T cell-mediated lung ischemia-reperfusion injury

描述(由申请人提供)：肺移植后早期死亡的一个主要来源是缺血再灌注损伤。这项建议的目的是更好地了解启动和调节这一炎症过程的细胞机制。我们的实验室已经证实，肺IR损伤依赖于肺泡巨噬细胞的激活、CD4+T细胞的浸润和肿瘤坏死因子-α的诱导。最近的数据也支持产生IL-17和IL-17的CD4+T细胞，如iNKT，在IR后的肺部炎症中起重要作用。因此，目标1将确定iNKT细胞是否通过产生IL-17启动肺IR损伤和中性粒细胞浸润。氧化应激和通过NADPH氧化酶释放的活性氧物种也是IR损伤和吞噬细胞激活的一个组成部分。因此，目标2将确定NADPH氧化酶产生的ROS是否是IR后iNKT细胞激活的关键机制。我们的总体假设是肺IR损伤是通过产生IL-17和NADPH氧化酶依赖的ROS来激活CD4+iNKT细胞而开始的。这项建议的结果将有助于设计成功的策略，以改善肺移植接受者的结果。 公共卫生相关性：项目描述：肺再灌注损伤是移植后的一个主要并发症，导致危险的炎症、较高的手术后死亡率和包括慢性排斥反应在内的晚期并发症。这项建议的目的是为了更好地了解启动和介导肺再灌注损伤的细胞机制。这项建议的结果将有助于设计成功的策略，以改善肺移植的结果。

DESCRIPTION (provided by applicant): Ischemia-reperfusion (IR) injury remains a major source of early mortality after lung transplantation. The objective of this proposal is to better understand the cellular mechanisms that initiate and mediate this inflammatory process. Our laboratory has established that lung IR injury is dependent on alveolar macrophage activation, CD4+ T cell infiltration, and TNF-alpha induction. Recent data also supports an important role for IL-17 and IL-17-producing CD4+ T cells, such as iNKT, in mediating lung inflammation after IR. Thus Aim 1 will determine if iNKT cells initiate lung IR injury and neutrophil infiltration via IL-17 production. Oxidative stress and the release of reactive oxygen species via NADPH oxidase is also a component of IR injury as well as phagocytic cell activation. Thus Aim 2 will determine if NADPH oxidase-generated ROS is a key mechanism for the activation of iNKT cells after IR. Our overall hypothesis is that lung IR injury is initiated through CD4+ iNKT cell activation via production of IL-17 and NADPH oxidase-dependent ROS. Results from this proposal will help design successful strategies to improve outcomes in lung transplant recipients. PUBLIC HEALTH RELEVANCE: Project Narrative: Lung reperfusion injury is a major complication after transplantation resulting in dangerous inflammation, higher post-operative mortality, and late complications including chronic rejection. The objective of this proposal is to better understand the cellular mechanisms that initiate and mediate lung reperfusion injury. Results from this proposal will help design successful strategies to improve outcomes in lung transplantations.