Wong Aaron, Zamel Ricardo, Yeung Jonathan, Bader Gary D, Dos Santos Claudia C, Bai Xiaohui, Wang Yubo, Keshavjee Shaf, Liu Mingyao
Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
Latner Thoracic Surgical Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada.
Eur Respir J. 2020 Apr 9;55(4). doi: 10.1183/13993003.02222-2019. Print 2020 Apr.
The lung perfusion (EVLP) technique has been developed to assess the function of marginal donor lungs and has significantly increased donor lung utilisation. EVLP has also been explored as a platform for donor lung repair through injury-specific treatments such as antibiotics or fibrinolytics. We hypothesised that actively expressed pathways shared between transplantation and EVLP may reveal common mechanisms of injury and potential therapeutic targets for lung repair prior to transplantation.
Retrospective transcriptomics analyses were performed with peripheral tissue biopsies from "donation after brain death" lungs, with 46 pre-/post-transplant pairs and 49 pre-/post-EVLP pairs. Pathway analysis was used to identify and compare the responses of donor lungs to transplantation and to EVLP.
22 pathways were enriched predominantly in transplantation, including upregulation of lymphocyte activation and cell death and downregulation of metabolism. Eight pathways were enriched predominantly in EVLP, including downregulation of leukocyte functions and upregulation of vascular processes. 27 pathways were commonly enriched, including activation of innate inflammation, cell death, heat stress and downregulation of metabolism and protein synthesis. Of the inflammatory clusters, Toll-like receptor/innate immune signal transduction adaptor signalling had the greatest number of nodes and was central to inflammation. These mechanisms have been previously speculated as major mechanisms of acute lung injury in animal models.
EVLP and transplantation share common molecular features of injury including innate inflammation and cell death. Blocking these pathways during EVLP may allow for lung repair prior to transplantation.
肺灌注（EVLP）技术已被开发用于评估边缘供肺的功能，并显著提高了供肺的利用率。EVLP也被探索作为一个通过抗生素或纤溶剂等损伤特异性治疗来修复供肺的平台。我们假设，移植和EVLP之间共同活跃表达的通路可能揭示损伤的共同机制以及移植前肺修复的潜在治疗靶点。
对“脑死亡后捐献”肺的外周组织活检进行回顾性转录组学分析，有46对移植前/后样本和49对EVLP前/后样本。通路分析用于识别和比较供肺对移植和EVLP的反应。
22条通路主要在移植中富集，包括淋巴细胞活化和细胞死亡上调以及代谢下调。8条通路主要在EVLP中富集，包括白细胞功能下调和血管过程上调。27条通路共同富集，包括先天性炎症激活、细胞死亡、热应激以及代谢和蛋白质合成下调。在炎症簇中，Toll样受体/先天性免疫信号转导衔接子信号传导的节点数量最多，是炎症的核心。这些机制先前已被推测为动物模型中急性肺损伤的主要机制。
EVLP和移植具有包括先天性炎症和细胞死亡在内的共同损伤分子特征。在EVLP期间阻断这些通路可能有助于移植前的肺修复。
