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

基本信息

批准号：
10198021
负责人：
RAHIM R RIZI
金额：
$ 75.94万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10198021
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 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 pulmonary function response response to injury stem success treatment response trend

项目摘要

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功能障碍（PGD）的并发症外，明显的短缺可用的供体肺部已阻止肺移植实现宽度的利用率作为末期肺部疾病的治疗方法。尽管越来越多的肺移植在全球范围内，等待他们的患者人数增长速度更快 - 促进了许多旨在通过积极的捐助者管理和创新来扩大捐助者池的努力器官保存策略主要旨在改善“边际”的移植结果供体脑死亡（DBD）后收获肺。 DBD肺同种异体移植因血流动力学损伤的结合而增加PGD的风险炎症性上调导致供体肺部导致脑死亡。最近的研究确定了成功预防和/或打击这种伤害及其有害的几种策略移植后效应 - 包括供体预处理，器官恢复和前肺灌注（EVLP）。但是，该领域的进步受到对 DBD损害移植活力的机制。为了应对这种需求，并按照此RFA的主要重点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的早期客观评估。结合超极化（HP）气-MRI和HP碳13磁共振光谱成像（MRSI），我们将建立大脑后供体肺损伤的早期细胞动力学死亡并跟踪这种伤害的进展，并响应各种治疗和保存策略。该项目的第一个任务是使用我们的组合成像技术来建立成像大鼠模型中供体脑死亡后立即急性肺损伤的特征。第二，我们会的使用这些成像参数通过跟踪来识别器官恢复的最佳窗口随着时间的流逝，供体肺损伤的进展，无论是在没有和响应的情况下已经经过证明的预处理。第三，我们将使用磷和13C MR光谱评估供体肺中的供体肺中的代谢活性，其参数将是由我们对器官的收获前成像提出。我们将使用成像的组合参数和组织学比较所有队列中移植后移植表现并评估给定理论策略预防PGD的成功。最后，我们会的重复对几个人类肺部进行EVLP研究，以评估翻译的潜力我们的成像技术和参数。