Nitric Oxide/Carbon Monoxide in Pulmonary Hypertention

描述（由申请人提供）： 我们已经发现，原发性肺动脉高压（PPH）患者呼出气中一氧化氮（NO）水平较低，这是一种有效的血管扩张剂，表明NO在肺动脉高压的病理生理学中发挥作用。本研究的目的是确定PPH中低NO的机制。潜在的机制，将解决在实验中的NO生产的抑制CO和酶动力学异常影响NO合成酶（NOS）对氧的敏感性。我们以前已经表明，在生理范围内的氧浓度决定了在肺中的NO合成的速率。然而，PPH患者尽管接受了辅助供氧治疗，但NO水平仍较低。 这表明PPH中的NO脱氢酶可能对氧不太敏感，因此需要高于正常的氧来产生NO。此外，CO可以直接影响内源性NO的合成。在初步数据中，CO在PPH中的范围可能导致NOS活性和NO生成的抑制。我们推测，NO减少PPH可能是由于高CO水平和/或受损的NO生产响应氧气。作为这一假设的延伸，我们还提出，有效的治疗，如前列环素，可能会通过增加NO水平在PPH的一部分。 为了验证这一假设，我们提出了以下具体目标：目标1。确定一氧化碳（CO）水平与NO和PPH疾病严重程度的关系。 目标二。研究氧和依前列醇对PPH中NO水平的影响。目标3。体外研究O2和CO对NOS表达和活性的影响。正式的课程工作和教育已纳入本提案的培训部分。候选人将通过指导小组获得肺生物学和肺动脉高压领域领导者的指导。通过5年的奖励，候选人将发展他的技能（i）假设驱动的研究设计，（ii）数据分析和解释，以及（iii）撰写手稿，摘要和在会议上展示数据。这项建议的培训部分将使候选人过渡到完全独立的调查员。

DESCRIPTION (provided by applicant): We have shown that patients with primary pulmonary hypertension (PPH) have low levels of nitric oxide (NO), a potent vasodilator, in exhaled breath suggesting a role for NO in the pathophysiology of pulmonary hypertension. The purpose of this proposed research is to determine the mechanism(s) for low NO in PPH. Potential mechanisms that will be addressedin the experiments are inhibition of NO production by CO and enzyme kinetic abnormalities affecting the sensitivity of NO synthase (NOS) to oxygen. We have previously shown that oxygen concentrations in the physiologic range determine the rate of NO synthesis in the lung. However, PPH individuals have low NO despite receiving supplemental oxygen therapy. This suggests that NO synthases in PPH may be less sensitive to oxygen and thus require higher than normal oxygen to produce NO. Furthermore, CO can directly affect endogenous NO synthesis. In preliminary data, CO in PPH is in the range that may lead to inhibition of NOS activity and NO generation. We hypothesize that NO is decreased in PPH perhaps as a consequence of high CO levels and/or impaired NO production in response to oxygen. As an extension of this hypothesis, we also propose that effective therapies such as epoprostenol, may act in part by increasing NO levels in PPH. To test this hypothesis, we propose the following specific aims: Aim 1. Determine the levels of Carbon monoxide (CO) in relationship to NO and severity of disease in PPH. Aim 2. Study the effect of oxygen and epoprostenol on NO levels in PPH in vivo. Aim 3. Study the effect of 02 and CO on NOS expression and activity in vitro. Formal course work and education are incorporated into the training component of this proposal. The candidate will have direction from leaders in the field of lung biology and pulmonary hypertension through a mentoring group. Through the 5 year award, the candidate will develop his skills in (i) hypotheses-driven design of studies, (ii) analyses and interpretation of data, and (iii) writing of manuscripts, abstracts and presenting data at meetings. The training component of this proposal will lead to the candidate's transition to a fully independent investigator.