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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：
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
项目类别：
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

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.

总结