INHALED NITRIC OXIDE

描述：（改编自申请人的摘要） 该建议是为了提高吸入一氧化氮的功效和效用 作为心肺疾病的选择性肺血管扩张剂。 在 除了放松肺循环的张力外， 血小板聚集和清除超氧自由基。 申请人还 计划研究NO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 包括内皮型、神经型和诱导型NOS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、高氧的和补体 介导的肺损伤形式。 有三个具体目标： 具体目标1将调查对以下问题缺乏答复的原因： 35%的患者吸入NO。 申请人计划 探讨NO-cGMP信号转导通路， 磷酸二酯酶活性，内毒素影响，反馈 吸入NO对NOS活性及快速耐受诱导作用及比较 这些机制中的几个在大鼠到羊。 具体目标2是研究吸入NO与 肺内NOS活性。 这涉及到研究三种异构体的 NOS以及通过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 研究呼出气NO作为肺NOS活性的标志物， 缺陷敲除小鼠。 具体目标3是确定内源性释放和 外源性NO影响损伤肺的反应。 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).