Redox Regulation in the Perinatal Pulmonary Vasculature

围产期肺血管的氧化还原调节

• 批准号: 10018670
• 负责人: PAUL T SCHUMACKER
• 金额: $ 44.44万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-04 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018670
• 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; Growth Factor; Health Care Costs; Hyperoxia; Impairment; 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; Perinatal; Pharmacological Treatment; Pharmacology; 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; alveolar epithelium; angiogenesis; cell growth; critical period; density; environmental stressor; experience; improved; inhibitor/antagonist; insulin regulation; lung development; lung injury; mortality; mouse model; neonatal period; neonate; new therapeutic target; novel; novel therapeutics; phosphodiesterase V; prevent; 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.

概括 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。最近，肺动脉高压（pH）和右心肥大（RVH） 大约25％的中度或重度BPD婴儿被认为是并发症。一次 婴儿会出现pH值，对如何治疗它们知之甚少，发病率和死亡率的风险很高。一 BPD疗法的支柱是氧（O2），但上生物生理学的O2浓度与 机械通气增加活性氧（ROS）的产生，诱导明显的血管 新生儿功能障碍。 ROS介导的肺脉管系统中ROS介导的失调的潜在关键靶标 参与了CGMP信号传导 - 可溶性鸟苷酸环化酶（SGC）和磷酸二酯酶5（PDE5）。在 以前的资金期，我们利用了高氧诱导的肺疾病和pH的小鼠模型来证明 暴露高氧小鼠会出现明显的肺和血管疾病，其特征是肺泡 简化，毛细血管较少，小肺动脉（PA）重塑和RVH。我们证明了这一点 高氧迅速降低肺和PA可溶性鸟苷酸环化酶（SGC）表达和活性 肺和PA磷酸二酯酶5（PDE5）活性增加，导致CGMP介导的中断 下游信号传导。给出低剂量西地那非，PDE5抑制剂，与高氧同时发生 PDE5活性增加，血管重塑和RVH，但无法恢复正常的毛细管密度 和牙槽化。在该提案的初步数据中，我们证明了另一种环境 压力源，由于胎盘不足而导致的宫内生长限制（IUGR），导致显着延迟 肺泡化，肺部生长因子的表达降低，胰岛素样生长因子1（IGF-1）， SGC表达和活性降低，肺泡化受损。 iugr鼠有夸张的 具有高氧与适当生长的小鼠的表型，SGC表达和活性进一步降低 肺泡化受损。我们假设生长限制和高氧诱导 线粒体ROS破坏关键的SGC-CGMP信号通路，导致受损 牙槽化和血管生成。我们将利用我们已建立的高氧诱导肺的老鼠模型 损伤与IUGR新型模型结合使用，以阐明ROS和ROS的分子机制 生长限制破坏SGC-CGMP信号传导和肺发育。这些研究将提供 病理生理，机械框架，以改善pH的BPD婴儿的药理治疗。我们 相信SGC是多个信号的关键积分器，这些信号会影响新生儿的牙槽化和血管生成 时期。 SGC刺激剂（例如Riocingoat）在患有pH的成年人中被批准，代表了一种新颖的和 如果可以证明BPD-PH婴儿的可能立即治疗选择。

项目成果

SOD2 activity is not impacted by hyperoxia in murine neonatal pulmonary artery smooth muscle cells and mice.

• DOI: 10.3390/ijms16036373
• 发表时间: 2015-03-19
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Gupta A;Perez M;Lee KJ;Taylor JM;Farrow KN
• 通讯作者: Farrow KN

Neonatal lung function and therapeutics.

新生儿肺功能和治疗。

• DOI: 10.1089/ars.2014.5959
• 发表时间: 2014
• 期刊: Antioxidants & redox signaling
• 影响因子: 6.6
• 作者: Auten,RichardL;Farrow,KathrynN
• 通讯作者: Farrow,KathrynN

Dose-dependent effects of glucocorticoids on pulmonary vascular development in a murine model of hyperoxic lung injury.

• DOI: 10.1038/pr.2016.1
• 发表时间: 2016-05
• 期刊: Pediatric research
• 影响因子: 3.6
• 作者: Perez M;Wisniewska K;Lee KJ;Cardona HJ;Taylor JM;Farrow KN
• 通讯作者: Farrow KN

Sildenafil therapy for bronchopulmonary dysplasia: not quite yet.

西地那非治疗支气管肺发育不良：尚未完成。

• DOI: 10.1038/jp.2011.158
• 发表时间: 2012
• 期刊: Journal of perinatology : official journal of the California Perinatal Association
• 作者: Farrow,KN;Steinhorn,RH
• 通讯作者: Steinhorn,RH