MICROVASCULAR REMODELING IN CHRONIC AIRWAY INFLAMMATION

项目P-4将研究慢性呼吸道炎症中微血管重塑的机制、后果和可逆性。麦克唐纳、巴鲁克和瑟斯顿博士将使用正常和基因改变的小鼠以及大鼠中的肺支原体感染作为模型，以表征慢性呼吸道炎症中发生的血管生成和微血管扩大。总体假设是，炎症呼吸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以导致微血管系统中不同类型的异常，如果不加以控制，这些异常有利于炎症反应的持续。该项目有四个具体目标。(1)第一个目的是研究在不同遗传背景的小鼠慢性呼吸道炎症中形成的新的毛细血管样血管(血管生成)和重塑的小静脉样血管(微血管增大)的特征。这些实验将检验这一假设，即慢性炎症中血管生成和微血管扩大的数量由宿主先天和获得性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、血管生成素-1)及其受体的细胞定位和作用，以验证慢性炎症呼吸道血管生成和微血管扩大的相对量是这些内皮细胞特异性生长因子的不同模式所致的假说。(3)探讨慢性气道炎患者血浆渗漏的机制及血管内皮生长因子在血浆渗漏中的作用。这些研究将验证一种假设，即慢性炎症中持续的血浆渗漏是由于血管内皮生长因子或血管内皮生长因子受体的表达增加，导致重塑的血管内皮细胞形成细胞间隙。(4)最终目的是观察血管重构的可逆性。这些研究将验证这样一种假设，即血管系统是一个潜在的治疗靶点，逆转微血管重构可以阻断维持炎症反应的血浆渗漏和炎性细胞流入。这个项目的基本原理是，我们在小鼠和大鼠慢性呼吸道炎症的肺分支杆菌模型中的经验，结合研究气道血管的新方法，将为慢性炎症性呼吸道疾病中微血管重构的机制和后果提供新的见解。该项目具有探索将微血管系统用作慢性呼吸道炎症性疾病的治疗靶点的可行性，并更详细地了解支原体引起的呼吸道疾病，这可能是哮喘的一个促成因素。

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.