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: 7916262
• 负责人: CANDICE D FIKE
• 金额: $ 55.6万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7916262
• 关键词: Address; Animal Model; Animals; Arginine; Aspartate; Blood Vessels; Breathing; Bronchopulmonary Dysplasia; Cardiac; Cardiopulmonary; Cessation of life; Chronic; Citrulline; Clinical; Clinical Trials; Complication; Data; Development; Disease; Drug Kinetics; Drug or chemical Tissue Distribution; Ensure; Enzymes; Experimental Designs; Exposure to; Failure; Family suidae; Generations; Goals; Heart Diseases; Hypoxia; Impairment; Infant; Knowledge; Lead; Lung; Modeling; Multienzyme Complexes; Neonatal; Neutral Amino Acid Transport Systems; Neutral Amino Acids; Newborn Animals; Newborn Infant; Oral; Pathogenesis; Pathway interactions; Plasma; Process; Production; Publishing; Pulmonary Circulation; Pulmonary Heart Disease; Pulmonary Hypertension; Recycling; Regimen; Reporting; Safety; Signal Pathway; Signal Transduction; Source; Testing; Therapeutic; Translating; Vasodilator Agents; argininosuccinate lyase; congenital heart disorder; design; extracellular; improved; in vivo Model; innovation; mature animal; neonatal pulmonary hypertension; novel; prevent; public health relevance; treatment strategy; uptake

DESCRIPTION (provided by applicant): Our long-term objective is to improve therapies for chronic progressive pulmonary hypertension (CPPH) in infants suffering from chronic cardiopulmonary disorders associated with persistent and episodic hypoxia. To do this, we developed a model of CPPH in newborn pigs. We have shown that after 3 days of chronic hypoxia, pulmonary hypertension develops and pulmonary vascular production of the vasodilator NO is intact. When hypoxic exposure is extended to 10 days, pulmonary hypertension worsens and is accompanied by reduced pulmonary vascular NO production. It follows that counteracting or restoring impairments in NO signaling could ameliorate CPPH. Our experimental design will test the hypothesis that treatment with oral L-citrulline, a precursor for L-arginine and NO, increases pulmonary vascular NO production and ameliorates the progressive development of chronic hypoxia-induced pulmonary hypertension. The aims of this proposal are to: 1) evaluate the ability of and mechanisms by which L-citrulline increases pulmonary vascular NO production 2) evaluate the efficacy and safety of oral L-citrulline to ameliorate chronic hypoxia-induced pulmonary hypertension. Treatments started on the day of placement in hypoxia and continued throughout 3 or 10 days total hypoxic exposure will determine the ability to prevent pulmonary hypertension. Treatments started at the end of the 3rd day of hypoxia and continued for the subsequent 7 days of hypoxia will evaluate the ability to arrest or reverse the progression of pulmonary hypertension. As part of the first aim, studies will be performed to address current gaps in our knowledge about L-citrulline sources, availability, and processing. This will include studies to determine whether chronic hypoxia reduces plasma (extracellular) or intracellular levels of L- citrulline, diminishes the expression of neutral amino acid (L-citrulline) transporters, alters L-citrulline uptake, and/or impairs the amounts, activities or complexing of the enzymes and co-precursors (aspartate) needed for adequate intracellular generation/recycling of L-citrulline (e.g. diminished interaction of eNOS and the L- citrulline to L-arginine recycling enzymes, argininosuccinate and argininosuccinate lyase). As part of the second aim, we will perform pharmacokinetic studies of oral L-citrulline to optimize the therapeutic regimen. We will determine if optimized L-citrulline therapy improves the parameters of NO signaling that are perturbed with exposure to chronic hypoxia. These studies will provide invaluable information about offsetting and restoring impaired NO signaling pathways that can ultimately be translated into important clinical trials to treat infants with chronic cardiopulmonary conditions and CPPH due in part to hypoxia. PUBLIC HEALTH RELEVANCE: Pulmonary hypertension is a well recognized complication of infants with chronic lung and heart disorders. Currently there are few good options for treating these infants. The goal of this project is to use a relevant animal model to help us understand why infants with lung and heart disorders associated with chronic or intermittent hypoxia develop progressive pulmonary hypertension, determine what happens in the lung blood vessels during disease development, and develop treatments for this disease.

描述（由申请人提供）：我们的长期目标是改善患有与持续性和阵发性缺氧相关的慢性心肺疾病的婴儿的慢性进行性肺动脉高压（CPPH）的治疗。为此，我们开发了新生猪 CPPH 模型。我们已经证明，慢性缺氧 3 天后，会出现肺动脉高压，而肺血管生成的血管舒张剂 NO 却完好无损。当缺氧时间延长至10天时，肺动脉高压恶化，并伴有肺血管NO产生减少。由此可见，抵消或恢复 NO 信号传导损伤可以改善 CPPH。我们的实验设计将验证以下假设：口服 L-瓜氨酸（L-精氨酸和 NO 的前体）治疗可增加肺血管 NO 的产生并改善慢性缺氧引起的肺动脉高压的进展。该提案的目的是：1) 评估 L-瓜氨酸增加肺血管 NO 产生的能力和机制 2) 评估口服 L-瓜氨酸改善慢性缺氧引起的肺动脉高压的有效性和安全性。治疗从置于缺氧环境的当天开始并持续 3 或 10 天的总缺氧暴露将决定预防肺动脉高压的能力。在缺氧第 3 天结束时开始并持续缺氧 7 天的治疗将评估阻止或逆转肺动脉高压进展的能力。作为第一个目标的一部分，我们将进行研究以解决目前我们在 L-瓜氨酸来源、可用性和加工方面的知识空白。这将包括确定慢性缺氧是否会降低血浆（细胞外）或细胞内 L-瓜氨酸水平、减少中性氨基酸（L-瓜氨酸）转运蛋白的表达、改变 L-瓜氨酸摄取和/或损害其数量、活性的研究或酶与辅助前体（天冬氨酸）的络合，以充分细胞内生成/回收 L-瓜氨酸（例如，减少相互作用） eNOS 和 L-瓜氨酸至 L-精氨酸再循环酶、精氨基琥珀酸和精氨基琥珀酸裂合酶）。作为第二个目标的一部分，我们将对口服 L-瓜氨酸进行药代动力学研究，以优化治疗方案。我们将确定优化的 L-瓜氨酸治疗是否可以改善因慢性缺氧而受到干扰的 NO 信号参数。这些研究将提供关于抵消和恢复受损的 NO 信号通路的宝贵信息，这些信息最终可以转化为重要的临床试验，用于治疗患有慢性心肺疾病和部分由于缺氧而导致的 CPPH 的婴儿。 公众健康相关性：肺动脉高压是患有慢性肺和心脏疾病的婴儿的一种公认的并发症。目前治疗这些婴儿的好的选择很少。该项目的目标是使用相关的动物模型来帮助我们了解为什么患有与慢性或间歇性缺氧相关的肺和心脏疾病的婴儿会出现进行性肺动脉高压，确定疾病发展过程中肺血管中发生的情况，并开发治疗方法这种病。