Mechanical Stress as a Stimulus for Airway Remodeling

机械应力作为气道重塑的刺激

• 批准号: 7242883
• 负责人: Jeffrey Mark Drazen
• 金额: $ 40.81万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 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/7242883
• 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

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细胞信号传导事件，这些事件以前主要归因于基于免疫的炎症机制。在过去的几年中，我们已经表明，机械应力诱导的信号事件修改上皮细胞本身的表型和激活成纤维细胞在共培养的方式让人想起在人类哮喘中观察到的。事实上，这种多细胞活化模式在体外概括了哮喘气道中存在的促纤维化和粘液分泌微环境，而没有任何免疫炎症机制的活化。对机械应激气道上皮细胞中表达的基因的微阵列分析表明，机械应激对上皮细胞和间充质细胞的下游效应是特异性的和靶向的。我们已经证明，机械扰动的气道上皮细胞可以修改上皮细胞的表型培养导致微环境的可用性表皮生长因子配体和尿激酶纤溶酶原激活剂家族的成员。在拟议的工作中，我们将定义的机制，这些因素的可用性与发生在共培养的成纤维细胞的表型变化，当这些细胞被放置在接近气道上皮细胞经历一个单一的事件的机械应力。我们还将定义的机制，反复发作的机械应力对气道上皮细胞的分泌表型的变化，发生这种压力的结果。我们的工作包括系统研究这些关键的候选途径在气道壁的多细胞上皮-间充质结构的天然背景下所起的作用。我们建议收集的数据将阐明连接压应力激活的各种生化效应器系统的分子机制。这项工作将提供所需的证据来验证范式的转变，从认为气道重塑事件主要是由免疫机制引起的，到表明支气管收缩单独可以在气道上留下特定的重塑特征。简介：当哮喘发作时，气道变窄，气道内的细胞受到压缩。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了这些细胞。在这项研究中，我们将研究细胞的压缩和它们的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。