Lymphangiogenesis and Angiogenesis in Airway Inflammation

气道炎症中的淋巴管生成和血管生成

• 批准号: 8239550
• 负责人: Donald M McDonald
• 金额: $ 32.84万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8239550
• 关键词: Address; Adult; Angiogenic Factor; Angiopoietin-2; Angiopoietins; Anti-Inflammatory Agents; Antigens; Automobile Driving; Birth; Blocking Antibodies; Blood Vessels; Blood capillaries; CCL2 gene; Cell Adhesion Molecules; Cells; Characteristics; Chronic; Data; Defect; Disease; Drainage procedure; Edema; Embryo; Endothelial Cells; Equilibrium; Extravasation; Fluid Balance; Functional disorder; Gatekeeping; Gene Deletion; Gene Expression; Goals; Growth; Growth Factor; Growth Factor Overexpression; Immune; Immune response; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Intercellular Junctions; Interleukin-1; Lead; Leukocytes; Limb structure; Liquid substance; Lymphangiogenesis; Lymphatic; Lymphatic Abnormalities; Lymphatic vessel; Lymphedema; Mediating; Mediator of activation protein; Modeling; Mus; Mycoplasma pulmonis; Newborn Infant; Obstruction; Pattern; Physiological; Plasma; Play; Prevention; Process; Proliferating; Recruitment Activity; Research; Route; Signaling Molecule; Source; Tissues; Trachea; Tyrosine Kinase Inhibitor; VEGF Trap; Vascular Endothelial Growth Factors; Vascular remodeling; adaptive immunity; airway inflammation; airway obstruction; airway remodeling; angiogenesis; antigen challenge; asthmatic airway; capillary; chemokine; cytokine; disorder prevention; gain of function; inhibitor/antagonist; loss of function mutation; lymph nodes; mouse model; prevent; programs; receptor; research study; therapeutic target; trafficking; venule

This project will examine the mechanisms, consequences, and reversibility of lymphangiogenesis and angiogenesis in chronic ainway inflammation. The overall hypothesis is that abnormalities in mucosal lymphatics and blood vessels contribute in multiple ways to the pathophysiology of airway inflammation and can be exploited as therapeutic targets. Lymphatics drain fluid and, as part of the afferent limb of adaptive immunity, serve as routes for antigen and immune cell transit from airways to lymph nodes. Blood vessels, as gatekeepers for plasma leakage and leukocyte influx into inflamed ain/vays, regulate the magnitude of native and adaptive immune responses. The goal of Aim #1 is to define the abnormalities of lymphatic vessels in chronic ainway inflammation, identify the driving factors, and determine the consequences and reversibility of the changes. Our hypothesis is that persistent airway inflammation leads to abnormalities in mucosal lymphatics that impair fluid drainage, and could lead to bronchial lymphedema, which worsens ainway obstruction and perturbs immune responses by altering the normal balance of fluid/cell extravasation and clearance. Proposed experiments will identify factors that promote lymphatic remodeling, determine conditions that lead to defective endothelial junctions in initial lymphatics, and explore the reversibility of the abnormalities. The goal of Aim #2 is to determine the mechanism, consequences, and reversibility of angiogenesis and blood vessel remodeling in airway inflammation. Our hypothesis is that leukocyte recruiting chemokines, acting in concert with proinflammatory cytokines and local angiogenic factors, drive endothelial cell remodeling that favors leakiness and leukocyte influx characteristic of ainway inflammation. Proposed experiments will determine the amounts, cellular sources, and actions of chemokines and cytokines that mediate leukocyte influx and growth, remodeling, and functional plasticity of lymphatics and blood vessels. Mouse models of chronic ainway inflammation after Mycoplasma pulmonis infection or prolonged antigen challenge will be compared to changes in genetically altered mice that have conditional gain-of-function or loss-of-function mutations. The contribution of putative mediators and reversibility will be determined through the use of function-blocking antibodies, soluble decoy receptors, and receptor tyrosine kinase inhibitors. Together, the studies will provide a conceptual framework for determining how changes in lymphatics and blood vessels contribute to tissue remodeling and altered ainway function and for developing strategies to ameliorate airway inflammation by reversing the vascular changes.

本研究将探讨慢性气道炎症中淋巴管生成和血管生成的机制、后果和可逆性。总的假设是，粘膜炎症和血管的异常以多种方式促进气道炎症的病理生理学，并且可以被利用作为治疗靶点。淋巴管排出液体，并且作为适应性免疫的传入分支的一部分，充当抗原和免疫细胞从气道转运到淋巴结的途径。血管作为血浆渗漏和白细胞流入发炎血管的守门人，调节天然和适应性免疫应答的大小。目标#1的目标是定义慢性气道炎症中淋巴管的异常，识别驱动因素，并确定变化的后果和可逆性。我们的假设是，持续的气道炎症导致粘膜炎症的异常，损害液体排出，并可能导致支气管水肿，其通过改变液体/细胞外渗和清除的正常平衡来破坏气道阻塞和干扰免疫反应。拟议的实验将确定促进淋巴重塑的因素， 条件，导致有缺陷的内皮连接在初始的血管化，并探讨可逆性的异常。目的#2的目标是确定气道炎症中血管生成和血管重塑的机制、后果和可逆性。我们的假设是，白细胞募集趋化因子，与促炎细胞因子和局部血管生成因子协同作用，驱动内皮细胞重塑，有利于渗漏和白细胞流入特征的气道炎症。 拟议的实验将确定趋化因子的数量、细胞来源和作用， 介导白细胞流入和生长、重塑以及血管和血管的功能可塑性的细胞因子。将肺支原体感染或长期抗原激发后的慢性气道炎症小鼠模型与具有条件性功能获得或功能丧失突变的遗传改变小鼠的变化进行比较。将通过使用功能阻断抗体、可溶性诱饵受体和受体酪氨酸激酶抑制剂来确定推定介质和可逆性的贡献。总之，这些研究将提供一个概念框架，用于确定气道和血管的变化如何有助于组织重塑和气道功能的改变，以及通过逆转血管变化来改善气道炎症的策略。