MECHANICAL STRESS AS STIMULUS FOR AIRWAY WALL REMODELING

机械应力刺激气道壁重塑

• 批准号: 6184457
• 负责人: Jeffrey Mark Drazen
• 金额: $ 37.75万
• 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 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6184457
• 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，处于连续的重塑状态。 这种重塑的一个方面是胶原蛋白在上皮结缔组织中的沉积，这导致了地下膜增厚的外观。 目前，人们认为，从招募到气道壁的炎性细胞得出的介体，细胞因子和生长因子负责气道壁重塑。 我们的前提是，正如气道收缩期间发生的机械刺激是导致气道壁重塑的分子信号的足够来源。 我们的建议基于我们最近的证明，即对气道上皮细胞的机械应力可以产生有助于气道壁重塑的炎症微环境。 这些新颖的观察结果使我们提出了以下假设：遭受机械应力的气道上皮细胞是细胞因子，生长因子和介体的来源，这些细胞因子和介体可以启动分子事件，这些事件是气道重塑反应的核心。为了检验这一假设，我们提出了三个特定目标，每个目标都将测试特定的亚物种。 具体目标1将测试人类气道上皮细胞能够转导反映所研究细胞的表型（即分泌与非分泌）的机械信号的亚物种。 特定的目标2将测试亚类作用，即机械转传导致特定的细胞内力透射途径产生。这些途径将通过使用与细胞骨架结合的配体涂层的铁磁珠的磁场操纵在培养中的人类气道上皮细胞来激活。 特定的目标3将测试上皮机械转导可能会直接通过对气道成纤维细胞的影响而导致气道重塑的亚物种。 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可以在多大程度上创造出一个微环境，从而鼓励气道墙重塑。 这些实验可能会导致我们对导致气道壁慢性重塑的事件的理解的范式转变。在这里提出的假设使传统思维在其头上，建议气道缩小本身可能是链条中的重要因果关系，导致气道重塑。