PROINFLAMMATORY ROLE OF URIC ACID IN LUNG DISEASE: NOVEL MODELS AND CLINICAL VALI

描述（由申请人提供）：代谢综合征（MS）是肺部炎症性疾病的独立风险因素，对MS导致肺部炎症的机制的进一步理解为开发新的治疗策略提供了希望。慢性、低度全身性炎症是MS的一个组成部分，可能部分通过尿酸（UA）的促炎特性促进肺部炎症，尿酸在MS患者中增加。目前，UA在ALI/ARDS中的作用知之甚少，并且被通常与MS相关的合并症因素如高血糖或胰岛素抵抗混淆，这些因素也可能影响肺部炎症。我们最近在小鼠中开发了XOR的条件性敲除，使我们能够研究血清UA在ALI/ARDS小鼠模型中的特定作用。这项资助将通过表征XOR和UA在新型MS小鼠模型中的作用来提高我们对MS介导的炎症性肺病的认识，该模型将通过对人类MS相关炎症性肺病的前瞻性分析进行验证。我们的目的是（1）通过使用新产生的XORf 1/f1小鼠品系敲除肝细胞XOR来确定血清UA是否有助于ALI/ARDS小鼠模型，所述XORf 1/f1小鼠品系将用肝细胞靶向Cre重组酶处理。这些实验将与通过喂食果糖造成高尿酸血症的小鼠进行对比。在XOR消融后使用Th 1细胞因子或LPS吹入诱导ALI/ARDS。(2)为了确定在高尿酸血症的遗传模型中血清UA是否有助于ALI/ARDS，我们将在Leprdb-lb小鼠中敲除肝细胞XOR，所述Leprdb-lb小鼠将在细胞因子或LPS吹入之前用肝细胞靶向抗XOR-shRNA处理。这些实验将与在LPS或Thl细胞因子吹入之前用XOR的全身药理学抑制剂处理的Leprdb-lb小鼠进行对比。(3)为了确定血清UA是否可预测MS的ALI/ARDS患者的临床结果，我们将筛选科罗拉多大学医院ICU开发的人类患者数据，以将血清UA与表现出ALI/ARDS的MS患者的患者结果相关联。本研究产生的数据可能推荐UA作为人体临床试验中测量的重要参数，并可能表明其作为MS相关肺部炎症性疾病管理中的治疗靶点的相关性。

DESCRIPTION (provided by applicant): The Metabolic Syndrome (MS) is an independent risk factor for inflammatory diseases of the lung, and improved understanding of the mechanism by which MS contributes to lung inflammation offers hope for the development of new treatment strategies. Chronic, low grade systemic inflammation is a component of MS that may promote lung inflammation in part through the proinflammatory properties of uric acid (UA), which is increased in MS patients. Presently, the role of UA in ALI/ARDS is poorly understood and is confounded by comorbidity factors commonly associated with MS such as hyperglycemia or insulin resistance that may also affect lung inflammation. We recently developed a conditional knockout of XOR in mice that enables us to investigate the specific role of serum UA in mouse models of ALI/ARDS. This grant will advance our knowledge of MS mediated inflammatory lung disease by characterizing the role of XOR and UA in novel robust mouse models of MS that will be validated by prospective analysis of MS associated inflammatory lung disease in humans. Our aims are (1) To determine whether serum UA contributes to mouse models of ALI/ARDS by knocking out hepatocyte XOR using a newly generated XORfl/fl mouse strain that will be treated with hepatocyte targeted Cre recombinase. These experiments will be contrasted to mice made hyperuricemic by fructose feeding. ALI/ARDS will be induced using Th1 cytokine or LPS insufflation subsequent to XOR ablation. (2) To determine whether serum UA contributes to ALI/ARDS in a genetic model of hyperuricemia we will knockout hepatocyte XOR in Leprdb-lb mice that will be treated with hepatocyte targeted anti-XOR-shRNA prior to cytokine or LPS insufflation. These experiments will be contrasted to Leprdb-lb mice treated with systemic pharmacological inhibitors of XOR prior to LPS or Th1 cytokine insufflation. (3) To determine whether serum UA is predictive of clinical outcome in ALI/ARDS patients presenting with MS we will screen human patient data developed at the University of Colorado Hospital ICU to correlate serum UA with patient outcome for MS patients exhibiting ALI/ARDS. Data produced by this study may recommend UA as an important parameter for measurement in human clinical trials and may indicate its relevance as a therapeutic target in the management of MS associated lung inflammatory disorders.