Acute Response of Airway Muscle to Extreme Temperature Includes Disruption of Actin–Myosin Interaction

Abstract

Despite the emerging use of bronchial thermoplasty in asthma therapy, the response of airway smooth muscle (ASM) to extreme temperatures is unknown. We investigated the immediate effects of exposing ASM to supraphysiologic temperatures. Isometric contractions were studied in bovine ASM before and after exposure to various thermal loads and/or pharmacologic interventions. Actin-myosin interactions were investigated using a standard in vitro motility assay. We found steep thermal sensitivity for isometric contractions evoked by acetylcholine, with threshold and complete inhibition at less than 50°C and greater than 55°C, respectively. Contractile responses to serotonin or KCl were similarly affected, whereas isometric relaxations evoked by the nitric oxide donor S-nitrosyl-N-acetylpenicillamine or the β-agonist isoproterenol were unaffected. This thermal sensitivity developed within 15 minutes, but did not evolve further over the course of several days (such a rapid time-course rules out heat shock proteins, apoptosis, autophagy, and necrosis). Although heat-sensitive transient receptor potential (TRPV2) channels and the calmodulin-dependent (Cam) kinase-II-induced inactivation of myosin light chain kinase are both acutely thermally sensitive, with a temperature producing half-maximal effect (T(1/2)) of 52.5°C, the phenomenon we describe was not prevented by blockers of TRPV2 channels (e.g., ruthenium red, gadolinium, zero-Ca(2+) or zero-Na(+)/zero-Ca(2+) media, and cromakalim) or of Cam kinase-II (e.g., W7, trifluoperazine, and KN-93). However, direct measurements of actin-myosin interactions showed the same steep thermal profile. The functional changes preceded any histologic evidence of necrosis or apoptosis. We conclude that extreme temperatures (such as those used in bronchial thermoplasty) directly disrupt actin-myosin interactions, likely through a denaturation of the motor protein, leading to an immediate loss of ASM cell function.

How to: Bronchial thermoplasty in asthma

“…Several other mechanisms, either alone or in combination, could explain the beneficial effects of bronchial thermoplasty in the treatment of asthma. For example, bronchial thermoplasty might alter airway function by reducing contractility of airway smooth muscle [11] or by stiffening the airway wall [6] or by reducing the secretion of pro-inflammatory mediators from airway smooth muscle cells [5]. In addition, it is possible that bronchial thermoplasty might alter airway epithelial, neural or inflammatory cell function.…”

Thermal ablation for asthma: current status and technique

“…This causes airway narrowing, increased airway resistance and leads to the symptom syndrome of asthma: wheezing, dyspnea and chest tightness. Although the specific mechanisms of action for BT is not clear, it is generally understood that BT delivers thermal energy and directly targets the airway smooth muscles with the goal of reducing the airway smooth muscle mass (6,7). The thermal energy is delivered using the Alair BT System (Boston Scientific, Natick, MA, USA) which consists of a radiofrequency controller and catheter (8).…”

Termoplastia bronquial

“…Un segundo mecanismo podría implicar un efecto sobre las propiedades contráctiles del músculo liso bronquial o un endurecimiento de la pared bronquial a la que se une el músculo. Se han investigado los efectos de la aplicación de diferentes temperaturas en la contracción in vitro del músculo liso bovino; la contracción inducida por acetilcolina se inhibió a temperaturas superiores a los 55ºC, mientras que la relajación medida por un betaagonista 2, no se vio afectada (7). No obstante, no está claro si los fenómenos observados en la respuesta aguda puedan persistir a largo plazo in vivo.…”