Chronic progressive hypoxia-induced pulmonary hypertension in newborns

 描述（由申请人提供）：我们的长期目标是改善患有与持续性或间歇性缺氧相关的慢性心肺疾病的婴儿进行性肺动脉高压（PH）的治疗。为此，我们在新生猪中开发了PH模型。我们已经证明，PH在缺氧暴露3天内发生，当缺氧暴露延长至10天时，PH会发生。新生猪PH的进行性发展伴随着NO信号传导障碍，包括eNOS解偶联。这些发现是检验恢复eNOS解偶联将改善NO产生和改善PH的假设的基础。我们的实验设计将检验以下假设：与L-精氨酸- NO前体L-瓜氨酸和辅因子BH 4联合治疗，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转移到NO的产生。这项建议的目的是：1）评估L-瓜氨酸和BH 4联合治疗增加肺血管NO生成的机制2）确定口服L-瓜氨酸或BH 4联合治疗与单独治疗改善慢性缺氧的有效性和安全性-研究将评价这些疗法在长期给予暴露于以下物质的仔猪时阻止PH进行性发展的能力：缺氧和急性改善肺血管对NO的反应时，与PH仔猪。作为第一个目标的一部分，研究将解决目前的差距，我们的知识的氧化和损失的BH 4在新生儿肺循环。这将包括描绘超氧化物的来源，包括NADPH氧化酶家族酶，其有助于BH 4的氧化，因此，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BH 4的联合治疗是否能改善慢性缺氧干扰的NO信号传导参数。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重要的临床试验，以治疗部分由于缺氧而患有慢性心肺疾病和PH的婴儿。

 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.