Molecular and genetic research on the development and maintenance of alveolar structure in the lung.

2021 Fiscal Year Final Research Report

• Project/Area Number: 19H03382
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: Kobe Pharmaceutical University
• Principal Investigator: Emoto Noriaki 神戸薬科大学, 薬学部, 教授 (30294218)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: エンドセリン / 気管支肺異形成 / 慢性閉塞性肺疾患 / 肺線維症

Outline of Final Research Achievements

The aim of this research was to investigate the molecular mechanisms of the alveologenesis of the lungs and pathophysiological roles of endothelin-2 (ET-2) in the respiratory diseases.
The single cell RNA sequencing analysis demonstrated that the number of the activated undifferentiated neutrophils increased in the lungs of ET-2 deficient mice. The expression of ET-2 was confirmed in the pulmonary epithelial cells and vascular endothelial cells. However, both of the pulmonary epithelial cell-specific ET-2 deletion mice and the vascular endothelial cell-specific ET-2 deletion mice exhibited the normal alveologenesis, suggesting that ET-2 expressed in these cells are not essential for the alveologenesis. ET-2 deletion in epithelial cells of mice results in the exacerbation of bleomycin-induced pulmonary fibrosis, indicating that ET-2, expressed in epithelial cells, exerts protective effects against the development of pulmonary fibrosis in mice.

Free Research Field

血管生物学

Academic Significance and Societal Importance of the Research Achievements

分子の発見から30年あまりを経て、今なおET-2の生理学的・病態生理学的役割は謎に包まれている。今回、ET-2が肺において肺胞成熟ならびに肺胞構造の維持に重要な役割を果たしていることを明らかにし、その分子機構に迫る知見を得た。さらに肺線維症を含め呼吸器疾患の病態に対しET-2が保護的に働くことを示した。
エンドセリン受容体拮抗薬は、肺高血圧症やくも膜下出血後の血管攣縮予防として臨床応用されているが、その標的はET-2のアイソペプチドであるET-1と考えられている。ET-2の機能解析は、作用を最大限にし、副作用を最小限にしたエンドセリン受容体拮抗薬の開発に重要な情報をもたらすことが期待される。