The role of ADMA in the pathology of asthma

描述(由申请人提供)：炎症在哮喘的发病机制中起着核心作用。一种重要的炎症介质是一氧化氮(NO)，它是一种支气管循环的血管扩张剂。最近的研究表明，哮喘可能是一种无生物利用度降低的状况。一氧化氮是由L-精氨酸(L-精氨酸)通过一氧化氮合酶(NOS)合成的。最近有报道称，哮喘患者体内L-精氨酸生物利用度降低可能与哮喘患者体内NO缺乏有关。不对称二甲基精氨酸(ADMA)是一氧化氮合酶(NOS)的内源性抑制物，已被证实是一种新的心血管危险因子，并已在多种疾病中蓄积。虽然临床和实验证据表明ADMA升高可能导致相对的L-精氨酸缺乏，但目前还没有关于哮喘患者相对ADMA水平的数据。因此，这项建议的目标是确定ADMA在上皮细胞中的作用机制，并通过小鼠模型证明ADMA水平与哮喘病理之间的活体关联。在成功完成这项提议后，我们期望这些研究不仅将为哮喘的病理提供新的见解，还可能确定这种疾病发展的新因素。

DESCRIPTION (provided by applicant): Inflammation plays a central role in the pathogenesis of asthma. One important inflammatory mediator is nitric oxide (NO), a vasodilator of the bronchial circulation. Recent studies suggest that asthma may be a condition of decreased NO bioavailability. NO is produced by L-arginine (L-arg) by NO syntheses (NOS). It has been recently reported that a decreased L-arg bioavailability in asthmatic patients likely contributes to the NO deficiency in asthma. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS, has been established as a novel cardiovascular risk factor and its accumulation has been reported in a variety of disorders. Although clinical and experimental evidence indicates that elevation of ADMA may cause a relative L-arg deficiency, no data are available on the relative ADMA levels in asthmatic patients. Therefore, the goal of this proposal is to determine the mechanism of ADMA's effects in epithelial cells and demonstrate an in vivo association between ADMA levels and the pathology of asthma using a murine model. Upon successful completion of this proposal, our expectation is that these studies will not only provide new insights into the pathology of asthma, but also potentially identify a novel factor in the development of this disease.