Redox Regulation of Vascular cGMP Signaling in Neonatal Lungs

新生儿肺血管 cGMP 信号传导的氧化还原调节

• 批准号: 9175594
• 负责人: KATHRYN N FARROW
• 金额: $ 43.04万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-15 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9175594
• 关键词: Adult; Affect; Alveolar; Antioxidants; Back; Birth; Blood Vessels; Blood capillaries; Bronchopulmonary Dysplasia; Cardiovascular system; Chemicals; Complication; Cyclic GMP; Data; Development; Disease; Dose; Elastin; Endothelial Cells; Epithelial Cells; Fetal Growth Retardation; Functional disorder; Funding; Growth; Health Care Costs; Hyperoxia; Infant; Insulin-Like Growth Factor I; Knockout Mice; Lesion; Lung; Lung diseases; Mechanical ventilation; Mediating; Mitochondria; Mitochondrial Matrix; Modeling; Molecular; Morbidity - disease rate; Mus; Neonatal; Oxidation-Reduction; Oxygen; Pathway interactions; Phenotype; Placental Insufficiency; Premature Birth; Prevention; Production; Pulmonary Hypertension; Pulmonary artery structure; Reactive Oxygen Species; Recombinant IGF-I; Regulation; Right Ventricular Hypertrophy; Risk; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Soluble Guanylate Cyclase; Stress; Techniques; Therapeutic; Vascular Diseases; Vascular remodeling; angiogenesis; capillary; critical period; density; environmental stressor; experience; improved; inhibitor/antagonist; lung development; lung injury; mortality; mouse model; neonate; new therapeutic target; novel; novel therapeutics; phosphodiesterase V; prevent; pulmonary artery endothelial cell; restoration; sildenafil; transcriptome; transcriptome sequencing

SUMMARY Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth affecting 30% of infants with birthweights < 1000 grams. Recently, pulmonary hypertension (PH) and right ventricular hypertrophy (RVH) have been recognized as complications in approximately 25% of infants with moderate or severe BPD. Once infants develop PH, little is known about how to treat them, and risk of morbidity and mortality is very high. One of the mainstays of BPD therapy is oxygen (O2), but supraphysiologic O2 concentrations in combination with mechanical ventilation increase reactive oxygen species (ROS) production, inducing significant vascular dysfunction in neonates. Potential key targets for ROS-mediated dysregulation in the pulmonary vasculature are involved in cGMP signaling - soluble guanylate cyclase (sGC) and phosphodiesterase 5 (PDE5). In the previous funding period, we utilized a mouse model of hyperoxia-induced lung disease and PH to demonstrate that hyperoxia-exposed mice develop significant pulmonary and vascular disease, characterized by alveolar simplification, fewer capillaries, small pulmonary arteries (PA) remodeling, and RVH. We demonstrated that hyperoxia rapidly decreased lung and PA soluble guanylate cyclase (sGC) expression and activity and increased lung and PA phosphodiesterase 5 (PDE5) activity, leading to disruption of cGMP-mediated downstream signaling. Giving low-dose sildenafil, a PDE5 inhibitor, concurrent with hyperoxia prevented increased PDE5 activity, vascular remodeling, and RVH, but was unable to restore normal capillary density and alveolarization. In preliminary data for this proposal, we have demonstrated that another environmental stressor, intrauterine growth restriction (IUGR) due to placental insufficiency, leads to a significant delay in alveolarization with decreased expression of a key lung growth factor, insulin-like growth factor-1 (IGF-1), decreased sGC expression and activity, and impaired alveolarization. IUGR mice have an exaggerated phenotype with hyperoxia vs. appropriately grown mice with further decreased sGC expression and activity and impaired alveolarization. We hypothesize that both growth restriction and hyperoxia-induced mitochondrial ROS disrupt the critical sGC-cGMP signaling pathway, leading to impaired alveolarization and angiogenesis. We will utilize our established mouse model of hyperoxia-induced lung injury in combination with a novel model of IUGR to elucidate the molecular mechanism by which ROS and growth restriction disrupt sGC-cGMP signaling and lung development. These studies will provide the pathophysiologic, mechanistic framework to improve pharmacologic treatment of BPD infants with PH. We believe sGC is a key integrator for multiple signals that impact alveolarization and angiogenesis in the neonatal period. sGC stimulators such as riocinguat are approved in adults with PH and represent a novel and potentially immediate therapeutic option for BPD-PH infants if a rationale for their use can be demonstrated.

摘要 支气管肺发育不良(BPD)是早产的常见并发症，影响30%的婴儿 出生体重1000克。近年来，肺动脉高压(PH)和右室肥厚(RVH) 在大约25%患有中度或重度BPD的婴儿中，已被认为是并发症。一次 婴儿发展为PH，对如何治疗知之甚少，发病和死亡的风险非常高。一 BPD治疗的主要因素是氧气(O2)，但超生理氧气浓度与 机械通风增加了活性氧(ROS)的产生，诱导了显著的血管 新生儿的功能障碍。ROS介导的肺血管调节失调的潜在关键靶点 参与cGMP信号转导的可溶性鸟苷环化酶(SGC)和磷酸二酯酶5(PDE5)。在 在之前的资助期间，我们使用了高氧诱导的肺部疾病和PH的小鼠模型来证明 暴露在高氧环境中的小鼠会患上严重的肺部和血管疾病，其特征是肺泡 简化，较少的毛细血管，小的肺动脉(PA)重塑，和RVH。我们证明了这一点 高氧迅速降低肺和PA可溶性鸟苷环化酶(SGC)的表达和活性，并 肺和PA磷酸二酯酶5(PDE5)活性增加，导致cGMP介导的破坏 下行信令。小剂量给予PDE5抑制剂西地那非预防高氧血症 PDE5活性增加，血管重塑和RVH增加，但无法恢复正常的毛细血管密度 和牙槽骨化。在这项提案的初步数据中，我们已经证明了另一种环境 应激源，由于胎盘功能不全引起的宫内生长受限(IUGR)，导致显著延迟 肺泡化，关键的肺生长因子，胰岛素样生长因子-1(IGF-1)表达减少， SGC表达和活性降低，肺泡化受损。IUGR小鼠有夸张的 高氧小鼠与sGC表达和活性进一步降低的适当发育小鼠的表型比较 和肺泡化受损。我们假设生长受限和高氧诱导的 线粒体ROS破坏关键的sGC-cGMP信号通路，导致受损 肺泡化和血管生成。我们将利用我们建立的高氧肺小鼠模型 损伤与IUGR的一个新模型相结合以阐明ROS和 生长受限干扰sGC-cGMP信号转导和肺发育。这些研究将提供 改善BPD合并PH患儿药物治疗的病理生理学、机械学框架。我们 我相信sGC是影响新生儿牙槽骨形成和血管生成的多种信号的关键整合因子 句号。SGC刺激剂，如利奥瓜特，被批准用于患有PH的成年人，代表了一种新的和 如果可以证明使用BPD-PH婴儿的理由，可能立即选择BPD-PH婴儿。