Monitoring contractile forces during airway constriction

项目摘要：在所有已知可以对抗健康肺部的支气管收缩的因素中，深呼吸 是最有效的方法之一。然而，在哮喘肺中，这种保护现象基本上是在- 虚弱，在自发性哮喘发作期间，有时甚至逆转。一些人建议 深呼吸不能扩张狭窄的哮喘气道可能是导致哮喘的一个重要原因。 隐性呼吸道狭窄。为了解释这些观察，我们最近的发现在一定程度上引起了人们的注意 呼吸实际上拉伸了气道壁，也就是施加的周向张力的大小。 周向应变又必须作为两个物理因素的函数而成反比变化：(I) 气道壁中细胞和细胞外基质(ECM)的非收缩成分，以及，(Ii)产生的力 通过呼吸道平滑肌(ASM)本身。然而，直接测量这些数据几乎是不可能的 人体实质内呼吸道环境中的因素及其相对贡献。在没有的情况下 保持隐藏状态。 深层次灵感的有益影响？ 伸缩性？为了找到这些问题的答案，在这项基础拨款中，我们建议开发新的赋权 测量技术。使用我们首创的称为牵引力的生物力学方法-- (TFM)，我们在目标1中建议测量位于以下位置的ASM产生的收缩力- 在完整的人体实质内的呼吸道中，并接受模拟呼吸。我们在目标2中建议取消- 一种原位测量气道壁细胞外基质成分硬度的新技术

Project summary: Among all factors known to antagonize bronchoconstriction in a healthy lung, a deep breath is among the most effective. In the asthmatic lung, however, this protective phenomenon is substantially at- tenuated and during a spontaneous asthmatic attack it is sometimes even reversed. Some have suggested that the inability of a deep breath to dilate the constricted asthmatic airway might be an important cause of ex- cessive airway narrowing. To explain these observations, our recent findings call attention to the extent to which breathing actually stretched the airway wall, i.e. the magnitude of circumferential strain that is imposed. The circumferential strain, in turn, must vary inversely as a function of two physical factors: (i) stiffness of the non-contractile elements of the cells and extracellular matrix (ECM) in the airway wall, and, (ii) force generated by the airway smooth muscle (ASM) itself. However, it has been nearly impossible to directly measure these factors and their relative contributions in the settings of the intraparenchymal human airway. In the absence of such knowledge, governing mechanisms will remain poorly elucidated and key pathophysiological insights will remain hidden. For example, in asthma, does enhanced ECM stiffness render the airway refractory to the beneficial effects of deep inspirations? Or is the disease pathophysiology dominated by aberrant ASM con- tractility? To find answers to these questions, in this foundational grant, we propose to develop novel enabling measurement technologies. Using a biomechanical approach that we have pioneered called traction force mi- croscopy (TFM), we propose in aim 1 to measure contractile forces generated by the ASM that is situated with- in intact human intraparenchymal airways and subjected to simulated breathing. We propose in aim 2 to de- velop new technology to measure in situ stiffness of extracellular matrix (ECM) components of the airway wall and to correlate local ECM stiffness with local cell-ECM borne stresses.