2024 Fiscal Year Final Research Report

Translational research of ischemia reperfusion injury after lung transplantation from donation after circulatory death

Research Project

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Project/Area Number	20KK0203
Research Category	Fund for the Promotion of Joint International Research (Fostering Joint International Research (B))
Allocation Type	Multi-year Fund
Review Section	Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
Research Institution	Okayama University
Principal Investigator	Okazaki Mikio 岡山大学, 医歯薬学域, 准教授 (50467750)
Co-Investigator(Kenkyū-buntansha)	坂上倫久愛媛大学, 医学系研究科, 講師(特定教員) (20709266) 豊岡伸一岡山大学, 医歯薬学域, 教授 (30397880) 塩谷俊雄岡山大学, 医学部, 客員研究員 (90851246) 田中真岡山大学, 大学病院, 助教 (20831308)
Project Period (FY)	2020-10-27 – 2025-03-31
Keywords	肺移植 / 虚血再灌流障害 / 心停止ドナー / 脳死ドナー / NR4A1
Outline of Final Research Achievements	In Japan, lungs from donors after cardiac death (DCD) are not yet in clinical use, as they are prone to graft dysfunction due to ischemia-reperfusion injury (IRI) caused by warm ischemia. It is therefore essential to elucidate their pathophysiology and identify potential therapeutic targets. We conducted a comprehensive gene expression analysis on clinical lung transplant samples from both DCD and brain-dead donors (DBD), collected at Puerta de Hierro University Hospital in Spain. The gene expression profiles were clearly distinct: inflammation-related genes were highly expressed in DBD lungs, whereas genes associated with DNA damage and repair were prominently expressed in DCD lungs. Among these, we identified NR4A1 as a potential therapeutic target. Using a mouse lung transplant model, we demonstrated that knockout of NR4A1 in DCD lungs suppressed IRI.
Free Research Field	肺移植
Academic Significance and Societal Importance of the Research Achievements	我々はマウス肺移植モデルを用いて、未だに不明な部分の多いDCD肺に対する基礎研究を行ってきたが、次の段階としてスペインPuerta de Hiello大学病院と国際共同研究を行った。DCDおよびDBD肺移植後の臨床検体に対して網羅的遺伝子解析を実施し、両者の遺伝子発現パターンは全く異なっていることを明らかにした。これによって、DCD肺移植後のIRIに対しては、DBD肺移植とは異なった治療法が必要であることが示唆された。今回検証したNR4A1以外にもDCD肺移植後のIRIに対する治療標的候補となる遺伝子を多数同定できており、今後のDCD肺移植後のIRIに特化した治療開発に繋げていく。