline of a forced vital capacity. The phase Ⅱb trial of TAS-115 is ongoing in Japan. To find out the novel target, we focused on the fibrocytes, which are recognized to be bone marrow-derived collagen-producing cells. We analyzed the profibrotic function of fibrocytes and found that fibrocytes had the paracrine effects to activate lung fibroblasts by producing of growth factor and releasing extracellular vesicles. To identify the specific marker for fibrocytes, we performed a single-cell RNA sequencing(scRNA-seq)of CD45+ cells in both tumor and fibrotic lung tissues in mouse models. From scRNA-seq of tumor-infiltrating CD45+ cells, we successfully identified fibrocyte clusters and found the specific marker of fibrocytes. We are developing the novel antifibrotic therapy targeting to fibrocytes with specific antibodies. We hope that our basic and clinical research will lead to develop novel antifibrotic drugs for patients with IPF.
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第60回(2023年度)ベルツ賞受賞論文2等賞
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Source:
医学のあゆみ 288巻2号, 162-175 (2024);
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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 cel(l 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 Sjögrenʼs 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.