The resident cell in the asthmatic airway: A victim of its physical microenviron

描述(申请人提供)：吸入型皮质类固醇(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不改变疾病发展的自然过程。这就留下了一个悬而未决的问题，即确定可能解释呼吸道重塑和持续性哮喘的新途径。在这里，我们认为呼吸道的异常重塑可能是由炎症细胞微环境的体液特征启动的，但由于物理微环境的变化而持久和放大。我们在这里提出了被动基质扩张性和主动基质拉伸的概念，就像在活体正常的气道中发现的那样，倾向于防止异常重塑。这一假设是新颖的，是机械论的，并且可以在三个实验目标中得到验证。目的1验证生理膨胀性底物对增殖/合成表型具有保护作用的假设。目的2测试具有生理拉伸水平的底物引起细胞骨架流态化的假设，该流态化也对增殖/合成表型具有保护作用。目标3提出的问题是，驻留在正常和哮喘呼吸道的细胞对物理微环境的反应是否不同。也就是说，哮喘气道中的驻留细胞是其物理微环境的受害者吗？或者相反，先天差异是否主导了细胞表型？这些目标将在分离的人肺成纤维细胞中实现，结果的普遍性将在人的气道平滑肌细胞中得到证实，这两个细胞都在哮喘气道重塑中发挥核心作用。 与公共健康相关：就像它们受到由体液因子和基质相关蛋白连接所定义的化学微环境的影响一样，驻留在呼吸道内的细胞也可能受到由物理力量定义的机械微环境的影响。机械微环境的作用代表了一个新的维度，有可能加深我们对持续哮喘患者正常气道行为及其重塑的理解。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Just as they are influenced by a chemical microenvironment defined by ligation of humoral factors and matrix- associated proteins, cells resident within the airway may be influenced by a mechanical microenvironment defined by physical forces. The role of the mechanical microenvironment represents a new dimension with the potential of deepening our understanding of the behavior of the normal airway and its remodeling in persistent asthma.