Angiogenesis in the Lung

肺部血管生成

基本信息

  • 批准号:
    7924795
  • 负责人:
  • 金额:
    $ 41.26万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2003
  • 资助国家:
    美国
  • 起止时间:
    2003-07-01 至 2012-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The process of systemic angiogenesis in the lung remains poorly understood despite it being an integral part of a wide range of human diseases including asthma, COPD, cystic fibrosis, lung cancer, and chronic thromboembolism. Despite the importance and prevalence of this systemic vascular remodeling, methods to study the process in humans are not feasible, and few animal models exist. Thus, the proposed model of left pulmonary artery occlusion in the mouse provides a unique opportunity to study the mechanisms of systemic neovascularization in the lung. The experiments proposed in this application will determine the initiating signals and the essential inflammatory cells and cytokines in promoting new vessel growth. Our data demonstrate that an increase in the number of inflammatory cells in the lung appears to play a major role in directing neovascularization. However, the factors that initiate leukocyte activation and the cascade of events that promote new vessel growth are not known. Obstruction of the left pulmonary artery results in a loss of shear stress, relative hyperoxia, and decreased glucose supply, all of which contribute to an increase in oxidative stress. Several studies have shown oxidant-dependent activation of monocytes/macrophages. Additionally, reactive oxygen species (ROS) have been shown to cause lung matrix degradation, the products of which are known to activate macrophages through Toll-like receptors (TLR). Our preliminary work demonstrates, 1) that inhibition of ROS limits angiogenesis, 2) that there is an increase in matrix fragmentation coincident with ROS release, 3) that TLR-2 modulates angiogenic outcome, and 4) that the number of lavaged macrophages are predictive of the magnitude of the angiogenic response. These experiments led us to hypothesize that ROS, released from ischemic pulmonary endothelium, stimulate lung monocytes/macrophages to release pro- angiogenic growth factors that induce systemic vascularization of the lung. We predict both direct activation of monocytes by ROS as well as indirect activation by lung matrix components. We will use the established, in vivo mouse model of lung angiogenesis after left pulmonary artery ligation to determine cellular and molecular mechanisms of neovascularization. We will focus on three specific aims to measure and determine that 1) ROS release by pulmonary endothelium is essential for systemic angiogenesis, 2) ROS activate lung monocytes/macrophages to a pro-angiogenic phenotype, and 3) monocyte/macrophage-derived growth factors are essential for systemic angiogenesis. We will use oxidant-sensitive dyes to measure ROS, evaluate differentiation/proliferation of monocytes, and perfusion of the systemic vasculature to the lung by labeled microspheres, in mice without/with antioxidant enzymes/treatments. The results of this project will allow us to determine how ROS-induced activation of monocytes promotes systemic neovascularization. PUBLIC HEALTH RELEVANCE: Excessive systemic vascular proliferation occurs in many pulmonary diseases such as asthma, cystic fibrosis, and chronic thromboembolism where inflammation, edema, and hemoptysis contribute to lung pathology. The mechanisms responsible for the growth of new vessels are not understood. In an animal model of chronic pulmonary thromboembolic disease, this project will determine the inflammatory cytokines and cells responsible for new vessel growth, and pharmacological and interventional inhibitors.
描述(由申请人提供):尽管肺中的全身性血管生成过程是包括哮喘、COPD、囊性纤维化、肺癌和慢性血栓栓塞在内的多种人类疾病的组成部分,但对肺中的全身性血管生成过程仍然知之甚少。尽管这种全身血管重塑的重要性和普遍性,但在人类中研究该过程的方法是不可行的,并且存在很少的动物模型。因此,所提出的小鼠左肺动脉闭塞模型提供了一个独特的机会,研究肺中系统性新血管形成的机制。本申请中提出的实验将确定促进新血管生长的起始信号和必需的炎性细胞和细胞因子。我们的数据表明,肺中炎性细胞数量的增加似乎在指导新生血管形成中起主要作用。然而,启动白细胞活化的因素和促进新血管生长的级联事件尚不清楚。左肺动脉阻塞导致剪切应力损失、相对高氧和葡萄糖供应减少,所有这些都导致氧化应激增加。几项研究表明单核细胞/巨噬细胞的氧化剂依赖性活化。此外,活性氧(ROS)已被证明会导致肺基质降解,其产物已知通过Toll样受体(TLR)激活巨噬细胞。我们的初步工作表明,1)ROS的抑制限制了血管生成,2)与ROS释放一致的基质碎片化增加,3)TLR-2调节血管生成结果,和4)灌洗的巨噬细胞的数量预测血管生成反应的大小。这些实验使我们假设从缺血性肺内皮释放的ROS刺激肺单核细胞/巨噬细胞释放促血管生成生长因子,其诱导肺的全身血管化。我们预测ROS对单核细胞的直接激活以及肺基质成分的间接激活。我们将使用已建立的左肺动脉结扎后肺血管生成的体内小鼠模型来确定新血管生成的细胞和分子机制。我们将重点关注三个具体目标,以测量和确定:1)肺内皮细胞释放的ROS对系统性血管生成至关重要,2)ROS激活肺单核细胞/巨噬细胞成为促血管生成表型,3)单核细胞/巨噬细胞衍生的生长因子对系统性血管生成至关重要。我们将使用氧化剂敏感染料来测量ROS,评价单核细胞的分化/增殖,以及通过标记微球在无/有抗氧化酶/治疗的小鼠中向肺灌注全身血管系统。这个项目的结果将使我们能够确定ROS诱导的单核细胞活化如何促进全身性新血管形成。 公共卫生相关性:过度的全身血管增生发生在许多肺部疾病中,例如哮喘、囊性纤维化和慢性血栓栓塞,其中炎症、水肿和咯血导致肺部病理学。新血管生长的机制尚不清楚。在慢性肺血栓栓塞性疾病的动物模型中,该项目将确定负责新血管生长的炎性细胞因子和细胞,以及药理学和干预性抑制剂。

