Hypoxic-Inducible Factors in Neonatal Pulmonary Hypertension

发展为支气管肺的呼吸窘迫综合征(RDS)的肺动脉高压(PHN) 发育不良(BPD)是由于肺充气不良和通过未闭导管的血流量增加所致。 动脉硬化，慢性肺反应性改变、血管重塑和肺发育不良。 血管床。与正常足月分娩时的21%02相比，肺在相对低氧状态下发育， 尤其是对早产儿普遍面临的高氧血症。低氧诱导因子(HIF)可降低 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 发展。初步数据显示，HIF可以影响出生时的肺扩张，表达 表面活性蛋白和脂类，动脉导管的通畅性，血管生成因子和 肺的发育过程--所有这些都可以改变肺动脉高压。进一步的数据显示 HIF在妊娠晚期胎儿灵长类动物肺中高度表达并稳定，而其中一种HIF-1a， 早产后会急剧下降。使用辅因子02、Fe2+、草戊二酸和抗坏血酸，HIF-Pro- 羟基酶(PhD)专门调节HIF的稳定性。我们报道了PHDI抑制剂(PHDI) 深刻改变HIFs的稳定性和肺组织下游基因(血管内皮生长因子及其受体)的表达 内皮细胞和上皮细胞，以及胎肺外植体，即使在极端高氧的情况下也是如此。我们假设 PHDI通过恢复胎儿血管内皮生长因子/eNOS轴和改善围产期肺表面活性物质降低PHN 动态平衡。我们建议检查PHDI在出生前或出生后的影响，并通过不同的方法 在早产期和足月期绵羊模型中，RDS和持久性PHN的路径分别为。 长期植入器械的胎儿/新生儿羔羊在出生前和/或出生后将有血流动力学、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、表面活性蛋白和脂类、炎性细胞因子和细胞以及肺 形态计量学评估血管发育和重塑。结果将提供有价值的信息 HIFs在围产期PHN中的病理生理作用及PHDI在RDS和RDS中的潜在治疗应用 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.