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: 7689984
• 负责人: Donald M McDonald
• 金额: $ 49.4万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-05-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7689984
• 关键词: Abbreviations; Academy; Address; Adult; Albumins; Anatomy; Angiogenic Factor; Angiopoietin-1; Angiopoietin-2; Angiopoietins; Anti-Inflammatory Agents; Antigens; Automobile Driving; Biology; Birth; Blocking Antibodies; Blood Platelets; Blood Vessels; Blood capillaries; Bronchi; Bronchus-Associated Lymphoid Tissue; CCL2 gene; CD31 Antigens; CD44 Antigens; Cadherins; Cell Adhesion Molecules; Cells; Characteristics; Chronic; Data; Defect; Disease; Doctor of Medicine; Doctor of Philosophy; Drainage procedure; E-Selectin; Edema; Embryo; Endothelial Cells; Equilibrium; Extravasation; Fibroblast Growth Factor; Fluid Balance; Fluorescein; Fluoresceins; Functional disorder; Gatekeeping; Gene Deletion; Gene Expression; Goals; Green Fluorescent Proteins; Growth; Growth Factor; Growth Factor Overexpression; ITGAX gene; Immune; Immune response; Immunity; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Intercellular Junctions; Interleukin-1; Interleukin-1 Receptors; Interleukins; Isothiocyanates; Label; Lead; Letters; Leukocytes; Ligands; Limb structure; Lipopolysaccharides; Liquid substance; Literature; Lymphangiogenesis; Lymphatic; Lymphatic Abnormalities; Lymphatic vessel; Lymphedema; Lymphoid Tissue; Macrophage Colony-Stimulating Factor; Matrix Metalloproteinases; Mediating; Mediator of activation protein; Methods; Modeling; Mus; Mycoplasma pulmonis; Neurobiology; Newborn Infant; Ovalbumin; PDGFRB gene; Pathology; Pattern; Pediatrics; Physiological; Plasma; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor Receptor; Play; Polymerase Chain Reaction; Prevention; Principal Investigator; Process; Proliferating; Proto-Oncogene Protein c-met; Publications; Recruitment Activity; Research; Research Design; Reverse Transcription; Role; Route; Signaling Molecule; Source; TNFRSF1A gene; Time; Tissues; Trachea; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Tyrosine Kinase Inhibitor; VEGF Trap; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor D; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factor Receptor-3; Vascular Endothelial Growth Factors; Vascular remodeling; Vertebrates; airway inflammation; airway obstruction; airway remodeling; angiogenesis; antigen challenge; asthmatic airway; beta-Chemokines; c-fms Proto-Oncogenes; cadherin 5; capillary; chemokine; cytokine; disorder prevention; gain of function; inhibitor/antagonist; loss of function mutation; lymph nodes; mast cell; mouse model; oncology; prevent; professor; programs; promoter; public health relevance; receptor; research study; therapeutic target; trafficking; venule

DESCRIPTION (provided by applicant): This project will examine the mechanisms, consequences, and reversibility of lymphangiogenesis and angiogenesis in chronic airway 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 airways, regulate the magnitude of native and adaptive immune responses. The goal of Aim #1 is to define the abnormalities of lymphatic vessels in chronic airway 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 airway 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 airway 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 airway 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 airway function and for developing strategies to ameliorate airway inflammation by reversing the vascular changes. PUBLIC HEALTH RELEVANCE: Lymphatic vessels and blood vessels, as gatekeepers for entry and clearance of fluid and cells in tissues, play key roles in inflammatory airway disease. Lymphatics and blood vessels proliferate and change in sustained inflammation, and their abnormalities contribute to mucosal edema and airway dysfunction by increasing leakage and impairing fluid clearance. By elucidating the mechanisms, consequences, and reversibility of these vascular changes, the project will advance the understanding needed to use remodeled lymphatics and blood vessels as therapeutic targets in airway inflammation.

描述（由申请人提供）：该项目将检查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。总体假设是，粘膜淋巴管和血管异常以多种方式促进气道炎症的病理生理学，并可以被用作治疗靶点。淋巴管排出液体，作为适应性免疫传入的肢体的一部分，它是抗原和免疫细胞从气道到淋巴结的途径。血管作为血浆泄漏和白细胞流入发炎的气道的守门人，调节了天然和适应性免疫反应的大小。 AIM＃1的目的是定义慢性气道炎症中淋巴管的异常，确定驱动因素并确定变化的后果和可逆性。我们的假设是，持续的气道炎症会导致粘膜淋巴管的异常，从而损害流体流动，并可能导致支气管淋巴水肿，从而恶化气道阻塞，并通过改变流体/细胞的正常平衡和细胞的平衡和清除率来使人免疫反应。提出的实验将确定促进淋巴重塑的因素，确定导致初始淋巴管中内皮连接缺陷的条件，并探索异常的可逆性。目标＃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，白细胞促进趋化因子与促炎性细胞因子和局部血管生成因子作用，驱动内皮细胞重塑，有利于泄漏和白细胞炎症的白细胞涌入特征。提出的实验将确定介导白细胞涌入和生长，重塑以及淋巴管和血管的功能可塑性的趋化因子和细胞因子的量，细胞来源和作用。慢性气道炎症的小鼠模型将在肺炎感染或延长的抗原挑战后与具有条件功能获得或功能丧失突变的遗传改变的小鼠的变化进行比较。推定介体和可逆性的贡献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。总之，这些研究将提供一个概念框架，用于确定淋巴管和血管的变化如何有助于组织重塑和气道功能改变，以及开发策略来通过逆转血管变化来减轻气道炎症。公共卫生相关性：淋巴血管和血管，作为用于进入和清除组织中流体和细胞的守门人，在炎症性气道疾病中起关键作用。淋巴管和血管扩散和持续炎症的变化，它们的异常因增加渗漏和损害液体清除率而导致粘膜水肿和气道功能障碍。通过阐明这些血管变化的机制，后果和可逆性，该项目将促进使用改建后的淋巴管和血管作为气道炎症中的治疗靶标所需的理解。