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research-article

Mechanopharmacology and Synergistic Relaxation of Airway Smooth Muscle

[+] Author and Article Information
Lu Wang

Respiratory Division, Department of Medicine; Centre for Heart Lung Innovation - St. Paul's Hospital, University of British Columbia, Vancouver, BC, V6Z 1Y6 Canada
lu.wang@hli.ubc.ca

Pasquale Chitano

Department of Pathology and Laboratory Medicine; Centre for Heart Lung Innovation - St. Paul's Hospital, University of British Columbia, Vancouver, BC, V6Z 1Y6 Canada
pasquale.chitano@hli.ubc.ca

Peter D. Paré

Respiratory Division, Department of Medicine; Centre for Heart Lung Innovation - St. Paul's Hospital, University of British Columbia, Vancouver, BC, V6Z 1Y6 Canada
alphonse.pare@gmail.com

Chun Seow

Department of Pathology and Laboratory Medicine; Centre for Heart Lung Innovation - St. Paul's Hospital, University of British Columbia, Vancouver, BC, V6Z 1Y6 Canada
chun.seow@hli.ubc.ca

1Corresponding author.

ASME doi:10.1115/1.4042477 History: Received August 30, 2018; Revised December 20, 2018

Abstract

Asthmatic airways are stiffer than normal. We have shown that the cytoskeletal passive stiffness of airway smooth muscle (ASM) can be regulated by intracellular signalling pathways, especially those associated with Rho kinase (ROCK). We have also shown that oscillatory strain reduces passive stiffness of ASM and its ability to generate force. Here we investigated the combined effect of inhibiting ASM contraction with ß2 agonist and decreasing ASM cytoskeletal stiffness with ROCK inhibitor and/or force oscillation (FO) on the relaxation of contracted ASM. We hypothesize that ASM relaxation can be synergistically enhanced by the combination of these interventions because drug-induced softening of the cytoskeleton enhances FO-induced relaxation and vice versa. Sheep tracheal strips were isotonically contracted to acetylcholine (3x10-5 M). At the plateau of shortening, ß2 agonist salbutamol (10-7 M), ROCK inhibitor H1152 (10-7 M), and FO (square wave, 1 Hz, amplitude 6% maximal active force) were applied either alone or in combination. After adjusting for non-specific time-dependent variation, re-lengthening by individual interventions with low dose salbutamol or H1152, or small amplitude FO was not significantly different from zero. However, significant re-lengthening was observed in all combination treatments. The re-lengthening was greater than the mathematical sum of re-lengthening caused by individual treatments thereby demonstrating synergistic relaxation. ASM stiffness did not change with salbutamol or H1152 treatments, but was lower with FO in combination with H1152. The results suggest that mechanopharmacological treatment can be an effective therapy for asthma.

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