Advanced diagnostics for donor lung assessment and ex vivo lung perfusion candidate selection

项目摘要/摘要 原发性移植物功能障碍(Pgd)是继肺部之后最常见的发病率和死亡率的原因。 移植。最近的数据表明，一些特定的途径参与了急性肺损伤模型和 移植后PGD。对这些特定途径的更好理解将为PGD提供机制线索 发病机制和潜在的刺激研究新的治疗途径。此外，识别 特定的、个体化的PGD危险因素可能使未来的个体化治疗成为可能。我们的初步数据 根据来自供体肺的转录本，表明先天免疫激活在PGD的发病机制中起重要作用 在体外肺灌流衰竭(非移植)的灌流液中发现了组织和细胞外小泡。 根据这些发现，尽管生理正常，但肺似乎受到了无法测量的损伤。 需要进一步表征的测量结果。 我们这一系列研究的长期目标是了解PGD在人肺中的机制 以确定战略，以确定有风险的捐赠者，防止受者死亡，并扩大 通过更好地选择供者和使用体外肺灌流(EVLP)策略来建立供体池。我们的方法是 应用供体肺泡灌洗液中基因表达预测PGD及检测先天因素 移植供者和不能移植供者置于EVLP中参与PGD的免疫途径。这个 中心假设是供体肺在移植前发生的肺损伤可以通过以下方法进行评估 基因表达方法用于确定PGD风险和了解EVLP失败的常见机制。

Project Summary/Abstract Primary graft dysfunction (PGD) is the most common cause of morbidity and mortality after lung transplantation. Recent data indicate participation of a few specific pathways in acute lung injury models and post-transplant PGD. A better understanding of these specific pathways would offer mechanistic clues to PGD pathogenesis and potentially stimulate investigation of novel therapeutic avenues. In addition, identification of specific, individualized risk factors for PGD might allow future personalized therapy. Our preliminary data indicate that innate immune activation is important in PGD pathogenesis based on transcripts from donor lung tissue and in extracellular vesicles identified in perfusate from ex vivo lung perfusion failures (no transplant). Given these findings, there appears to be unmeasured injury to the lung despite normal physiologic measurements which needs to be further characterized. The long-term objective of our line of research is to understand the mechanism of PGD in human lung transplantation in order to identify strategies to identify donors at risk, prevent recipient death and expand the donor pool through better donor selection and use of ex vivo lung perfusion (EVLP) strategies. Our approach is to use gene expression in donor lung bronchoalveolar lavage to predict PGD and to examine the innate immunity pathways involved in PGD of transplanted donors and untransplantable donors placed on EVLP. The central hypotheses are that lung injury occurring in the donor lung prior to procurement can be evaluated by gene expression methods to determine PGD risk and understand common mechanisms of EVLP failure.