MECHANICAL STRESS AS STIMULUS FOR AIRWAY WALL REMODELING

机械应力刺激气道壁重塑

• 批准号: 6039111
• 负责人: Jeffrey Mark Drazen
• 金额: $ 37.77万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6039111
• 关键词: asthma; biological signal transduction; biomarker; corticosteroids; cytoskeleton; endothelin; fibroblasts; gene expression; human tissue; immediate early protein; immunocytochemistry; inflammation; magnetic field; mechanical stress; respiratory airflow disorder; respiratory epithelium; tissue /cell culture; transforming growth factors

In patients with asthma, the airway wall is a dynamic structure that is in a continuous state of remodeling. One aspect of this remodeling is the deposition of collagen in the subepithelial connective tissue, which gives rise to the appearance of a thickened basement membrane. It is currently thought that mediators, cytokines, and growth factors derived from inflammatory cells recruited to the airway wall are responsible for airway wall remodeling. Our premise is that mechanical stimulation of the airway epithelium, as occurs during airway constriction, is a sufficient source for the molecular signals that result in airway wall remodeling. Our proposal is based on our recent demonstration that mechanical stress on airway epithelial cells can create an inflammatory microenvironment conducive to airway wall remodeling. These novel observations lead us to tender the following hypothesis: Airway epithelial cells subjected to mechanical stresses are a source of cytokines, growth factors, and mediators that can initiate the molecular events which are at the core of the airway remodeling response. To test this hypothesis, we propose three specific aims, each of which will test a specific subhypothesis. Specific Aim 1 will test the subhypothesis that human airway epithelial cells are capable of transducing mechanical signals that reflect the phenotype (i.e. secretory versus non-secretory) of the cell under study. Specific Aim 2 will test the subhypothesis that mechanotransduction results from specific intracellular force transmission pathways; these pathways will be activated by deforming human airway epithelial cells in culture using magnetic field manipulation of ligand coated ferromagnetic beads bound to the cytoskeleton. Specific Aim 3 will test the subhypothesis that epithelial mechanotransduction can lead directly to airway remodeling through effects on airway fibroblasts. Data from these experiments will allow us to determine the extent to which mechanical perturbations of airway epithelial cells can create a microenvironment that encourages airway wall remodeling. These experiments may result in a paradigm shift in our understanding of the events leading to chronic remodeling of the airway wall. The hypothesis proposed here turns traditional thinking on its head by suggesting that airway narrowing per se may be an important causal link in the chain leading to airway remodeling.

在哮喘患者中，气道壁是一种动态结构，处于持续重塑状态。 这种重塑的一个方面是胶原蛋白在上皮下结缔组织中的沉积，这引起增厚的基底膜的外观。 目前认为，来自募集到气道壁的炎性细胞的介质、细胞因子和生长因子负责气道壁重塑。 我们的前提是，机械刺激的气道上皮细胞，发生在气道收缩，是一个足够的来源的分子信号，导致气道壁重塑。 我们的建议是基于我们最近的证明，气道上皮细胞的机械应力可以创造一个炎症微环境，有利于气道壁重塑。 这些新的观察使我们提出以下假设：气道上皮细胞受到机械应力是细胞因子，生长因子和介质的来源，可以启动的分子事件，这是在气道重塑反应的核心。为了检验这一假设，我们提出了三个具体的目标，每个目标将检验一个具体的子假设。 具体目标1将检验亚假设，即人气道上皮细胞能够转导反映研究细胞表型（即分泌型与非分泌型）的机械信号。 具体目标2将测试的亚假设，机械转导的结果从特定的细胞内力传递途径;这些途径将被激活，通过变形的人气道上皮细胞在培养中使用磁场操纵的配体包被的铁磁珠结合到细胞骨架。 具体目标3将检验上皮机械转导可通过对气道成纤维细胞的作用直接导致气道重塑的亚假设。 这些实验的数据将使我们能够确定气道上皮细胞的机械扰动在多大程度上可以创造一个微环境，鼓励气道壁重塑。 这些实验可能导致我们对导致气道壁慢性重塑的事件的理解发生范式转变。这里提出的假设改变了传统的思维方式，认为气道狭窄本身可能是导致气道重塑的重要因果关系。