Angiogenesis in the Lung

肺部血管生成

• 批准号: 6687131
• 负责人: Elizabeth Wagner
• 金额: $ 39.61万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6687131
• 关键词: alveolar macrophages; angiogenesis; biological models; cell migration; cell proliferation; chemokine; enzyme linked immunosorbent assay; gene targeting; genetically modified animals; laboratory mouse; lung ischemia /hypoxia; lung lavage; metalloendopeptidases; microcapsule; neutralizing antibody; neutrophil; polymerase chain reaction; pulmonary artery; pulmonary circulation; respiratory pharmacology; thoracic surgery; vascular endothelial growth factors; vascular endothelium permeability; wound healing

DESCRIPTION (provided by applicant): Angiogenesis, the process whereby new blood vessels sprout and emerge from an established network, has been widely investigated in most organs. Understanding the mechanisms involved is important both for therapeutic promotion of new vessel growth in ischemic tissues as well as retardation of the process in tumors. In this proposal, we utilize a unique mouse model that allows study of the signaling of both of these processes in the lungs within individual animals. The lung is unique in that angiogenesis takes place in an ischemic but hyperoxic environment and the new vasculature is from systemic (bronchial or intercostal) arteries and not the pulmonary vasculature. After lateral thoracotomy and ligation of the left pulmonary artery in the mouse, rapid new blood vessel growth results from the intercostal arteries in immediate proximity to the site of thoracotomy. Within 5-7 days, these new blood vessels invade the upper ischemic lung region but not the lower ischemic lung. Pulmonary ischemia is essential since sham thoracotomy does not result in lung angiogenesis. These observations suggest cross communication of the thoracic wall undergoing wound repair with the upper ischemic lung. Preliminary data demonstrate that the ELR+, C-X-C chemokines in both the thoracic wall and the upper ischemic lung are essential proteins participating in this cross communication. We hypothesize that pulmonary ischemia induces lung tissue proteins that stimulate nearby intercostal vessels, to proliferate and invade the ischemic lung. Specific aims of this proposal are to determine the dynamics of chemokine synthesis in the lung and thoracic wall, with emphasis on the relative differences between the ischemic upper and lower lung regions after left pulmonary artery ligation. We will correlate the changes in chemokine expression with physiologic assessment of the magnitude and distribution of new systemic blood flow to the lung. In vitro studies assessing mouse endothelial cell proliferation and migration will be used to determine critical factors defining the proangiogenic phenotype of systemic arterial endothelial cells relative to pulmonary endothelial cells. The results of these studies will provide important new information defining the molecular, structural, and functional events of lung angiogenesis.

描述（由申请人提供）：血管生成，即新血管从已建立的网络中发芽和出现的过程，已在大多数器官中进行了广泛研究。 了解所涉及的机制对于促进缺血组织中新血管生长的治疗以及延缓肿瘤中的过程都是重要的。 在这个提议中，我们利用了一个独特的小鼠模型，可以研究单个动物肺部这两个过程的信号传导。 肺的独特之处在于，血管生成发生在缺血但高氧的环境中，并且新的脉管系统来自全身（支气管或肋间）动脉而不是肺脉管系统。 在小鼠的侧胸切开术和左肺动脉结扎后，从紧邻开胸部位的肋间动脉产生快速的新血管生长。 在5-7天内，这些新血管侵入上部缺血肺区域，但不侵入下部缺血肺。 肺缺血是必要的，因为假胸廓切开术不会导致肺血管生成。 这些观察结果表明进行伤口修复的胸壁与上部缺血肺交叉连通。 初步数据表明，ELR+，C-X-C趋化因子在胸壁和上部缺血肺是参与这种交叉通信的必需蛋白质。 我们假设肺缺血诱导肺组织蛋白刺激附近肋间血管增殖并侵入缺血肺。 该建议的具体目的是确定肺和胸壁中趋化因子合成的动力学，重点是左肺动脉结扎后缺血的上肺和下肺区域之间的相对差异。 我们将把趋化因子表达的变化与对肺的新的全身血流的大小和分布的生理评估相关联。 评估小鼠内皮细胞增殖和迁移的体外研究将用于确定定义全身动脉内皮细胞相对于肺内皮细胞的促血管生成表型的关键因素。 这些研究的结果将提供重要的新信息，定义肺血管生成的分子，结构和功能事件。