Ex vivo perfusion in a lung box for rehabilitation of donor lungs

肺箱中的离体灌注用于供体肺的康复

• 批准号: 8847791
• 负责人: Irving L. Kron
• 金额: $ 64.77万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8847791
• 关键词: Address; Adenosine; Agonist; Alveolar; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Biological Preservation; Boxing; Brain Death; Cardiac Death; Cells; Clinical Trials; Cryopreservation; Data; Epithelial Cells; Family suidae; Flow Cytometry; Functional disorder; Health; Heart Arrest; Human; Hypoxia; IL8 gene; Individual; Infiltration; Inflammation; Injury; Lung; Lung Transplantation; Measures; Mediating; Methods; Modeling; Mus; Neutrophil Infiltration; Organ; Patients; Perfusion; Plague; Prevention; Production; Purinergic P1 Receptors; Rehabilitation therapy; Reperfusion Injury; Respiratory physiology; Techniques; Testing; Time; Translating; Transplantation; Waiting Lists; Warm Ischemia; base; chemokine; cytokine; ex vivo perfusion; graft failure; improved; interest; lung ischemia; neutrophil; novel strategies; pre-clinical; prevent; receptor

DESCRIPTION (provided by applicant): The majority of potential donor lungs are rejected for transplantation and thus many patients die while waiting for a suitable donor. Donor lungs are typically retrieved from individuals after brain death; however, there is renewed interest in utilizing non-heart- beating donor (NHBD) lungs retrieved after cardiac death. The major challenge for utilization of NHBD lungs is the difficulty in assessing function after a warm ischemic period which results in significant injury. Two novel approaches show promise to greatly expand the utilization of NHBD lungs: 1) use of a "lung box" for ex vivo lung perfusion (EVLP) to assess and rehabilitate lungs prior to transplantation, and 2) use of adenosine 2A receptor (A2AR) agonist to rehabilitate lungs and prevent ischemia-reperfusion (IR) injury. This proposal combines these two approaches to perfect a lung box-based method of EVLP to assess and therapeutically rehabilitate NHBD lungs for successful transplantation. We have demonstrated the rehabilitation and successful transplantation of NHBD porcine lungs after EVLP with an A2AR agonist, and we have demonstrated that an adenosine 2B receptor (A2BR) antagonist attenuates IR injury. Thus our proposed studies will test the hypothesis that NHBD lungs can be rehabilitated for successful transplantation by EVLP-mediated therapy using an A2AR agonist or A2BR antagonist. We will test this hypothesis with three aims. Aim 1 will use a porcine lung transplant model to determine if EVLP with A2AR agonist can safely extend both warm and cold ischemic times of NHBD lungs. Aim 2 will determine if EVLP with A2AR agonist therapy will rehabilitate marginal and previously rejected human donor lungs to an acceptable state for transplantation. Aim 3 will determine if EVLP with A2BR antagonist will rehabilitate porcine and human NHBD lungs. Within each aim, we will also determine if the rehabilitation of NHBD lungs by EVLP entails the inhibition of NKT cell activation, epithelial cell activation and neutrophil infiltration. This project addresses two major problems that plague lung transplantation: far too few suitable lungs for transplant and primary graft failure after transplat due to IR injury. If NHBD lungs can be safely rehabilitated for transplantation, then the lung donor shortage could be eliminated. Thus this project will provide a means to greatly extend the donor lung pool size and support clinical trials aimed at saving many more lives of those patients on the lung transplant waiting list.

描述（由申请人提供）：大多数潜在的供体肺都被拒绝移植，因此许多患者在等待合适的供体时死亡。供体肺通常是从脑死亡后的个体中取出的。然而，人们对利用心源性死亡后回收的无心跳供体（NHBD）肺重新产生了兴趣。利用 NHBD 肺的主要挑战是在导致严重损伤的热缺血期后难以评估功能。两种新方法有望大大扩大 NHBD 肺的利用：1）使用“肺盒”进行离体肺灌注（EVLP）以在移植前评估和恢复肺，2）使用腺苷 2A 受体（A2AR） ) 激动剂，可恢复肺部并预防缺血再灌注 (IR) 损伤。该提案结合了这两种方法来完善基于肺盒的 EVLP 方法，以评估和治疗性康复 NHBD 肺部，以实现成功移植。我们已经证明了使用 A2AR 激动剂进行 EVLP 后 NHBD 猪肺的康复和成功移植，并且我们已经证明腺苷 2B 受体 (A2BR) 拮抗剂可以减轻 IR 损伤。因此，我们提出的研究将检验这样的假设：使用 A2AR 激动剂或 A2BR 拮抗剂通过 EVLP 介导的治疗可以使 NHBD 肺康复并成功移植。我们将通过三个目标来检验这个假设。目标 1 将使用猪肺移植模型来确定使用 A2AR 激动剂的 EVLP 是否可以安全地延长 NHBD 肺部的热缺血时间和冷缺血时间。目标 2 将确定采用 A2AR 激动剂治疗的 EVLP 是否会将边缘和先前排斥的人类供体肺恢复到可接受的移植状态。目标 3 将确定使用 A2BR 拮抗剂的 EVLP 是否可以修复猪和人 NHBD 肺部。在每个目标中，我们还将确定 EVLP 对 NHBD 肺部的康复是否需要抑制 NKT 细胞活化、上皮细胞活化和中性粒细胞浸润。该项目解决了困扰肺移植的两个主要问题：适合移植的肺太少以及移植后由于IR损伤导致的原发性移植失败。如果 NHBD 的肺能够安全地康复用于移植，那么肺供体短缺的问题就可以解决。因此，该项目将提供一种方法来大大扩大供体肺库的规模，并支持旨在挽救肺移植等待名单上的患者更多生命的临床试验。