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）发展为支气管肺的肺动脉高压（PHN）