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）和右心室肥厚（RVH） 大约 25% 的中度或重度 BPD 婴儿被认为是并发症。一次 婴儿患上PH，人们对如何治疗知之甚少，而且发病和死亡的风险非常高。一 BPD 治疗的主要支柱是氧气 (O2)，但超生理的 O2 浓度与 机械通气增加活性氧（ROS）的产生，诱导显着的血管生成 新生儿功能障碍。 ROS介导的肺血管失调的潜在关键靶点 参与 cGMP 信号传导 - 可溶性鸟苷酸环化酶 (sGC) 和磷酸二酯酶 5 (PDE5)。在 在之前的资助期间，我们利用高氧诱导的肺病和肺PH的小鼠模型来证明 高氧暴露的小鼠会出现严重的肺部和血管疾病，其特征是肺泡 简化、毛细血管减少、小肺动脉 (PA) 重塑和 RVH。我们证明了 高氧迅速降低肺和 PA 可溶性鸟苷酸环化酶 (sGC) 的表达和活性 增加肺和 PA 磷酸二酯酶 5 (PDE5) 活性，导致 cGMP 介导的破坏 下游信令。给予低剂量西地那非（一种 PDE5 抑制剂）同时预防高氧血症 PDE5 活性、血管重塑和 RVH 增加，但无法恢复正常毛细血管密度 和肺泡化。在该提案的初步数据中，我们已经证明了另一种环境 压力源，胎盘功能不全导致的宫内生长受限（IUGR），导致生长显着延迟 肺泡化伴随关键肺生长因子胰岛素样生长因子-1 (IGF-1) 表达的减少， sGC 表达和活性降低，肺泡化受损。 IUGR小鼠具有夸张的 高氧表型与 sGC 表达和活性进一步降低的适当生长的小鼠相比 和肺泡化受损。我们假设生长受限和高氧诱导 线粒体 ROS 破坏关键的 sGC-cGMP 信号通路，导致功能受损 肺泡化和血管生成。我们将利用我们建立的高氧诱导肺小鼠模型 损伤与 IUGR 的新模型相结合，以阐明 ROS 和 生长限制会破坏 sGC-cGMP 信号传导和肺部发育。这些研究将提供 改善 BPD PH 婴儿药物治疗的病理生理学、机制框架。我们 相信 sGC 是影响新生儿肺泡化和血管生成的多种信号的关键整合者 时期。 sGC 刺激剂（例如 riocinguat）已被批准用于患有 PH 的成人，代表了一种新颖且有效的治疗方法。 如果能够证明其使用的理由，则可能是 BPD-PH 婴儿的潜在直接治疗选择。

项目成果

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

SOD2活性不会受到鼠新生儿肺动脉平滑肌细胞和小鼠的高氧影响。

• 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

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

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