Zhang Yufei, Liu Tao, Guo Huaizu, Shi Jianxin, Yang Jun, Fu Shijie, Pan Xufeng, Li Feng, Zhang Hai, Zhang Dawei, Yang Hong, Zheng Lulu, Shi Meng, Zhou Wenyong
Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
Int J Surg. 2025 Jun 1;111(6):3781-3797. doi: 10.1097/JS9.0000000000002438. Epub 2025 May 16.
Ischemia/reperfusion injury (IRI) presents a significant hurdle in lung transplantation. Our previous research showed that the glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide (Lir) improves lipopolysaccharide-induced acute lung injury in murine models. This study aims to further investigate the lung-protective mechanisms of GLP-1R agonist.
An in vitro hypoxia/reoxygenation (H/R) model with BEAS-2B cells and an in vivo donation after cardiac death (DCD) rat lung transplant model were utilized. Lir was administered using an ex vivo lung perfusion (EVLP) system. Lung function, injury, and pyroptosis mechanisms were assessed. Validation experiments included quantitative reverse transcription PCR, immunoblot analysis, activity assays and proteomic analysis, among others, to evaluate how GLP-1R agonist protect lungs from IRI by modulating pyroptosis, thereby improving lung function and reducing injury.
Perfusion of the donor lung with Lir using EVLP improved the function of DCD lungs and mitigated IRI. Bioinformatics analysis and validation experiments provided evidence of increased expression of NOD-like receptors signals and pyroptosis in lung transplantation IRI, which was suppressed by Lir treatment. Further investigations revealed that the thioredoxin-binding protein (TXNIP) played a crucial regulatory role in the pyroptosis of IRI, with the NOD-like receptor family pyrin domain-containing 3 (NLRP3) emerging as a key target. In addition, this study found that Lir promotes GLP-1R-dependent TXNIP ubiquitination and modulates TXNIP mRNA stability via the GLP-1R/miR-17 axis.
This study demonstrates, for the first time, that a novel EVLP-based drug delivery approach using GLP-1R agonist can protect lungs from IRI by modulating pyroptosis, thereby improving lung function and reducing injury. The research uncovers a previously unknown mechanism where GLP-1R agonist modulates the protein TXNIP through GLP-1R/miR-17 signaling. These insights underscore the potential of GLP-1R agonists as targeted therapies for primary graft dysfunction in lung transplant recipients, opening new avenues for clinical interventions to improve transplant outcomes.
缺血/再灌注损伤（IRI）是肺移植中的一个重大障碍。我们之前的研究表明，胰高血糖素样肽-1受体（GLP-1R）激动剂利拉鲁肽（Lir）可改善小鼠模型中脂多糖诱导的急性肺损伤。本研究旨在进一步探究GLP-1R激动剂的肺保护机制。
使用BEAS-2B细胞建立体外缺氧/复氧（H/R）模型，并采用心脏死亡后供体（DCD）大鼠肺移植模型。通过体外肺灌注（EVLP）系统给予Lir。评估肺功能、损伤及焦亡机制。验证实验包括定量逆转录PCR、免疫印迹分析、活性测定和蛋白质组学分析等，以评估GLP-1R激动剂如何通过调节焦亡保护肺免受IRI影响，从而改善肺功能并减轻损伤。
使用EVLP向供体肺灌注Lir可改善DCD肺的功能并减轻IRI。生物信息学分析和验证实验提供了证据，表明肺移植IRI中NOD样受体信号和焦亡的表达增加，而Lir治疗可抑制这种增加。进一步研究表明，硫氧还蛋白结合蛋白（TXNIP）在IRI的焦亡中起关键调节作用，含NOD样受体家族pyrin结构域蛋白3（NLRP3）是关键靶点。此外，本研究发现Lir促进GLP-1R依赖性TXNIP泛素化，并通过GLP-1R/miR-17轴调节TXNIP mRNA稳定性。
本研究首次证明，一种基于EVLP的新型药物递送方法，即使用GLP-1R激动剂，可通过调节焦亡保护肺免受IRI影响，从而改善肺功能并减轻损伤。该研究揭示了一种此前未知的机制，即GLP-1R激动剂通过GLP-1R/miR-17信号调节蛋白TXNIP。这些见解强调了GLP-1R激动剂作为肺移植受者原发性移植物功能障碍靶向治疗的潜力，为改善移植结局的临床干预开辟了新途径。
