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.
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.
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