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。即使是现在，氧气治疗的使用水平也比1- 20年前低得多。肺在低的胎儿氧浓度（3-5%）下发育，在体外，在这些水平下比在21%的水平下发育得更好。在这些较高的氧水平下，内皮和血管生长受损。上皮和肺泡的发育反过来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显示出少得多的分支。血管生成在妊娠晚期迅速进行。缺氧诱导因子HIF- 1和HIF-2（HIF）调节血管生成中的关键生长因子、受体、激酶和其他蛋白质。氧张力是HIF-1 α和HIF-2 α的主要调节因子，HIF-1 α和HIF-2 α是这些转录因子的关键成分。在整个妊娠期间，在肺中或在晚期妊娠期间在远端肺上皮中敲低HIF-2，导致新生小鼠的肺发育和呼吸窘迫过度简化。最近发现HIF脯氨酰-4-羟化酶（P4 Hs或PHDs）催化HIF的O2依赖性降解。用酮戊二酸类似物或铁螯合剂抑制P4 H稳定HIF，增加VEGF，并引起血管生成。HIF特异性P4 H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疗法已导致畸形或渗漏血管的形成。在含氧量正常的肺中，“翻转开关”HIF可以引起更平衡的血管生成。我们假设HIF的缺失促进BPD的肺发育不良，稳定HIF将促进BPD早产儿的肺发育更正常。该提案是用于转化研究，以使用BPD的灵长类动物模型在体外和体内测试新的HIF特异性P4 H抑制剂对肺的作用。在体外，P4 H抑制引起HIF-1 α稳定性、VEGF表达、血管生成和在血管生长中重要的激酶活性增加。在肺外植体中，将测试新的HIF P4 H抑制剂稳定HIF和增加HIF相关蛋白和激酶活性的能力。此外，HIF P4 H抑制剂将通过静脉内、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 P4 H抑制剂水平，并且将离体定量肺泡和血管发育、肺HIF蛋白和HIF相关蛋白和激酶活性以及组织HIF P4 H抑制剂水平。在HIF转录因子水平治疗以改善血管生成和肺泡发育为预防BPD提供了希望。

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.