Rosner Sonia R, Pascoe Christopher D, Blankman Elizabeth, Jensen Christopher C, Krishnan Ramaswamy, James Alan L, Elliot John G, Green Francis H, Liu Jeffrey C, Seow Chun Y, Park Jin-Ah, Beckerle Mary C, Paré Peter D, Fredberg Jeffrey J, Smith Mark A
Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, United States of America.
University of British Columbia Center for Heart Lung Innovation, St Paul Hospital, Vancouver, British Columbia, Canada.
PLoS One. 2017 Mar 9;12(3):e0171728. doi: 10.1371/journal.pone.0171728. eCollection 2017.
Bronchospasm induced in non-asthmatic human subjects can be easily reversed by a deep inspiration (DI) whereas bronchospasm that occurs spontaneously in asthmatic subjects cannot. This physiological effect of a DI has been attributed to the manner in which a DI causes airway smooth muscle (ASM) cells to stretch, but underlying molecular mechanisms-and their failure in asthma-remain obscure. Using cells and tissues from wild type and zyxin-/- mice we report responses to a transient stretch of physiologic magnitude and duration. At the level of the cytoskeleton, zyxin facilitated repair at sites of stress fiber fragmentation. At the level of the isolated ASM cell, zyxin facilitated recovery of contractile force. Finally, at the level of the small airway embedded with a precision cut lung slice, zyxin slowed airway dilation. Thus, at each level zyxin stabilized ASM structure and contractile properties at current muscle length. Furthermore, when we examined tissue samples from humans who died as the result of an asthma attack, we found increased accumulation of zyxin compared with non-asthmatics and asthmatics who died of other causes. Together, these data suggest a biophysical role for zyxin in fatal asthma.
在非哮喘人类受试者中诱发的支气管痉挛可通过深呼吸（DI）轻松逆转，而哮喘受试者中自发发生的支气管痉挛则不能。DI的这种生理效应归因于DI导致气道平滑肌（ASM）细胞伸展的方式，但其潜在的分子机制以及它们在哮喘中的失效仍不清楚。我们使用野生型和zyxin基因敲除小鼠的细胞和组织，报告了对生理幅度和持续时间的短暂拉伸的反应。在细胞骨架水平，zyxin促进应力纤维断裂部位的修复。在分离的ASM细胞水平，zyxin促进收缩力的恢复。最后，在嵌入精密切割肺切片的小气道水平，zyxin减缓气道扩张。因此，在每个水平上，zyxin都能在当前肌肉长度下稳定ASM结构和收缩特性。此外，当我们检查因哮喘发作死亡的人类组织样本时，我们发现与因其他原因死亡的非哮喘患者和哮喘患者相比，zyxin的积累增加。总之，这些数据表明zyxin在致命性哮喘中具有生物物理作用。
