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（由申请人提供）：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以前归因于免疫基炎症机制的细胞信号传导事件。在过去的几年中，我们已经表明，机械应力诱导的信号事件改变了上皮细胞本身的表型，并以共同培养的方式激活成纤维细胞，以使人联想到人类哮喘中观察到的。实际上，这种多细胞活化的模式在体外概括了，而没有任何免疫炎症机制，这是哮喘气道中存在的促纤维化和粘液分泌微环境。在机械应力的气道上皮细胞中表达的基因的微阵列分析表明，机械应力对上皮细胞和间质细胞的下游影响是特异性的，并且是靶向的。我们已经证明，气道上皮的机械扰动可以改变培养中上皮细胞的表型，从而导致表皮生长因子配体的微环境可用性和尿激酶纤溶酶原激活剂家族的成员。在拟议的工作中，我们将定义这些因素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，当这些细胞靠近与气道上皮细胞接近机械应力发作。我们还将定义将气道上皮细胞上的机械应力重复发作与由于这种压力导致的分泌表型的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的多细胞上皮 - 间质结构的天然环境中所扮演的作用的系统研究。我们建议收集的数据将阐明通过压缩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，以验证范式从关于气道重塑事件的转变，这主要是由免疫机制引起的，这表明仅支气管收缩就可以在气道上留下特定的重塑签名。摘要摘要：当哮喘发作期间气道狭窄时，这些气道被压缩。我们的数据表明，这种压缩以类似于人类哮喘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的变化之间的联系。这种理解可能会导致治疗哮喘的新策略。