The resident cell in the asthmatic airway

项目摘要 吸入性皮质类固醇（ICS）可有效控制气道炎症和哮喘症状，但 多项长期研究表明ICS不会改变疾病进展的自然过程。这 没有回答的问题，确定新的途径，可能占气道重塑， 持续性哮喘在此，我们提出，气道的异常重塑可能是由体液免疫引起的。 炎性细胞微环境的特征，但通过细胞内 物理微环境我们在这里提出的概念，被动矩阵扩张性和主动矩阵 如在体内正常气道中所发现的那样，牵张倾向于保护免于异常重塑。这 假设是新颖的，是机械的，并在三个实验目标是可检验的。目标1检验假设， 具有生理可扩张性的底物可保护细胞不受增殖/合成表型的影响。Aim 2测试 具有生理水平拉伸的底物引起细胞骨架流化的假设也 针对增殖/合成表型的保护。目标3提出问题，对身体做出反应 在正常气道与哮喘气道中驻留的细胞之间的微环境不同。也就是说， 哮喘气道中的常驻细胞是其物理微环境的受害者吗？或者相反， 差异主导细胞表型？这些目标将在离体人肺中进行 结果的一般性将在人气道平滑肌细胞中得到证实， 其在哮喘气道重塑中起中心作用。

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.