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核心作用。一种重要的炎症介质是一氧化氮（NO），它是支气管循环的血管扩张剂。最近的研究表明，哮喘可能是一氧化氮生物利用度降低的一种情况。NO是由l -精氨酸（L-arg）通过NO合成（NOS）产生的。最近有报道称，哮喘患者l -精氨酸生物利用度降低可能导致哮喘患者NO缺乏。不对称二甲基精氨酸（ADMA）是一种内源性NOS抑制剂，已被确定为一种新的心血管危险因素，其积累已被报道在多种疾病中。尽管临床和实验证据表明ADMA升高可能导致L-arg相对缺乏，但没有关于哮喘患者ADMA相对水平的数据。因此，本提案的目标是确定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体内关联。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，而且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.