Role of NOD2 in Acute Lung Injury Following Ischemic Kidney Injury

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Abstract Acute respiratory distress syndrome (ARDS) is characterized by pulmonary endothelial inflammation that leads to alveolar edema and poor gas exchange. It has a high mortality, and effective treatment options to date are limited. Acute kidney injury increases the mortality from ARDS and there is substantial evidence that kidney injury can directly worsen the lung injury. The mechanisms underlying this kidney-lung interaction are not well understood and could hold therapeutic potential. Following renal ischemia reperfusion injury (IRI), endogenous stress molecules (DAMPs or damage associated molecular patterns) are released from dying renal tubular cells and bind to pathogen recognition receptors (PRRs) on neighboring cells, initiating an inflammatory cascade that worsens renal injury. In preliminary data we have already seen that renal derived DAMPs cause upregulation of inflammatory cytokines and MAPK activation in uninjured renal tubular epithelial cells. Expanding this model to kidney-lung cross talk, human pulmonary endothelial cells exposed to renal tubule-derived DAMPs were found to upregulate inflammatory cytokines and specific PRRs. These preliminary data also revealed that NOD2, a PRR known to play a key role in acute kidney injury, was disproportionately upregulated when compared to other PRRs. Our lab has previously shown that NOD2 knockout protects mice from renal IRI, and preliminary data suggest that inhibition of NOD2 via pharmacologic blockade decreases the inflammatory response of renal tubular epithelial cells to renal derived DAMPs. The hypothesis of this proposal is that NOD2 plays a critical role in lung injury following renal IRI by inducing proinflammatory responses in the pulmonary microendothelium, contributing to ARDS. Given the importance of microvascular endothelial cells in the pathogenesis of ARDS, this proposal focuses on the role of NOD2 on injurious responses in pulmonary microvascular endothelial cells after renal IRI. I will focus on the canonical NOD2 signaling pathways in pulmonary microvascular endothelial cells in response to renal derived DAMPs and also use an in vivo model of renal IRI to correlate NOD2 activation with lung injury. This proposal will provide important new knowledge and skill sets needed to set the stage for the development of my career as a physician-scientist. The work proposed in this application will be conducted in a rich training environment at UC San Diego and the Scripps Research Institute with an exceptional interdisciplinary mentoring team including leaders in the field of innate immunity, endothelial cell biology, and ARDS.