Bronchial Vascular Proliferation and Function

支气管血管增殖和功能

• 批准号: 7577107
• 负责人: Elizabeth Wagner
• 金额: $ 41万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-10 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7577107
• 关键词: Anatomy; Animal Model; Animals; Asthma; Beds; Blood Circulation; Blood Vessels; Blood flow; CXC Chemokines; Cells; Chronic; Cystic Fibrosis; Data; Diffuse; Disease; Distant; Drainage procedure; Edema; Growth; Growth Factor; Hemoptysis; Human; Inflammation; Inflammatory; Intercostal Artery; Ischemia; Laboratories; Left pulmonary artery; Leukocytes; Ligation; Lung; Lung Inflammation; Lung diseases; Lymph; Lymphatic; Lymphatic vessel; Measures; Mediastinal; Mediastinal lymph node group; Modeling; Mus; Pathology; Perfusion; Permeability; Phenotype; Physiological; Physiology; Play; Process; Proliferating; Property; Proteins; Publishing; Pulmonary Edema; Pulmonary artery structure; Rattus; Recruitment Activity; Respiratory physiology; Role; Structure of parenchyma of lung; Thromboembolism; Time; Vascular Proliferation; Work; angiogenesis; artery occlusion; base; bronchial artery; cytokine; inhibitor/antagonist; interstitial; neovasculature; new growth; protein expression; public health relevance; pulmonary function; vasomotion

DESCRIPTION (provided by applicant): Under conditions of chronic pulmonary artery ischemia, the systemic bronchial circulation undergoes massive proliferation. However, the functional consequences of this rapidly constructed new circulation remain largely unexplored. Systemic angiogenic beds in general have been shown to demonstrate a proinflammatory phenotype. Our laboratory has studied systemic angiogenesis in mice after chronic left pulmonary artery ligation where ELR+ CXC chemokines appear to play a role in intercostal artery angiogenesis. However, since mice lack an intraparenchymal bronchial circulation and therefore are unlike humans, a larger animal model is required to determine the physiology of the angiogenic bronchial vasculature within the lung. In this application, we propose to study the process and consequences of bronchial vascular growth and proliferation after left pulmonary artery obstruction in rats, a species known to display a bronchial vascular anatomy similar to humans. An underlying question in this model is how growth factors released within the perfusion-starved lung, communicate with distant, upstream bronchial vessels. We propose a conduit role for lung lymphatic vessels, which drain unidirectionally and in proximity to major bronchial arteries. We hypothesize that bronchial angiogenesis is dependent on growth factors (CXC chemokines) released by trapped inflammatory cells, that drain and diffuse through lung lymphatics and mediastinal lymph nodes, causing bronchial vascular proliferation and enlargement. Furthermore, we hypothesize that the neovasculature is like other systemic beds and is proinflammatory (vasodilated, hyperpermeable, leukocyte recruiting) within the lung. In a rat model of left pulmonary artery obstruction, we will determine the importance of proangiogenic ELR+ CXC chemokines for the growth of new bronchial blood vessels, determine whether mediastinal lymph drainage provides a mechanism whereby parenchymal growth factors transit upstream to promote bronchial angiogenesis, and measure bronchial vascular function (permeability, inflammation, vasoreactivity) at time points before and after a new vasculature is established. Results will provide new information concerning the mechanisms of bronchial vascular angiogenesis, function and impact on ischemic parenchyma. Furthermore, results may explain properties of bronchial vessels that contribute to hemoptysis and loss of pulmonary function. Public Health Relevance: Excessive bronchial 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 essential growth factors, pharmacological and interventional inhibitors, and physiology of bronchial angiogenesis.

描述（由申请人提供）：在慢性肺动脉缺血的情况下，全身支气管循环经历大量增殖。然而，这种快速构建的新循环的功能后果在很大程度上仍未得到探索。一般而言，全身血管生成床已显示出促炎表型。我们的实验室研究了慢性左肺动脉结扎后小鼠的全身血管生成，其中 ELR+ CXC 趋化因子似乎在肋间动脉血管生成中发挥作用。然而，由于小鼠缺乏实质内支气管循环，因此与人类不同，因此需要更大的动物模型来确定肺内血管生成支气管脉管系统的生理学。在本申请中，我们建议研究大鼠左肺动脉阻塞后支气管血管生长和增殖的过程和后果，已知大鼠的支气管血管解剖结构与人类相似。该模型的一个根本问题是，灌注匮乏的肺内释放的生长因子如何与远处的上游支气管血管通讯。我们提出肺淋巴管的导管作用，其单向引流并靠近主要支气管动脉。我们假设支气管血管生成依赖于被捕获的炎症细胞释放的生长因子（CXC趋化因子），这些细胞通过肺淋巴管和纵隔淋巴结引流和扩散，导致支气管血管增殖和扩大。此外，我们假设新血管系统与其他全身床一样，并且在肺内具有促炎性（血管舒张、通透性过高、白细胞募集）。在左肺动脉阻塞的大鼠模型中，我们将确定促血管生成 ELR+ CXC 趋化因子对新支气管血管生长的重要性，确定纵隔淋巴引流是否提供了实质生长因子向上游转运以促进支气管血管生成的机制，并在之前和之后的时间点测量支气管血管功能（通透性、炎症、血管反应性）。 新的脉管系统建立后。结果将提供有关支气管血管生成、功能和对缺血实质影响的机制的新信息。此外，结果可以解释导致咯血和肺功能丧失的支气管血管的特性。公共卫生相关性：支气管血管过度增殖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、水肿和咯血会导致肺部病变。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，该项目将确定必需的生长因子、药理学和介入抑制剂以及支气管血管生成的生理学。