Investigation into molecular basis of sterile inflammation in pulmonary fibrosis

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K17222
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Jichi Medical University
• Principal Investigator: Mizushina Yoshiko 自治医科大学, 医学部, 講師 (70458321)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 炎症 / 細胞死 / 細胞・組織 / 肺疾患 / 免疫学

Outline of Final Research Achievements

We investigated the role of pyroptosis in acute exacerbation of idiopathic pulmonary fibrosis using the nanosilica-induced acute lung injury (ALI) model. Although nanosilica induced GSDME processing by activating caspase-3 in pulmonary epithelial cell line A549 cells, cell death was not ameliorated in caspase-3-deficient A549 cells. Therefore, we focused on another type of regulated cell death, necroptosis. The RIP3 inhibitor (necroptosis inhibition) ameliorated nanosilica-induced A549 cell death. These results suggest that necroptosis contributes to nanosilica-induced alveolar epithelial cell death.

Free Research Field

呼吸器内科学

Academic Significance and Societal Importance of the Research Achievements

IPF急性増悪やCOVID-19肺炎の重症化機序にはALI/ARDSが関与し、COVID-19肺炎ではNLRP3インフラマソームの活性化やPyroptosisが関与していることが報告されている。しかしながら、ALIの病因におけるPyroptosisの役割や肺胞上皮細胞のPyroptosisは不明な点が多く、本研究の新規性は高い。本研究の成果は、ALIの病態解明や新たな治療戦略の開発にも繋がることが期待される。さらにPyroptosis以外の細胞死の関与やPyroptosisが惹起される機序を解明することで、無菌性炎症が関与する様々な疾患の病態解明にも役立つ可能性がある。