Chronic progressive hypoxia-induced pulmonary hypertension in newborns

新生儿慢性进行性缺氧引起的肺动脉高压

• 批准号: 9195826
• 负责人: CANDICE D FIKE
• 金额: $ 53.28万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-14 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9195826
• 关键词: Chronic; progressive; hypoxia; induced; pulmonary

 DESCRIPTION (provided by applicant): Our long-term objective is to improve therapies for progressive pulmonary hypertension (PH) in infants suffering from chronic cardiopulmonary disorders associated with persistent or episodic hypoxia. To do this, we developed a model of PH in newborn pigs. We have shown that PH develops within 3 days exposure to hypoxia and worsens when hypoxic exposure is extended to 10 days. The progressive development of PH in newborn pigs is accompanied by NO signaling impairments, including eNOS uncoupling. These findings serve as the basis for testing the hypothesis that restoring eNOS uncoupling will improve NO production and ameliorate PH. Our experimental design will test the hypothesis that combined treatment with the L-arginine- NO precursor L-citrulline, plus the co-factor BH4, restores pulmonary vascular NO signaling and ameliorates PH more effectively than either treatment alone, by more effectively recoupling eNOS, shifting the balance of eNOS-generated free radicals away from superoxide and toward NO production. The aims of this proposal are to: 1) evaluate the mechanisms by which combined therapy with L-citrulline and BH4 increase pulmonary vascular NO production 2) establish the efficacy and safety of combined vs sole therapy with oral L-citrulline or BH4 to ameliorate chronic hypoxia-induced PH. Studies will evaluate the ability of these therapies to arrest the progressive development of PH when given chronically to piglets exposed to hypoxia and to acutely improve pulmonary vascular responses to NO when administered to piglets with PH. As part of the first aim, studies will address current gaps in our knowledge about the oxidation and loss of BH4 in the neonatal pulmonary circulation. This will include delineating the sources of superoxide, including NADPH oxidase family enzymes, that contribute to oxidation of BH4, and, hence, uncoupled eNOS. As part of the second aim, we will determine if combined therapy with L-citrulline and BH4 improves the parameters of NO signaling that are perturbed with chronic hypoxia. These studies will provide invaluable information about restoring impaired NO signaling pathways that can ultimately be translated into important clinical trials to treat infants with chronic cardiopulmonary conditions and PH due in part to hypoxia.

 描述(由申请人提供)：我们的长期目标是改进对患有慢性心肺疾病的婴儿进行性肺动脉高压(PH)的治疗方法，这些疾病与持续性或间歇性低氧相关。为了做到这一点，我们开发了一种新生猪的PH模型。我们已经证明，PH在缺氧暴露的3天内发生，当缺氧暴露延长到10天时，PH恶化。新生猪PH的进行性发展伴随着NO信号的损伤，包括eNOS解偶联。这些发现为验证这样的假设提供了基础，即恢复eNOS解偶联将增加NO的产生并改善PH。我们的实验设计将检验这样一个假设，即联合使用L-精氨酸-NO前体L-瓜氨酸，加上辅助因子BH4，通过更有效地重新偶联eNOS，将eNOS产生的自由基的平衡从超氧化物歧化转向NO产生，恢复肺血管NO信号，并比单独使用任何一种治疗方法都更有效地改善PH。本研究的目的是：1)评价L-瓜氨酸和BH_4联合治疗增加肺血管NO生成的机制；2)比较口服L-瓜氨酸或BH_4单用与联合治疗改善慢性缺氧性肺高压的疗效和安全性。研究将评估这些疗法的能力，当长期给予暴露在低氧中的仔猪时，阻止PH的进行性发展，并在给予患有PH的仔猪时，显著改善肺血管对NO的反应。作为第一个目标的一部分，研究将解决目前我们对新生儿肺循环中BH4的氧化和丢失的认识空白。这将包括描绘超氧化物的来源，包括NADPH氧化酶家族酶，有助于BH4的氧化，从而导致解偶联eNOS。作为第二个目标的一部分，我们将确定L-瓜氨酸和BH4联合治疗是否改善了受慢性缺氧干扰的NO信号参数。这些研究将提供关于恢复受损的NO信号通路的宝贵信息，这些信息最终可以转化为治疗患有慢性心肺疾病和部分由于缺氧引起的PH的婴儿的重要临床试验。