MICROVASCULAR REMODELING IN CHRONIC AIRWAY INFLAMMATION

慢性气道炎症的微血管重塑

• 批准号: 6781169
• 负责人: Donald M McDonald
• 金额: $ 14.27万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 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 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6781169
• 关键词: Mycoplasma; angiogenesis; angiogenesis factor; antiinflammatory agents; bronchomotion; bronchus circulation; cell adhesion; confocal scanning microscopy; genetic strain; genetically modified animals; growth factor receptors; histochemistry /cytochemistry; inflammation; laboratory mouse; laboratory rat; microcirculation; mycoplasmal pneumonia; pulmonary edema; respiratory epithelium; respiratory infections; scanning electron microscopy; transmission electron microscopy; vascular endothelial growth factors; vascular endothelium permeability

Project P-4 will examine mechanisms, consequences, and reversibility of microvascular remodeling in chronic inflammation of the airways. Drs. McDonald, Baluk, and Thurston will use Mycoplasma pulmonis infection in normal and genetically altered mice and in rats as models to characterize the angiogenesis and microvascular enlargement that occur in chronic airway inflammation. The overall hypothesis is that different patterns of endothelial cell specific growth factors and cytokines produced in inflamed airways can cause different types of abnormalities in the microvasculature and that these abnormalities, when unchecked, favor the perpetuation of the inflammatory response. The project has four specific aims. (1) The first aim is to characterize the new capillary-like vessels (angiogenesis) and remodeled venule-like vessels (microvascular enlargement) that form in chronic airway inflammation in mice with different genetic backgrounds. These experiments will test the hypothesis that the amounts of angiogenesis and microvascular enlargement in chronic inflammation are governed by genetic determinants of the host innate and acquired immunologic response. (2) The second aim is to determine the cellular location and effects of two angiogenic growth factors (vascular endothelial growth factor, Angiopoietin-1) and their receptors to test the hypothesis that the relative amounts of angiogenesis and microvascular enlargement in chronically inflamed airways result from different patterns of these endothelial cell-specific growth factors. (3) The third aim is to determine the mechanism of plasma leakage in chronic airway inflammation and the role of VEGF in this leakage. These studies will test the hypothesis that the sustained plasma leakage in chronic inflammation is due to increased expression of VEGF or VEGF receptors, which result in the formation of intercellular gaps in the endothelium of remodeled vessels. (4) The final aim is to examine the reversibility of the vascular remodeling. These studies will test the hypothesis that the vasculature is a potential therapeutic target, and reversal of the microvascular remodeling can interrupt the plasma leakage and inflammatory cell influx that sustain the inflammatory response. The rationale for this project is that our experience with the M. pulmonis model of chronic airway inflammation in mice and rats combined with novel methods for studying the airway vasculature will provide new insights into the mechanisms and consequences of microvascular remodeling in chronic inflammatory airway disease. The project has the significance of exploring the feasibility of using the microvasculature as a therapeutic target in chronic inflammatory diseases of the respiratory tract, and of obtaining a more detailed understanding of mycoplasma-induced airway disease, which may be a contributing factor in asthma.

P-4 项目将研究气道慢性炎症中微血管重塑的机制、后果和可逆性。 博士。 McDonald、Baluk 和 Thurston 将使用正常小鼠和基因改造小鼠以及大鼠中的肺支原体感染作为模型，以表征慢性气道炎症中发生的血管生成和微血管扩张。 总体假设是，发炎气道中产生的内皮细胞特异性生长因子和细胞因子的不同模式可导致微血管系统中不同类型的异常，并且这些异常如果不加以控制，有利于炎症反应的持续存在。 该项目有四个具体目标。 (1) 第一个目标是表征不同遗传背景的小鼠慢性气道炎症中形成的新毛细血管样血管（血管生成）和重塑的小静脉样血管（微血管扩张）。 这些实验将检验以下假设：慢性炎症中血管生成和微血管扩张的数量受宿主先天和后天免疫反应的遗传决定因素控制。 (2) 第二个目的是确定两种血管生成生长因子（血管内皮生长因子，Angiopoietin-1）及其受体的细胞位置和作用，以检验慢性炎症气道中血管生成和微血管扩张的相对量导致的假设来自这些内皮细胞特异性生长因子的不同模式。 (3)第三个目的是确定慢性气道炎症中血浆渗漏的机制以及VEGF在这种渗漏中的作用。 这些研究将检验以下假设：慢性炎症中持续的血浆渗漏是由于 VEGF 或 VEGF 受体表达增加所致，从而导致重塑血管内皮细胞间隙的形成。 (4)最终目的是检查血管重塑的可逆性。这些研究将检验以下假设：脉管系统是潜在的治疗靶点，微血管重塑的逆转可以中断维持炎症反应的血浆渗漏和炎症细胞流入。 该项目的基本原理是，我们在小鼠和大鼠慢性气道炎症肺支原体模型方面的经验与研究气道脉管系统的新方法相结合，将为慢性炎症性气道疾病微血管重塑的机制和后果提供新的见解。 该项目的意义在于探索利用微脉管系统作为呼吸道慢性炎症性疾病治疗靶点的可行性，并更详细地了解支原体诱发的气道疾病（可能是哮喘的一个促成因素）。