Hypoxic-Inducible Factors in Neonatal Pulmonary Hypertension

新生儿肺动脉高压的缺氧诱发因素

• 批准号: 8214146
• 负责人: Carl W White
• 金额: $ 6.48万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8214146
• 关键词: ABCA3 gene; Acute; Adult; Adult Respiratory Distress Syndrome; Affect; Air; Albumins; Alveolar; Amniotic Fluid; Anemia; Angiogenic Factor; Animals; Area; Autopsy; Birth; Blood Circulation; Blood Vessels; Blood capillaries; Blood flow; Blood gas; Breathing; Bronchoalveolar Lavage; Bronchopulmonary Dysplasia; Carrier Proteins; Cells; Cessation of life; Child; Chronic; Data; Development; Disease; Dose; Ductal; Ductus Arteriosus; Economic Inflation; Endothelial Cells; Endothelium; Environment; Epithelial Cells; Epithelium; Equilibrium; Erythropoietin; Face; Fetal Lung; Fetus; Frequencies; Gene Expression; Gene Family; Genes; Growth and Development function; Homeostasis; Hyperoxia; Hypoxia; Hypoxia Inducible Factor; Infant; Inflammation; Inflammatory; Injury; Knock-out; Knowledge; Lecithin; Left pulmonary artery; Lipids; Lung; Lung Compliance; Measurement; Measures; Mechanics; Messenger RNA; Modeling; Neonatal; Newborn Infant; Operative Surgical Procedures; Oxygen; Oxygen measurement, partial pressure, arterial; Patent Ductus Arteriosus; Perinatal; Perinatal Pulmonary Hypertension; Pharmaceutical Preparations; Phenotype; Pregnancy; Premature Birth; Premature Infant; Primates; Process; Procollagen-Proline Dioxygenase; Production; Proteins; Pulmonary Circulation; Pulmonary Edema; Pulmonary Gas Exchange; Pulmonary Hypertension; Pulmonary artery structure; Recombinant Proteins; Relative (related person); Relaxation; Reporting; Research Personnel; Respiratory distress; Respiratory physiology; Role; Route; Signal Transduction; Structure of parenchyma of lung; Surface; System; Term Birth; Therapeutic; Therapeutic Uses; Third Pregnancy Trimester; Transgenic Mice; Vascular Diseases; Vascular Endothelial Growth Factors; Vascular remodeling; Vasodilation; angiogenesis; ascorbate; base; capillary; cofactor; cost; cytokine; fetal; hemodynamics; human NOS3 protein; hypoxia inducible factor 1; improved; in utero; in vitro Model; in vivo; indexing; inhibitor/antagonist; instrument; instrumentation; lipid transport; lung development; lung hypoxia; morphometry; neonatal pulmonary hypertension; neonate; persistent pulmonary hypertension; postnatal; prenatal; pressure; programs; protein expression; receptor; respiratory distress syndrome; surfactant; trend; vascular bed

Pulmonary hypertension (PHN) in respiratory distress syndrome (RDS) evolving to bronchopulmonary dysplasia (BPD) results acutely from poor lung inflation and increased blood flow through the patent ductus arteriosus, and chronically from altered reactivity, vascular remodeling, and hypoplasia of the pulmonary vascular bed. The lung develops in relative hypoxia compared to 21% 02 seen at normal term delivery and, especially, to hyperoxia that preterm neonates commonly face. Hypoxia-inducible factors (HIFs) could lower pulmonary artery pressures by modulating surfactant, ductus arteriosus, and pulmonary vascular development. Preliminary data show that HIFs can impact lung expansion at birth, expression of surfactant proteins and lipids, patency of the ductus arteriosus, and angiogenic factors and processes in developing lungs - all of which canmodify pulmonary hypertension. Further data show that HIFs are highly expressed and stable in third trimester fetal primate lungs, while one of them, HIF-1a, declines dramatically after preterm birth. Using cofactors 02, Fe2+, oxoglutarate, and ascorbate, HIF prolyl- hydroxylases (PHDs) specifically regulate HIFstability. We reported that PHDinhibitors (PHDi) profoundly alter stability of HIFs and downstream gene expression (VEGF and its receptors) in lung endothelial and epithelial cells, and fetal lung explants, even in extreme hyperoxia. We hypothesize that PHDi can decrease PHNby restoring the fetal VEGF/eNOS axis and improving perinatal surfactant homeostasis. We propose to examine effects of PHDi delivered antenatally or postnatally, and by differing routes, in ovine models of RDS and persistent PHN in preterm and term ovine models, respectively. Chronically instrumented fetal/neonatal lambs will have pre- and/or postnatal hemodynamic, blood gas, and respiratory physiology measurements. In lung tissue from these animals, we will measure HIFs, HIF- dependent gene products, surfactant proteins and lipids, inflammatory cytokines and cells, and lung morphometry to assess vascular development and remodeling. Results will provide valuable information about pathophysiologic roles of HIFs in perinatal PHN and potential therapeutic uses of PHDi in RDS and PHN.

呼吸窘迫综合征 (RDS) 中的肺动脉高压 (PHN) 演变为支气管肺疾病 发育不良 (BPD) 是由于肺膨胀不良和通过导管未闭的血流量增加引起的 动脉，并长期因反应性改变、血管重塑和肺发育不全而 血管床。与正常足月分娩时的 21% 02 相比，肺部在相对缺氧的情况下发育，并且， 尤其是早产儿常见的高氧血症。缺氧诱导因子（HIF）可以降低 通过调节表面活性剂、动脉导管和肺血管来调节肺动脉压力 发展。初步数据表明，HIF 可以影响出生时的肺扩张、 表面活性蛋白和脂质、动脉导管的通畅性以及血管生成因子和 肺部发育过程 - 所有这些都可以改变肺动脉高压。进一步数据显示 HIF 在妊娠晚期灵长类胎儿肺中高度表达且稳定，而其中之一 HIF-1a， 早产后急剧下降。使用辅因子 02、Fe2+、氧化戊二酸和抗坏血酸，HIF 脯氨酰- 羟化酶 (PHD) 专门调节 HIF 稳定性。我们报道了 PHD 抑制剂 (PHDi) 深刻改变肺中 HIF 和下游基因表达（VEGF 及其受体）的稳定性 内皮细胞和上皮细胞以及胎肺外植体，即使在极度高氧条件下也是如此。我们假设 PHDi 可通过恢复胎儿 VEGF/eNOS 轴和改善围产期表面活性物质来减少 PHN 体内平衡。我们建议检查产前或产后分娩的 PHDi 的影响，并通过不同的方法 分别在 RDS 绵羊模型和早产儿和足月绵羊模型中持续性 PHN 中的途径。 长期进行仪器检测的胎儿/新生羔羊将进行产前和/或产后血流动力学、血气和 呼吸生理学测量。在这些动物的肺组织中，我们将测量 HIF、HIF- 依赖基因产物、表面活性蛋白和脂质、炎症细胞因子和细胞以及肺 形态测定法评估血管发育和重塑。结果将提供有价值的信息 关于 HIF 在围产期 PHN 中的病理生理作用以及 PHDi 在 RDS 中的潜在治疗用途 PHN。