Mechanical Stress as a Stimulus for Airway Remodeling

描述（由申请人提供）：哮喘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。在过去的几年里，我们已经证明，机械应力诱导的信号事件可以改变上皮细胞本身的表型，并以一种类似于人类哮喘观察到的方式激活共培养的成纤维细胞。事实上，这种多细胞激活模式在体外重现，没有任何免疫炎症机制的激活，促纤维化和粘液分泌微环境存在于哮喘气道中。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影响是特异性和靶向性的。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，导致表皮生长因子配体和尿激酶纤溶酶原激活物家族成员的微环境可用性。在我们提出的工作中，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，当这些细胞被放置在气道上皮细胞附近时，这些细胞会经历一次机械应力。我们还将定义将气道上皮细胞的机械应力反复发作与由于这种压力而发生的分泌表型变化联系起来的机制。我们的工作包括系统地研究这些关键的候选通路在气道壁多细胞上皮-间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由压缩应力激活的各种生化效应系统的分子机制。这项工作将提供验证范式转变所需的证据，从认为气道重塑事件主要是由免疫机制引起的转变为表明支气管收缩本身可以在气道上留下特定的重塑特征。当哮喘发作时气道变窄时，气道内的细胞被压缩。我们的数据显示，这种压缩激活这些细胞的方式与在人类哮喘中观察到的相似。在这项研究中，我们将探讨细胞压缩和细胞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。

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.