Regulation of Airway Mucus Expression by Complement

补体对气道粘液表达的调节

基本信息

批准号：
7841767
负责人：
SCOTT M DROUIN
金额：
$ 29.57万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-05 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7841767
关键词：
Address Allergens Anaphylatoxins Asthma Award CD4 Positive T Lymphocytes Cell Culture Techniques Cell Proliferation Cell physiology Cells Clara cell Complement Complement 3a Complement 5a Complement Activation Complex Data Development Disease Effector Cell Epidermal Growth Factor Receptor Epithelial Epithelial Cells Gene Expression Glycoproteins Goblet Cells Host Defense Human Immune In Vitro Inflammation Mediators Inflammatory Interleukin-13 Interleukin-4 Investigation Leukocytes Lung Mediating Mediator of activation protein Metaplasia Methods Modeling Mucins Mucous body substance Mus Obstructive Lung Diseases Pathology Pathway interactions Physiology Play Plug-in Production Reactive Oxygen Species Regulation Research Personnel Resources Rodent Model Role Signal Transduction T-Lymphocyte Wound Healing airway hyperresponsiveness airway inflammation airway obstruction allergic airway disease allergic airway inflammation antigen challenge cell type chemokine complement system cytokine eosinophil in vivo in vivo Model neutrophil novel programs receptor response

项目摘要

DESCRIPTION (provided by applicant): This R01 award will provide the necessary resources to examine the role of the complement system on airway obstruction during inflammatory diseases such as asthma. Increasing numbers of studies on human asthma and rodent models of allergic airway inflammation have focused on the function of the airway epithelial cell in obstructive airway disease. Airway epithelial cells are thought to contribute to the pathology in asthma through their production of mucus. Under normal conditions, mucus is an important component of host defense in the airway, but during severe episodes of asthma, mucus hypersecretion represents an important cause of airway obstruction. Mucus is comprised of mucin glycoproteins which are produced by specialized airway epithelial cells called goblet cells. Although studies have identified inflammatory mediators which will promote goblet cell development and mucus plugging of the airway, the direct effect of complement system activation and release of the complement anaphylatoxins C3a and C5a to mucin expression by goblet cells has not been elucidated. Cell culture techniques have recently been developed which permit investigation in vitro of airway epithelial cell function in parallel with in vivo models. Here we demonstrate a novel role for C3a and its receptor (C3aR) in the production of mucins by airway epithelial goblet cells and describe regulatory mechanisms involving T lymphocytes and production of IL-13 as well as airway epithelial production of chemokines and recruitment of leukocytes. Given the problems with mucus plugging in asthma, this proposal will delineate the complement-mediated mechanisms that regulate goblet cell development, mucus production, and airway obstruction in asthma.

描述（由申请人提供）：该R01奖将提供必要的资源，以检查补体系统在炎症性疾病（例如哮喘）期间的气道阻塞的作用。对过敏性气道炎症的人类哮喘和啮齿动物模型的越来越多的研究集中在阻塞气道疾病中气道上皮细胞的功能上。气道上皮细胞被认为通过粘液的产生有助于哮喘的病理。在正常情况下，粘液是气道中宿主防御的重要组成部分，但是在严重的哮喘发作中，粘液分泌是气道阻塞的重要原因。粘液由粘蛋白糖蛋白组成，这些糖蛋白由专门的气道上皮细胞（称为杯状细胞）产生。尽管研究已经确定了炎症介质，这些炎症介质将促进杯状细胞的发育和气道的粘液堵塞，但尚未阐明补体系统激活以及补体过敏毒素C3A和C5A对杯状细胞表达的直接作用。最近已经开发了细胞培养技术，该技术允许与体内模型同时研究气道上皮细胞功能。在这里，我们证明了C3A及其受体（C3AR）在气道上皮杯状细胞生产粘液中的新作用，并描述了涉及T淋巴细胞以及IL-13的产生的调节机制，以及气道上皮生产的趋化因子和LEUKOCYTES的趋势。鉴于粘液堵塞哮喘的问题，该提案将描述调节哮喘中杯状细胞发育，粘液产生和气道阻塞的补体介导的机制。