Inhaled nitric oxide

描述(由申请人提供)： 这笔赠款建议进行临床前研究，以提高吸入型一氧化氮(NO)的效用和疗效。该实验室报告了开创性的研究，提供了吸入NO气体产生选择性肺血管扩张的证据。在急性肺损伤的患者和动物模型中，吸入低水平的NO被证明可以选择性地逆转由于缺氧和其他刺激引起的肺血管收缩，并通过选择性地扩张患者和动物的肺通气区来增加全身氧合。自1999年以来，每年有超过12万名患者吸入低水平的NO来治疗肺动脉高压和急性呼吸衰竭。不幸的是，大约40%的患者对吸入NO后肺血管扩张和氧合改善没有反应。这种可变反应的病因学仍不完全清楚。这笔赠款支持的研究将有四个目标：(1)确定内毒素诱导的肺损伤所致的缺氧性肺血管收缩(HPV)受损的介质；(2)阐明NO、白三烯和活性氧在呼吸机诱导的肺损伤(VILI)相关的HPV损害中的作用；(3)研究白三烯在急性肺损伤中对吸入NO的肺血管反应性损害中的作用；以及(4)评估白三烯信号转导的抑制剂以及一氧化氮吸入对VILI发生的影响。在前三项研究中提出了内毒素血症和高潮气量机械通气所致的急性肺损伤。通过在小鼠身上的研究开发的新的治疗方法将在第二个物种--羔羊身上进行测试，作为下一步的关键步骤，然后将这些新的治疗方法带到患者的床边。通过了解内源性和吸入性NO与白三烯合成在急性肺损伤相关的肺血管功能障碍中相互作用的本质，拟议的研究将加强吸入性NO治疗急性肺损伤的有效性。

DESCRIPTION (provided by applicant): This grant proposes preclinical studies to improve the utility and efficacy of inhaled nitric oxide (NO). This laboratory has reported pioneering studies providing evidence that inhaled NO gas produces selective Pulmonary vasodilation. Inhaling low levels of NO has been shown to selectively reverse pulmonary vasoconstriction due to hypoxia and other stimuli and increase systemic oxygenation by selectively vasodilating ventilated lung regions in patients and animal models of acute lung injury. Since1999, over 120,000 patients per year have breathed low levels of NO to treat pulmonary hypertension and acute respiratory failure. Unfortunately, approximately 40% of patients do not respond to NO inhalation with pulmonary vasodilation and improved oxygenation. The etiology of this variable response remains incompletely understood. Studies supported by this grant will have four aims: (1) identify mediators of the impaired hypoxic pulmonary vasoconstriction (HPV) due to endotoxin-induced lung injury, (2) elucidate the roles of NO, leukotrienes, and reactive oxygen species in the impairment of HPV associated with ventilator-induced lung injury (VILI), (3) examine the role of leukotrienes in the impairment of pulmonary vascular responsiveness to inhaled NO in acute lung injury, and (4) evaluate the impact of inhibitors of leukotriene signaling, as well as nitric oxide inhalation, on the development of VILI. Studies proposed in the first three acute lung injury due to endotoxemia and high tidal volume ventilation. New therapeutic approaches developed as a result of studies in mice will be tested in a second species, the lamb, as a key next step before bringing these new strategies to the patient bedside. By understanding the nature of the interaction of endogenous and inhaled NO and leukotriene synthesis in the pulmonary vascular dysfunction associated with acute lung injury, the proposed studies should enhance the utility of inhaled NO therapy in acute lung injury.