Hypoxia-inducible factors bronchopulmonary dysplasia-BPD

描述(由申请人提供)： 肺泡复杂性降低和肺血管发育是支气管肺发育不良(BPD)的一个恒定特征。即使现在氧疗的使用量比1-20年前低得多，这种情况仍然存在。肺在较低的胎儿氧气浓度(3-5%)下发育，在体外，在这些水平下肺发育要比21%时好得多。在这些较高的氧气水平下，内皮和血管的生长会受到损害。反过来，上皮和肺泡的发育又取决于与发育中的血管系统的关键相互作用。因此，21%的胎儿肺的远端气道分支较少。血管生成在妊娠晚期进展迅速。低氧诱导因子-1和低氧诱导因子-2(HIF-1和HIF-2)调节血管生成中的关键生长因子、受体、激酶和其他蛋白质。氧分压是HIF-1α和-2α的主要调节因子，而HIF-1α和-2α是这些转录因子的关键成分。在整个妊娠期间，在肺中或在妊娠晚期的远端肺上皮中敲除HIF-2，会导致新生小鼠肺发育过于简单和呼吸窘迫。最近发现，HIF-Pro-4-羟基酶(P4Hs或PhDS)能催化依赖O2的HIF的降解。用氧戊二酸类似物或铁络合剂抑制P4H可以稳定HIF，增加血管内皮生长因子，并导致血管生成。HIF特异性P4H抑制剂正在迅速开发。在心血管医学的试验中，使用单一生长因子的血管生成治疗已导致畸形或渗漏血管的形成。在常氧肺中“拨动”HIFs的开关可以导致更平衡的血管生成。我们假设HIF的缺失促进了BPD的肺发育不全，稳定HIF将促进BPD进展的早产儿更正常的肺发育。这项建议是为了进行翻译研究，以测试新的HIF特异性P4H抑制剂在体外和体内使用BPD灵长类动物模型对肺的影响。在体外，抑制P4H可导致HIF-1α的稳定、血管内皮生长因子的表达、血管生成以及在血管生长中重要的激酶活性的增加。在肺外植体中，新的HIF P4H抑制剂将被测试其稳定HIF和增加HIF相关蛋白和激酶活性的能力。此外，HIF P4H抑制剂将通过静脉、气管内和两种途径联合给药。将在体内测量气体交换、肺力学和功能、各种临床参数和HIF P4H抑制物水平，并在体外定量测定肺泡和血管发育、肺HIF蛋白和HIF相关蛋白和激酶活性以及组织HIF P4H抑制物水平。在HIF转录因子水平上进行治疗，以改善血管生成和肺泡发育，有望预防BPD。

DESCRIPTION (provided by applicant): Diminished alveolar complexity and vascular development of the lung is a constant feature of bronchopulmonary dysplasia (BPD). It persists even now that oxygen therapy is used at much lower levels than 1-2 decades ago. The lung develops at low, fetal oxygen concentrations (3-5%), and, in vitro, it develops much better at these levels than in 21%. Endothelial and vascular growth is impaired at these higher oxygen levels. Epithelial and alveolar development, in turn, depend on critical interactions with the developing vasculature. Thus, the distal airways of fetal lung in 21% show much less branching. Angiogenesis is proceeding rapidly in the third trimester of gestation. Hypoxia-inducible factors HIF- 1 and -2 (HIFs) regulate critical growth factors, receptors, kinases, and other proteins in angiogenesis. Oxygen tension is the primary regulator of HIF- 1alpha and -2alpha, the key components of these transcription factors. Knocking down HIF-2 in lung throughout gestation, or in distal lung epithelium during the third trimester, results in oversimplified lung development and respiratory distress in newborn mice. Recently HIF prolyl-4- hydroxylases (P4Hs or PHDs) were found to catalyze O2-dependent degradation of HIFs. Inhibiting P4Hs with oxoglutarate analogs or iron chelators stabilize HIFs, increase VEGF, and cause angiogenesis. HIFspecific P4H inhibitors are being rapidly developed. In trials in cardiovascular medicine, angiogenic therapy with single growth factors has caused formation of dysmorphic or leaky vessels. "Flipping the switch" of HIFs in the normoxic lung can cause more balanced angiogenesis. We hypothesize that loss of HIFs promotes lung hypoplasia in BPD, and that stabilizing HIFs will promote more normal lung development in the premature neonate with evolving BPD. This proposal is for translational research to test the effect of new HIF-specific P4H inhibitors on lung in vitro and in vivo using the primate model of BPD. In vitro, P4H inhibition causes HIF-1alpha stability, VEGF expression, angiogenesis, and increased activity of kinases important in vascular growth. In lung explants, new HIF P4H inhibitors will be tested for their ability to stabilize HIFs and increase HIF-related proteins and kinase activities. In addition, HIF P4H inhibitor will be administered intravenously, intratracheally, and by both routes combined. Gas exchange, pulmonary mechanics and function, various clinical parameters, and HIF P4H inhibitor levels will be measured in vivo, and alveolar and vascular development, lung HIF proteins and HIF-related proteins and kinase activities, and tissue HIF P4H inhibitor levels will be quantitated ex vivo. Therapy at the level of HIF transcription factors to improve angiogenesis and alveolar development offers promise to prevent BPD.