Cationic Amino Acid Transporters and Lung NO Production

一氧化氮（NO）是参与多种生理功能的重要分子。在肺部 高血压疾病时，NO 产生减少，导致血管收缩和血管重塑。 而在肺部炎症性疾病中，一氧化氮的产生增加，导致组织损伤。否是 由一氧化氮合酶 (NOS) 从 L-精氨酸 (L-arg) 生成。 L-arg 对 NOS 的细胞生物利用度为 很大程度上是由阳离子氨基酸转运蛋白 (CAT) 对细胞外 L-arg 的摄取决定的。 初步研究表明，L-arg 摄取的操纵改变了临床上重要的参数 高度脆弱的患者群体。因此，本申请中描述的研究集中于 阐明 CAT 内皮细胞摄取 L-arg 的功能和机制及其作用 调节肺中 NO 的产生。这些研究的长期目标是开发能够 通过促进肺动脉高压疾病中 CAT 介导的 L-arg 摄取来增加 NO 的产生，以及 在炎症性肺部疾病中，通过抑制 CAT 介导的 L-arg 摄取来减少 NO 的产生。的 工作假设是，NO 的产生可以通过控制 L-arg 对 NOS 的生物利用度来调节 通过改变 CAT 介导的 L-arg 转运。这些研究将在 3 个具体方面解决该假设 目的：1) 检验 CAT 活性的改变通过改变 L-arg 对 NOS 的生物利用度； 2) 检验 Src 家族酪氨酸激酶和丝裂原的假设 激活的蛋白激酶介导炎症诱导的 CAT 和/或 NOS 表达变化； 3) 检验体内调节 CAT 表达的基因转移会影响 NO 产生的假设 在肺部，从而影响肺血管舒缩张力和肺损伤。 相关性：旨在控制 NO 介导的肺部疾病效应的疗法主要集中在 药物抑制NO产生或吸入外源NO，然而其中大多数 危重患者对这些疗法没有反应。 L-arg 摄取代表肺 NO 的限速步骤 生产。本提案将为设计合理的临床方案提供必要的转化数据 确定 L-arg 摄取率安全有效的药理学和基因操作的试验，以及 因此，在严重的肺部疾病（如急性呼吸窘迫综合征（ARDS）和肺动脉高压）中，会产生一氧化氮（NO）。

Nitric oxide (NO) is an important molecule involved in a myriad of physiological functions. In pulmonary hypertensive diseases, NO production is decreased resulting in vasoconstriction and vascular remodeling. While in pulmonary inflammatory diseases, NO production is increased resulting in tissue damage. NO is generated from L-arginine (L-arg) by the NO synthases (NOS). The cellular bioavailability of L-arg to NOS is determined in large part by uptake of extracellular L-arg via the cationic amino acid transporters (CAT). Preliminary studies suggest that manipulation of L-arg uptake modifies clinically important parameters in highly vulnerable patient populations. Thus, the studies described in the present application are focused on elucidation of the functional and mechanistic aspects of endothelial cell uptake of L-arg by CAT and its role in regulation of NO production in the lung. The long-term goals of these studies are to develop therapies that increase NO production by facilitating CAT-mediated L-arg uptake in pulmonary hypertensive diseases, and that decrease NO production by inhibiting CAT-mediated L-arg uptake in inflammatory lung diseases. The working hypothesis is that NO production can be modulated by control of L-arg bioavailability to NOS through alterations in CAT-mediated L-arg transport. The studies will address the hypothesis in 3 specific aims: 1) to test the hypothesis that alterations in CAT activities regulate NO production by altering the bioavailability of L-arg to NOS; 2) to test the hypothesis that Src-family tyrosine kinases and mitogen- activated protein kinases mediate inflammation-induced alterations in the expression of CAT and/or NOS; and 3) to test the hypothesis that gene transfer to regulate CAT expression in vivo will affect NO production in the lung, and thereby affect pulmonary vasomotor tone and lung injury. RELEVANCE: Therapies aimed at manipulating NO-mediated effects in lung diseases have centered on pharmacological inhibition of NO production or inhalation of exogenous NO, however a majority of these critically ill patients do not respond to these therapies. L-arg uptake represents a rate-limiting step in lung NO production. The present proposal will provide translational data necessary for the design of rational clinical trials to determine safe and effective pharmacological and genetic manipulations of L-arg uptake rates, and thereby NO production, in severe pulmonary diseases, such as ARDS and pulmonary hypertension.