Hypoxic-Inducible Factors in Neonatal Pulmonary Hypertension

呼吸窘迫综合征（RDS）演变为支气管肺动脉高压（PHN） 肺发育不良（BPD）是由于肺充气不良和通过未闭导管的血流增加而急性引起的 动脉，和慢性从改变反应性，血管重塑，和肺发育不全 血管床与正常足月分娩时观察到的21%O2相比，肺在相对缺氧中发展， 尤其是早产儿常见的高氧血症。缺氧诱导因子（HIF）可以降低 通过调节表面活性物质、动脉导管和肺血管来调节肺动脉压力 发展初步数据显示，HIF可以影响出生时的肺扩张， 表面活性蛋白和脂质、动脉导管的通畅性和血管生成因子， 所有这些都可以改变肺动脉高压。更多数据显示 HIF在妊娠晚期灵长类胎儿肺部高度表达且稳定，而其中之一，HIF-1a， 在早产后急剧下降。使用辅因子02、Fe 2+、酮戊二酸盐和抗坏血酸盐，HIF脯氨酰- 羟化酶（PHD）特异性调节HIF稳定性。我们报道了PHDinhibitors（PHDi）， 深刻改变肺中HIF稳定性和下游基因表达（VEGF及其受体） 内皮细胞和上皮细胞以及胎肺外植体，即使在极端高氧下。我们假设 PHDi可通过恢复胎儿VEGF/eNOS轴和提高围生期表面活性物质水平来降低PHN 体内平衡我们建议检查出生前或出生后PHDi的影响，并通过不同的 途径，分别在RDS的绵羊模型和早产和足月绵羊模型中的持续性PHN中。 长期内固定的胎羊/新生羔羊将具有出生前和/或出生后的血流动力学、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- 依赖性基因产物、表面活性蛋白和脂质、炎性细胞因子和细胞以及肺 形态测量以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。

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.