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Inflammatory Role of Macrophage Xanthine Oxidoreductase in Pulmonary Hypertension: Implications for Novel Therapeutic Approaches

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Technical Report,30 Sep 2014,30 Sep 2015

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Regents Of The University Of Colorado Aurora United States

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In Year 1 of this project, we have made a substantial progress toward the proposed original specific aims SAs and the major goal of identifying the role of XOR in macrophage inflammatory activation. Both reactive oxygen species ROS and macrophages are involved in the pathogenesis of pulmonary hypertension. Xanthine oxidoreductase XOR is an ROS generator that plays a central role in inflammation that may contribute to pulmonary vascular inflammation. To identify the role of macrophage specific XOR, we developed a conditional cell specific XOR knockout in mice. During year 1, we characterized this novel previously unavailable conditional XOR KO and showed that macrophages from myeloid specific XOR knockout exhibited loss of inflammatory activation and increased expression of anti-inflammatory markers SA1a. Transcriptional profiling demonstrated an unexpected role for XOR in expression of the NLRP3 inflammasome and acquisition of the glycolytic phenotype by inflammatory macrophages. Recently we have obtained preliminary data showing XOR as a critical regulator of mitochondrial function during hypoxia SA1b. These data demonstrate XOR-Uric acid as a novel drugable targets in stress induced lung parenchymal as well as vascular inflammation.

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