Elucidation of the Mechanism of Mitochondrial DNA Release Mediated by Iron Metabolism in Idiopathic Pulmonary Fibrosis

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08214
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Nihon University
• Principal Investigator: MIZUMURA Kenji 日本大学, 医学部, 兼任講師 (20761688)
• Co-Investigator(Kenkyū-buntansha): 権 寧博 日本大学, 医学部, 教授 (80339316) ; 丸岡 秀一郎 日本大学, 医学部, 准教授 (80599358)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 特発性肺線維症 / 鉄代謝 / ミトコンドリアDNA / タバコ煙 / 線維化

Outline of Final Research Achievements

In this study, we focused on mtDNA as a second messenger in the control of pulmonary fibrosis, aiming to elucidate the mechanism by which iron metabolism mediates the extracellular release of mtDNA and its implications for fibrosis. We demonstrated that the iron metabolism pathway regulates the release of mtDNA from alveolar epithelial cells induced by cigarette smoke. The extracellular mtDNA acts on alveolar epithelial cells, enhancing the production of critical inflammatory cytokines such as IL-6 and IL-8, which are important in the pathophysiology of pulmonary fibrosis. In vivo, our findings suggest that the iron metabolism pathway regulates the development of pulmonary fibrosis. These results clarify the mechanism by which the iron metabolism pathway regulates pulmonary fibrosis through the release of mtDNA induced by cigarette smoke.

Free Research Field

呼吸器内科学

Academic Significance and Societal Importance of the Research Achievements

特発性肺線維症は肺の線維化を特徴とし, 予後不良であるが, 治療法は限られている. 本研究は, 肺線維化の新たなメカニズムとして鉄代謝とmtDNAに着目し, 診断と治療応用への研究基盤を確立することを目的とした. 本研究により, タバコ煙によるmtDNA放出を介した肺の線維化を, 鉄代謝経路が制御するメカニズムが明らかとなった. 肺線維症の病態形成において, mtDNAの細胞外放出が肺の線維化に関わり, 鉄代謝がその病態生理に中心的な役割を果たしている考えられ, 鉄代謝経路の制御は, 新たな特発性肺線維症の治療薬やバイオマーカーの開発につながる可能性がある.