项目成果

期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Effects of ischemia on lung macrophages.
  • DOI:
    10.1371/journal.pone.0026716
  • 发表时间:
    2011
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Moldobaeva A;van Rooijen N;Wagner EM
  • 通讯作者:
    Wagner EM
Differential activity of pro-angiogenic CXC chemokines.
  • DOI:
    10.1016/j.mvr.2010.01.011
  • 发表时间:
    2010-07
  • 期刊:
  • 影响因子:
    3.1
  • 作者:
    Moldobaeva A;Baek A;Eldridge L;Wagner EM
  • 通讯作者:
    Wagner EM
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Elizabeth Wagner其他文献

Elizabeth Wagner的其他文献

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{{ truncateString('Elizabeth Wagner', 18)}}的其他基金

Bronchial Vascular Proliferation and Function
支气管血管增殖和功能
  • 批准号:
    7577107
  • 财政年份:
    2008
  • 资助金额:
    $ 41.26万
  • 项目类别:
Bronchial Vascular Proliferation and Function
支气管血管增殖和功能
  • 批准号:
    7746434
  • 财政年份:
    2008
  • 资助金额:
    $ 41.26万
  • 项目类别:
Bronchial Vascular Proliferation and Function
支气管血管增殖和功能
  • 批准号:
    8197296
  • 财政年份:
    2008
  • 资助金额:
    $ 41.26万
  • 项目类别:
Effects of Distension on the Airway Vasculature
扩张对气道脉管系统的影响
  • 批准号:
    7392280
  • 财政年份:
    2007
  • 资助金额:
    $ 41.26万
  • 项目类别:
Effects of Distension on the Airway Vasculature
扩张对气道脉管系统的影响
  • 批准号:
    7312429
  • 财政年份:
    2006
  • 资助金额:
    $ 41.26万
  • 项目类别:
Effects of Distension on the Airway Vasculature
扩张对气道脉管系统的影响
  • 批准号:
    6967834
  • 财政年份:
    2004
  • 资助金额:
    $ 41.26万
  • 项目类别:
Angiogenesis in the Lung
肺部血管生成
  • 批准号:
    6768778
  • 财政年份:
    2003
  • 资助金额:
    $ 41.26万
  • 项目类别:
Angiogenesis in the Lung
肺部血管生成
  • 批准号:
    6687131
  • 财政年份:
    2003
  • 资助金额:
    $ 41.26万
  • 项目类别:
Angiogenesis in the Lung
肺部血管生成
  • 批准号:
    7727635
  • 财政年份:
    2003
  • 资助金额:
    $ 41.26万
  • 项目类别:
Angiogenesis in the Lung
肺部血管生成
  • 批准号:
    6904595
  • 财政年份:
    2003
  • 资助金额:
    $ 41.26万
  • 项目类别:

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