Wang Lu, Chitano Pasquale, Paré Peter D, Seow Chun Y
Respiratory Division, Department of Medicine; Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, BC V6Z 1Y6, Canada e-mail:
Department of Pathology and Laboratory Medicine, Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, BC V6Z 1Y6, Canada.
J Eng Sci Med Diagn Ther. 2019 Feb;2(1):0110041-110047. doi: 10.1115/1.4042477. Epub 2019 Feb 13.
Asthmatic airways are stiffer than normal. We have shown that the cytoskeletal passive stiffness of airway smooth muscle (ASM) can be regulated by intracellular signaling pathways, especially those associated with Rho kinase (ROCK). We have also shown that an oscillatory strain reduces the passive stiffness of ASM and its ability to generate force. Here, we investigated the combined effect of inhibiting the ASM contraction with β agonist and decreasing the ASM cytoskeletal stiffness with ROCK inhibitor and/or force oscillation (FO) on the relaxation of contracted ASM. We hypothesize that the ASM relaxation can be synergistically enhanced by the combination of these interventions, because drug-induced softening of the cytoskeleton enhances the FO-induced relaxation and vice versa. Sheep tracheal strips were isotonically contracted to acetylcholine (3 × 10 M). At the plateau of shortening, β agonist salbutamol (10 M), ROCK inhibitor H1152 (10 M), and FO (square wave, 1 Hz, amplitude 6% maximal active force) were applied either alone or in combination. After adjusting for nonspecific time-dependent variation, relengthening by individual interventions with low-dose salbutamol or H1152, or small amplitude FO was not significantly different from zero. However, significant relengthening was observed in all combination treatments. The relengthening was greater than the mathematical sum of relengthening caused by individual treatments thereby demonstrating synergistic relaxation. The ASM stiffness did not change with salbutamol or H1152 treatments, but was lower with FO in combination with H1152. The results suggest that the mechanopharmacological treatment can be an effective therapy for asthma.
哮喘气道比正常气道更僵硬。我们已经表明，气道平滑肌（ASM）的细胞骨架被动僵硬度可通过细胞内信号通路调节，尤其是那些与Rho激酶（ROCK）相关的信号通路。我们还表明，振荡应变可降低ASM的被动僵硬度及其产生力的能力。在此，我们研究了用β激动剂抑制ASM收缩以及用ROCK抑制剂和/或力振荡（FO）降低ASM细胞骨架僵硬度对收缩的ASM舒张的联合作用。我们假设，这些干预措施的组合可协同增强ASM舒张，因为药物诱导的细胞骨架软化可增强FO诱导的舒张，反之亦然。将羊气管条与乙酰胆碱（3×10⁻⁶M）进行等张收缩。在缩短的平台期，单独或联合应用β激动剂沙丁胺醇（10⁻⁶M）、ROCK抑制剂H1152（10⁻⁶M）和FO（方波，1Hz，幅度为最大主动力的6%）。在调整非特异性时间依赖性变化后，低剂量沙丁胺醇或H1152或小幅度FO的个体干预导致的再伸长与零无显著差异。然而，在所有联合治疗中均观察到显著的再伸长。再伸长大于个体治疗引起的再伸长的数学总和，从而证明了协同舒张。沙丁胺醇或H1152治疗后ASM僵硬度未改变，但FO与H1152联合应用时ASM僵硬度较低。结果表明，机械药理学治疗可能是一种有效的哮喘治疗方法。
