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.

概括 除了原发性移植物功能障碍 (PGD) 引起的并发症外，严重短缺 可用供体肺的数量阻碍了肺移植的广泛应用 作为终末期肺部疾病的治疗。尽管越来越多的肺移植手术 在世界各地，等待他们的患者数量正在快速增长，这促使许多人 旨在通过积极的捐助者管理和创新来扩大捐助者库的努力 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）后收获的肺。 由于血流动力学损伤的结合，DBD 同种异体肺移植物的 PGD 风险增加 以及脑死亡在供体肺中引起的炎症上调。最近的研究有 确定了几种成功预防和/或对抗这种伤害及其有害的策略 移植后影响——包括供体预处理、器官恢复延迟和离体肺 灌注（EVLP）。然而，由于对这一领域的不完全理解，该领域的进展受到限制。 DBD 损害移植物活力的机制。 为了响应这一需求并根据本 RFA 的主要重点，建议 项目将使用我们实验室为定量分析而创建的集成成像方法 测量肺的区域结构、功能和代谢参数，以便提供 在采购之前对器官质量进行早期、客观的评估。使用组合 超极化 (HP) 气体 MRI 和 HP 碳 13 磁共振波谱成像 （MRSI），我们将建立脑后供体肺损伤的早期细胞动力学 死亡并跟踪这种损伤随时间的进展以及对各种治疗和治疗的反应 保存策略。 该项目的首要任务是使用我们的组合成像技术来建立成像 大鼠模型供体脑死亡后立即发生的急性肺损伤概况。其次，我们将 使用这些成像参数通过跟踪来确定器官恢复的最佳窗口 供体肺损伤随着时间的推移而进展，无论是在缺乏或有反应的情况下 已经经过验证的预处理。第三，我们将使用磷和 13C MR 谱来评估 离体灌注期间供体肺的代谢活动，其参数将是 我们对器官的收获前成像表明。我们将结合我们的成像 参数和组织学，用于比较所有队列移植后的移植物性能 并评估给定治疗策略在预防 PGD 方面的成功程度。最后，我们将 对几个人肺重复进行 EVLP 研究，以评估转化潜力 我们的成像技术和参数。