Improving lung transplant outcomes through the use of imaging in a DBD rat model

摘要 伴随着由原发性移植物功能障碍(PGD)引起的并发症，严重的短缺 可用供体肺的减少阻碍了肺移植的广泛应用 作为治疗终末期肺部疾病的药物。尽管越来越多的肺移植手术 在世界范围内，等待他们的患者数量增长得更快-促使无数 旨在通过积极的捐助者管理和创新扩大捐助者人才库的努力 器官保存策略主要旨在改善‘边缘’的移植结果 供体脑死亡(DBD)后取肺。 DBD肺移植因合并血流动力学损伤而增加发生PGD的风险 以及脑死亡导致供体肺的炎性上调。最近的研究表明 确定了成功预防和/或抗击这种伤害及其危害的几种策略 移植后影响--包括供者预治疗、器官恢复延迟和体外肺 灌注(EVLP)。然而，这一领域的进展受到不完全理解的限制 DBD损害移植物生存能力的机制。 为回应这一需要，并根据本RFA的主要重点，拟议的 项目将使用我们实验室为定量创建的集成成像方法 测量肺的局部结构、功能和代谢参数，以便提供 在采购前对器官质量进行早期、客观的评估。使用以下组合 超极化(HP)气体磁共振和HP碳13磁共振波谱成像 (MRSI)，我们将建立脑后供体肺损伤的早期细胞动力学 死亡和跟踪这种伤害的进展随着时间的推移和对各种治疗和反应 保存策略。 这个项目的第一个任务将是使用我们的组合成像技术来建立一个成像 供体脑死亡后立即发生急性肺损伤的大鼠模型。第二，我们将 使用这些成像参数来确定器官恢复的最佳窗口 供体肺损伤随时间的进展，无论是在几种情况下都是如此 已经被证实的前处理。第三，我们将使用磷和13C磁共振波谱来评估 在体外灌流期间供体肺的代谢活性，其参数将被 从我们对器官的采集前成像中可以看出。我们将使用我们的成像组合 在所有队列中比较移植后移植物性能的参数和组织学 并评价给出的治疗策略在预防PGD方面的成功。最后，我们会 重复在几个人肺上进行EVLP研究，以评估翻译潜力 我们的成像技术和参数。

Summary Along with complications stemming from primary graft dysfunction (PGD), a significant shortage of available donor lungs has prevented lung transplantation from achieving widespread utilization as a treatment for end-stage lung disease. Despite a growing number of lung transplants taking place worldwide, the number of patients awaiting them is growing faster—prompting numerous efforts aimed at expanding the donor pool through aggressive donor management and innovative organ preservation strategies aimed primarily at improving transplant outcomes for ‘marginal’ lungs harvested after donor brain death (DBD). DBD Lung allografts are at increased risk of PGD due to the combination of hemodynamic injury and inflammatory upregulation that brain death causes in the donor lung. Recent studies have identified several strategies that successfully prevent and/or combat this injury and its deleterious post-transplant effects—including donor pre-treatment, delayed organ recovery, and ex-vivo lung perfusion (EVLP). However, advances in this area are limited by an incomplete understanding of the mechanisms by which DBD compromises graft viability. In response to this need and in accordance with the primary focus of this RFA, the proposed project will use an integrated imaging method which our lab has created for quantitatively measuring regional structural, functional and metabolic parameters of the lung in order to provide an early, objective assessment of organ quality prior to procurement. Using a combination of hyperpolarized (HP) gas-MRI and HP carbon-13 magnetic resonance spectroscopic imaging (MRSI), we will establish the early cellular dynamics of donor lung injury subsequent to brain death and track this injury’ progression over time and in response to various treatment and preservation strategies. The first task of this project will be to use our combined imaging technique to establish an imaging profile of acute lung injury immediately following donor brain death in a rat model. Second, we will use these imaging parameters to identify an optimal window for organ recovery by tracking the progression of donor lung injury over time, both in the absence of and in response to several already proven pre-treatments. Third, we will use phosphorus and 13C MR spectra to evaluate metabolic activity in the donor lung during ex-vivo perfusion, whose parameters will have been suggested by our pre-harvest imaging of the organ. We will use the combination of our imaging parameters and histology to compare graft performance after transplantation among all cohorts and to evaluate the success of given therapeutic strategies in preventing PGD. Finally, we will repeat perform EVLP studies on several human lungs in order to assess the translational potential of our imaging technique and parameters.