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

通过在 DBD 大鼠模型中使用成像来改善肺移植结果

• 批准号: 9764471
• 负责人: RAHIM R RIZI
• 金额: $ 78.24万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9764471
• 关键词: Acute Lung Injury; Animal Model; Area; Brain Death; Carbon; Cause of Death; Chronic; Clinical; Deterioration; Functional Imaging; Functional disorder; Gases; Goals; Graft Survival; Harvest; Histology; Human; Hypoxia; Image; Imaging Techniques; Inflammation; Inflammatory; Injury; Intervention; Ischemia; Lung; Lung Transplantation; Lung diseases; Magnetic Resonance Imaging; Maintenance; Measurement; Measures; Mechanics; Metabolic; Metabolism; Modeling; Molecular; Operative Surgical Procedures; Organ; Organ Harvestings; Organ Preservation; Outcome; Patients; Performance; Perfusion; Pharmacologic Substance; Phosphorus; Postoperative Period; Pre-Clinical Model; Predictive Value; Rattus; Recovery; Reperfusion Therapy; Research; Respiratory physiology; Risk; Role; Stress; Structure; Techniques; Therapeutic; Time; Tissues; Transplantation; Up-Regulation; Work; brain surgery; clinically relevant; cohort; combat; conditioning; effective therapy; ex vivo perfusion; hemodynamics; imaging modality; improved; in vivo imaging; innovation; lung allograft; lung imaging; lung injury; lung preservation; magnetic resonance spectroscopic imaging; metabolic imaging; mortality; normotensive; novel; post-transplant; preclinical study; preservation; prevent; response; response to injury; stem; success; treatment response; trend

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.

总结 沿着原发性移植物功能障碍（PGD）引起的并发症， 可用供体肺的缺乏阻碍了肺移植的广泛应用 作为晚期肺病的治疗方法。尽管越来越多的肺移植手术 在世界范围内，等待他们的病人数量正在快速增长， * 通过积极的捐助者管理和创新办法，努力扩大捐助者库 器官保存策略主要旨在改善“边缘”患者的移植结果 供体脑死亡（DBD）后获得的肺。 DBD由于血流动力学损伤的组合，肺同种异体移植物的PGD风险增加 以及脑死亡在供体肺中引起的炎症上调。最近的研究 确定了成功预防和/或对抗这种损伤及其有害影响的几种策略， 移植后效应-包括供体预处理、延迟的器官恢复和离体肺 灌注（EVLP）。然而，这一领域的进展受到对以下问题不完全理解的限制： DBD损害移植物活力的机制。 为了满足这一需求，并根据本RFA的主要重点， 该项目将使用我们实验室创建的定量集成成像方法， 测量肺的局部结构、功能和代谢参数，以提供 在采购前对器官质量进行早期客观评估。结合使用 超极化（HP）气体MRI和HP碳-13磁共振波谱成像 （MRSI），我们将建立脑移植后供体肺损伤的早期细胞动力学 死亡，并跟踪这种损伤随着时间的推移和对各种治疗的反应， 保护战略。 该项目的第一项任务将是使用我们的组合成像技术， 在大鼠模型中供体脑死亡后立即发生急性肺损伤的概况。二是 使用这些成像参数，通过跟踪 随着时间的推移，供体肺损伤的进展，无论是在没有和响应于几个 已经证实的预处理。第三，我们将使用磷和13 C MR谱来评估 在离体灌注期间供体肺中的代谢活性，其参数将是 这是器官移植前的影像所显示的我们将结合成像技术 比较所有队列移植后移植物性能的参数和组织学 并评估给定治疗策略在预防PGD中的成功率。最后我们将 对几个人肺重复进行EVLP研究，以评估翻译潜力 我们的成像技术和参数。