Gao Xinliang, Tang Mingbo, Li Jialin, Ma Jianzun, Liu Zhengrui, Liu Wei
Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, 130021, China.
Changchun Yifu Jilin Province Academician Workstation, Changchun, China.
Respir Res. 2025 Feb 27;26(1):69. doi: 10.1186/s12931-025-03151-7.
Lung transplantation is the primary treatment for end-stage lung diseases. However, ischemia-reperfusion injury (IRI) significantly impacts transplant outcomes. 4-Octyl itaconate (4-OI) has shown potential in mitigating organ IRI, although its effects in lung transplantation require further exploration.
BEAS-2B cells were used to model transplantation, assessing the effects of 4-OI through viability, apoptosis, and ROS assays. qRT-PCR analyzed cytokine transcription post-cold ischemia/reperfusion (CI/R). RNA sequencing and Gene Ontology analysis elucidated 4-OI's mechanisms of action, confirmed by Western blotting. ALI-airway and lung transplantation organoid models evaluated improvements in bronchial epithelial morphology and function due to 4-OI. ELISA measured IL-6 and IL-8 levels. Rat models of extended cold preservation and non-heart-beating transplantation assessed 4-OI's impact on lung function, injury, and inflammation.
Our findings indicate that 4-OI (100 µM) during cold preservation effectively maintained cell viability, decreased apoptosis, and reduced ROS production in BEAS-2B cells under CI/R conditions. It also downregulated pro-inflammatory cytokine transcription, including IL1B, IL6, and TNF. Inhibition of Nrf2 partially reversed these protective effects. In cold preservation solutions, 4-OI upregulated Nrf2 target genes such as NQO1, HMOX1, and SLC7A11. In ALI airway models, 4-OI enhanced bronchial epithelial barrier integrity and ciliary beat function after CI/R. In rat models, 4-OI administration improved lung function and reduced pulmonary edema, tissue injury, apoptosis, and systemic inflammation following extended cold preservation or non-heart-beating lung transplantation.
Incorporating 4-OI into cold preservation solutions appears promising for alleviating CI/R-induced bronchial epithelial injury and enhancing lung transplant outcomes via Nrf2 pathway activation.
肺移植是终末期肺部疾病的主要治疗方法。然而，缺血再灌注损伤（IRI）对移植结果有显著影响。尽管4-辛基衣康酸（4-OI）在减轻器官IRI方面显示出潜力，但其在肺移植中的作用仍需进一步探索。
使用BEAS-2B细胞建立移植模型，通过活力、凋亡和活性氧（ROS）检测评估4-OI的作用。qRT-PCR分析冷缺血/再灌注（CI/R）后细胞因子的转录情况。RNA测序和基因本体分析阐明4-OI的作用机制，并通过蛋白质免疫印迹法进行验证。ALI气道和肺移植类器官模型评估4-OI对支气管上皮形态和功能的改善作用。酶联免疫吸附测定法（ELISA）检测白细胞介素-6（IL-6）和白细胞介素-8（IL-8）水平。延长冷保存和非心跳供体肺移植大鼠模型评估4-OI对肺功能、损伤和炎症的影响。
我们的研究结果表明，在冷保存期间加入4-OI（100 μM）可有效维持BEAS-2B细胞在CI/R条件下的活力，减少细胞凋亡，并降低ROS生成。它还下调了促炎细胞因子的转录，包括白细胞介素-1β（IL1B）、IL-6和肿瘤坏死因子（TNF）。抑制核因子E2相关因子2（Nrf2）可部分逆转这些保护作用。在冷保存溶液中，4-OI上调了Nrf2靶基因，如醌氧化还原酶1（NQO1）、血红素加氧酶1（HMOX1）和溶质载体家族7成员11（SLC7A11）。在ALI气道模型中，4-OI可增强CI/R后支气管上皮屏障的完整性和纤毛摆动功能。在大鼠模型中，给予4-OI可改善延长冷保存或非心跳供体肺移植后的肺功能，减轻肺水肿、组织损伤、细胞凋亡和全身炎症反应。
将4-OI加入冷保存溶液中似乎有望通过激活Nrf2途径减轻CI/R诱导的支气管上皮损伤并提高肺移植效果。
