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

描述(申请人提供)：代谢综合征(MS)是肺部炎症性疾病的独立危险因素，对MS促进肺部炎症的机制的进一步了解为开发新的治疗策略带来了希望。慢性、低度全身炎症是多发性硬化症的一个组成部分，它可能部分通过尿酸(UA)的致炎特性促进肺部炎症，尿酸在多发性硬化症患者中增加。目前，UA在ALI/ARDS中的作用尚不清楚，并被MS常见的共病因素所混淆，如高血糖或胰岛素抵抗，这些因素也可能影响肺部炎症。我们最近在小鼠身上开发了一种条件基因敲除XOR，使我们能够研究血清UA在ALI/ARDS小鼠模型中的特定作用。这笔赠款将通过表征XOR和UA在新的稳健的MS小鼠模型中的作用来促进我们对MS介导的炎症性肺病的了解，该模型将通过对人类MS相关的炎症性肺病的前瞻性分析来验证。我们的目的是(1)通过敲除肝细胞异或基因，确定血清UA是否在ALI/ARDS小鼠模型中起作用。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。ALI/ARDS将在XOR消融后用Th1细胞因子或内毒素气腹诱导。(2)为了确定血清UA是否与高尿酸血症遗传模型中的ALI/ARDS有关，我们将敲除Leprdb-lb小鼠的肝细胞XOR，该小鼠将在注射细胞因子或LPS之前接受肝细胞靶向的抗XOR-shRNA治疗。这些实验将与在注射脂多糖或Th1细胞因子之前用XOR的全身药理抑制剂治疗的Leprdb-lb小鼠进行对比。(3)为了确定血清UA是否可以预测表现为MS的ALI/ARDS患者的临床结果，我们将对科罗拉多大学医院ICU开发的人类患者数据进行筛选，以将表现为ALI/ARDS的MS患者的血清UA与患者预后关联起来。这项研究产生的数据可能会推荐UA作为人类临床试验中测量的重要参数，并可能表明其作为治疗MS相关性肺炎性疾病的靶点的相关性。

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.