MICROVASCULAR REMODELING IN CHRONIC AIRWAY INFLAMMATION

项目P-4将研究慢性气道炎症中微血管重塑的机制、后果和可逆性。 McDonald、Baluk和Thurston博士将使用正常和基因改变小鼠和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。 总的假设是，在发炎的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以引起微血管中不同类型的异常，并且这些异常在未被抑制时有利于炎症反应的持续。 该项目有四个具体目标。 (1)第一个目的是表征在具有不同遗传背景的小鼠中慢性气道炎症中形成的新的毛细血管样血管（血管生成）和重塑的微静脉样血管（微血管扩大）。 这些实验将检验慢性炎症中血管生成和微血管扩大的量受宿主先天性和获得性免疫应答的遗传决定因素支配的假设。 (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，以检验慢性炎症气道中血管生成和微血管扩大的相对量由这些内皮细胞特异性生长因子的不同模式引起的假设。 (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。 这些研究将检验慢性炎症中持续的血浆渗漏是由于VEGF或VEGF受体表达增加导致重塑血管内皮细胞间间隙形成的假设。 (4)最终目的是检查血管重构的可逆性。这些研究将检验以下假设：血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。 这个项目的基本原理是，我们的经验与M。在小鼠和大鼠中建立慢性气道炎症的肺模型，结合研究气道血管的新方法，将为慢性炎症性气道疾病中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使用微血管作为慢性炎症性呼吸道疾病的治疗靶点的可行性，并获得对支原体诱导的气道疾病的更详细的了解，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.