The resident cell in the asthmatic airway

项目总结 吸入皮质类固醇(ICS)在控制呼吸道炎症和哮喘症状方面有效，但 多项长期研究表明，ICS不会改变疾病发展的自然过程。这 没有回答的问题是确定可能解释气道重塑和 持续性哮喘。在这里，我们认为呼吸道的异常重塑可能是由体液引起的。 炎性细胞微环境的特征，但由于 物理微环境。这里我们提出了无源矩阵膨胀性和有源矩阵的概念 伸展，就像在活体正常的呼吸道中发现的那样，往往对异常的重塑具有保护作用。这 假设是新颖的，是机械论的，并且在三个实验目标中是可检验的。AIM 1检验了假设 生理膨胀性的底物对增殖/合成表型具有保护作用。AIM 2测试 假设具有生理拉伸水平的底物会导致细胞骨架流态化，这也是 对增殖/合成表型有保护作用。目标3提出的问题是，对身体的反应 驻留在正常和哮喘呼吸道的细胞的微环境不同。也就是说，是不是 哮喘呼吸道中的常驻细胞是其物理微环境的受害者吗？或者取而代之的是与生俱来 差异主宰细胞表型吗？这些目标将在分离的人肺中实现 成纤维细胞，结果的普遍性将在人的呼吸道平滑肌细胞中得到证实，两者都是 它们在哮喘的气道重塑中起着核心作用。

PROJECT SUMMARY Inhaled corticosteroids (ICS) are effective in controlling airway inflammation and asthma symptoms, but multiple long term studies indicate that ICS do not change the natural course of disease progression. This leaves unanswered the question of identifying novel pathways that might account for airway remodeling and persistent asthma. Here we propose that aberrant remodeling of the airway might be initiated by humoral features of an inflammatory cellular microenvironment, but is perpetuated and amplified by changes in the physical microenvironment. We propose here the notion that passive matrix distensibility and active matrix stretch, as are found in the normal airway in vivo, tend to be protective against aberrant remodeling. This hypothesis is novel, is mechanistic and is testable in three experimental aims. Aim 1 tests the hypothesis that a substrate of physiological distensibility is protective against a proliferative / synthetic phenotype. Aim 2 tests the hypothesis that a substrate with physiological levels of stretch causes cytoskeletal fluidization that is also protective against a proliferative / synthetic phenotype. Aim 3 asks the question, Do responses to the physical microenvironment differ between cells resident in the normal versus the asthmatic airway. That is to say, is the resident cell in the asthmatic airway a victim of its physical microenvironment? Or instead, do innate differences dominate the cellular phenotype? These aims will be carried out in the isolated human lung fibroblast, and the generality of the results will be confirmed in the human airway smooth muscle cell, both of which play central roles in remodeling of the asthmatic airway.