Mechanical Stress as a Stimulus for Airway Remodeling

机械应力作为气道重塑的刺激

基本信息

批准号：
7392318
负责人：
Jeffrey Mark Drazen
金额：
$ 40.75万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
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：
2007-04-01 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7392318
关键词：
Asthma Attention Biochemical Bioinformatics Blast Cell Bronchoconstriction Candidate Disease Gene Cell Line Cells Characteristics Chronic Classification Coculture Techniques Collagen Data EGF gene Endothelin Environment Epidermal Growth Factor Epidermal Growth Factor Receptor Epithelial Epithelial Cells Epithelium Event Exposure to Family Fibroblasts Gene Expression Generations Genes Human Immune Immunofluorescence Immunologic In Vitro Inflammatory Investigation Knowledge Lead Left Ligands Link MUC5AC gene Mechanical Stress Mechanics Mesenchymal Metaplasia Microarray Analysis Modeling Molecular Mucous body substance Myofibroblast Numbers Pathway interactions Pattern Phenotype Polymerase Chain Reaction Population Proteins Recurrence Regulation Research Role Role playing therapy Secretory Cell Signal Transduction Smooth Muscle Actin Staining Method Staining method Stains Stimulus Stream Stress Structure System Testing Traction Urokinase Urokinase Plasminogen Activator Receptor Work airway epithelium airway remodeling asthmatic airway base bronchial epithelium member novel strategies prevent programs promoter protein expression response

项目摘要

DESCRIPTION (provided by applicant): The bronchoconstriction of asthma squeezes airway epithelial cells. This mechanical perturbation triggers a cascade of cellular signaling events that had previously been attributed largely to immune based inflammatory mechanisms. Over the past several years we have shown that mechanical stress-induced signaling events modify the phenotype of the epithelial cells themselves and activate fibroblasts in co-culture in a manner reminiscent of that observed in human asthma. In fact, this pattern of multicellular activation recapitulates in vitro, without activation of any immune inflammatory mechanism, the pro-fibrotic and mucus secretory micro-environment present in the asthmatic airway. Microarray analysis of the genes expressed in mechanically stressed airway epithelial cells has suggested that the downstream effects of mechanical stress on epithelial and mesenchymal cells are specific and targeted. We have demonstrated that mechanical perturbation of the airway epithelium can modify the phenotype of epithelial cells in culture leading to the microenvironmental availability of epidermal growth factor ligands and members of the urokinase plasminogen activator family. In the proposed work we will define the mechanisms that link the availability of these factors with the phenotypic changes that occur in co-cultured fibroblasts when these cells are placed in proximity to airway epithelial cells undergoing a single episode of mechanical stress. We will also define the mechanisms that link repeated episodes of mechanical stress on airway epithelial cells with the changes in secretory phenotype that occur as a result of this stress. Our work comprises a systematic investigation of the role played by these critical candidate pathways in the native context of the multicellular epithelial-mesenchymal structure of the airway wall. The data we propose to gather will elucidate the molecular mechanisms that link the various biochemical effector systems that are activated by compressive stress. This work will provide the evidence needed to validate the paradigm shift from regarding airway remodeling events as arising predominantly from an immunological mechanism to one which shows that bronchoconstriction alone can leave a specific remodeling signature on the airway. Lay Summary: When airways narrow during an asthma attack the cells lining these airways are compressed. Our data show that this compression activates these cells in a way similar to that observed in human asthma. In this research we will investigate the links between compression of cells and the changes in their activation state. This understanding could lead to new strategies for treating asthma.

描述（申请人提供）：哮喘的支气管收缩挤压气道上皮细胞。这种机械扰动触发了一系列细胞信号传导事件，而这些信号传导事件此前主要归因于基于免疫的炎症机制。在过去的几年中，我们已经证明，机械应力诱导的信号传导事件会改变上皮细胞本身的表型，并以类似于在人类哮喘中观察到的方式激活共培养中的成纤维细胞。事实上，这种多细胞激活模式在体外重现，没有激活任何免疫炎症机制，即哮喘气道中存在的促纤维化和粘液分泌微环境。对机械应激气道上皮细胞中表达的基因进行的微阵列分析表明，机械应激对上皮细胞和间质细胞的下游影响是特异性的和有针对性的。我们已经证明，气道上皮的机械扰动可以改变培养物中上皮细胞的表型，从而导致表皮生长因子配体和尿激酶纤溶酶原激活剂家族成员的微环境可用性。在拟议的工作中，我们将定义将这些因子的可用性与共培养成纤维细胞中发生的表型变化联系起来的机制，当这些细胞放置在经历单次机械应力的气道上皮细胞附近时。我们还将定义将气道上皮细胞机械应力重复发作与由于该应力而发生的分泌表型变化联系起来的机制。我们的工作包括对这些关键候选途径在气道壁多细胞上皮间质结构的天然背景中所发挥的作用进行系统研究。我们建议收集的数据将阐明连接由压应力激活的各种生化效应系统的分子机制。这项工作将提供所需的证据，以验证范式转变，从认为气道重塑事件主要由免疫机制引起，到表明仅支气管收缩就可以在气道上留下特定的重塑特征。简单总结：当哮喘发作期间气道变窄时，气道内壁的细胞就会受到压缩。我们的数据表明，这种压缩以类似于在人类哮喘中观察到的方式激活这些细胞。在这项研究中，我们将研究细胞压缩与其激活状态变化之间的联系。这种理解可能会导致治疗哮喘的新策略。