The elucidation of the pathogenesis of lung hypoplasia with CDH, focusing on the abnormalities of the bronchial cartilage and smooth muscle

2023 Fiscal Year Final Research Report

• Project/Area Number: 19K09101
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Tando So 京都府立医科大学, 医学(系)研究科(研究院), 助教 (80423870)
• Project Period (FY): 2019-04-01 – 2024-03-31
• Keywords: CDH / lung hypoplasia / primary cilia

Outline of Final Research Achievements

To elucidate the pathogenesis of lung hypoplasia with Congenital diaphragmatic hernia (CDH), we analyzed autopsied lungs using morphological techniques to assess the bronchial cartilage and alveolar maturity. The results indicated that opposite directional cartilage abnormalities around the distal and more proximal bronchi support our hypothesis that abnormal development of bronchial cartilage might play an essential role in the hypoplastic lung in CDH. Next, we showed the abnormalities of the tracheal cartilage in the nitrofen-induced CDH rat and performed the bulk RNA-seq using the E18 trachea of the CDH rat. The data indicated the downregulation of the cilia-related genes. Histologically, the primary cilia lengths in the abnormal cartilage were shorter than those of the control. Moreover, we found the downregulation of MAPKAP1 and pAkt in the abnormal cartilage, suggesting that primary cilia and the mTOR2 might be related to the pathogenesis of the abnormal cartilage in CDH.

Free Research Field

Pathology

Academic Significance and Societal Importance of the Research Achievements

先天性横隔膜ヘルニア(CDH)の重症度は、肺低形成の程度によって左右される。近年、救命率は向上しているが、依然として約20%の重症例は救命できていない。我々は、肺内気管支軟骨の異常が、CDHに伴う肺低形成の病態に深く関与していることを明らかにし、その病因として、一次繊毛の異常があることを示した。CDHの病態を繊毛の異常という観点からとらえなおすことは、新規治療法を考える上で、意義がある。