INHALED NITRIC OXIDE

描述：(改编自申请人的摘要)远景目标 这项建议是为了提高吸入一氧化氮的疗效和效用。 作为治疗心肺疾病的选择性肺血管扩张剂。在……里面 除了在肺循环中放松语气外，没有替代 血小板聚集和清除超氧阴离子自由基。申请人亦须 计划调查一氧化氮是否通过cGMP发挥其有益作用 信号转导途径。各种相关和重要的技术 包括内皮、神经元和诱导型一氧化氮合酶基因敲除 小鼠，补体激活，信号转导途径分析，和 吸入NO在凝血酶诱导的高氧血症和补体中的应用 肺损伤的中介形式。具体目标有三个： 具体目标1将调查缺乏反应的基础 接受这种治疗的患者中有35%吸入了NO。申请者计划 为探讨NO-cGMP信号转导途径， 磷酸二酯酶(PDE)活性、内毒素影响、反馈 吸入NO对一氧化氮合酶活性的影响及诱发快速反应的比较 这些机制中的几个在老鼠和绵羊之间。 具体目标2是研究吸入NO与 肺内一氧化氮合酶活性。这涉及到研究三种不同的亚型 以及通过基因敲除小鼠缺乏任何一种形式是否会改变 对吸入NO和细菌内毒素的反应。申请人还计划 呼气NO在各一氧化氮合酶中作为肺一氧化氮合酶活性标志物的研究 缺陷基因敲除小鼠。 具体目标3是确定内源释放和 外源性NO影响受损肺的共振。 将使用三种形式的肺损伤(即高氧、凝血酶和 补体激活)。

DESCRIPTION: (Adapted from the applicant's abstract) The long range goal of this proposal is to improve the efficacy and utility of inhaled nitric oxide as a selective pulmonary vasodilator in cardiopulmonary disease. In addition to relaxing tone in the pulmonary circulation, NO alternates platelet aggregation and scavenge superoxide radicals. The applicant also plans to investigate whether NO exerts its beneficial effects by the cGMP signal transduction pathway. A variety of relevant and important techniques will be employed, including endothelial, neuronal and inducible NOS knockout mice, complement activation, signal transduction pathway analysis, and application of inhaled NO to thrombin-induced, hyperoxic, and complement mediated forms of lung injury. There are 3 specific aims: Specific Aim 1 will investigate the basis for the lack of response to inhaled NO in 35% of the patients given this treatment. The applicant plans to investigate the NO-cGMP signal transduction pathway, role of phosphodiesterase (PDE) activity, influence of endotoxin, feedback inhalation of NO on NOS activity and induction of tachyphylaxis, and compare several of these mechanisms in rats to sheep. Specific Aim 2 is to investigate the interactions of inhaled NO with intrapulmonary NOS activity. This involves studying the three isoforms of NOS and whether absence of any one form via knockout mice alters the response to inhaled NO and to bacterial endotoxin. The applicant also plans to study exhaled NO as a marker of pulmonary NOS activity in each NOS deficient knockout mouse. Specific Aim 3 is to determine how both endogenously released and exogeneously administered NO influences the resonse of the injured lung. Three forms of lung injury will be used (i.e., hyperoxia, thrombin, and complement activation).