In vitro, in silico and in vivo study challenges the impact of bronchial thermoplasty on acute airway smooth muscle mass loss.

Igor L Chernyavsky,Peter H Howarth,Rekha Chaudhuri,Amisha Singapuri,Richard J Russell,Adel H Mansur,Ruth M Saunders,Latifa Chachi,Patrick Dennison,Christopher E Brightling,Stephen Bicknell,Felicity R.A.J Rose,Bindi S Brook,Salman Siddiqui,Rachid Berair,Gavin E Morris

doi:10.1183/13993003.01680-2017

Abstract

Bronchial thermoplasty is a treatment for asthma. It is currently unclear whether its histopathological impact is sufficiently explained by the proportion of airway wall that is exposed to temperatures necessary to affect cell survival.Airway smooth muscle and bronchial epithelial cells were exposed to media (37–70°C) for 10 s to mimic thermoplasty. In silico we developed a mathematical model of airway heat distribution post-thermoplasty. In vivo we determined airway smooth muscle mass and epithelial integrity pre- and post-thermoplasty in 14 patients with severe asthma.In vitro airway smooth muscle and epithelial cell number decreased significantly following the addition of media heated to ≥65°C. In silico simulations showed a heterogeneous heat distribution that was amplified in larger airways, with <10% of the airway wall heated to >60°C in airways with an inner radius of ∼4 mm. In vivo at 6 weeks post-thermoplasty, there was an improvement in asthma control (measured via Asthma Control Questionnaire-6; mean difference 0.7, 95% CI 0.1–1.3; p=0.03), airway smooth muscle mass decreased (absolute median reduction 5%, interquartile range (IQR) 0–10; p=0.03) and epithelial integrity increased (14%, IQR 6–29; p=0.007). Neither of the latter two outcomes was related to improved asthma control.Integrated in vitro and in silico modelling suggest that the reduction in airway smooth muscle post-thermoplasty cannot be fully explained by acute heating, and nor did this reduction confer a greater improvement in asthma control.

Highlights

Bronchial thermoplasty (BT) is a non-pharmacological therapy for treating severe asthma by selectively heating conductive airways (3–10 mm in diameter) from within the lumen with a low-power electrical current [1, 2]
In vitro apoptosis and necrosis of airway smooth muscle (ASM) and human bronchial epithelial cells (hBECs) cells A metabolic assay demonstrated that the addition of media heated to 65°C or 70°C for 10 s, but not 45–60° C, resulted in a significant reduction in the number of ASM and hBEC cells remaining adherent after 24 h compared to 37°C
This reduction in the number of viable adherent cells persisted over 2 weeks after the addition of media heated to 65°C or 70°C for ASM and to 70°C for hBEC cells compared to 37°C

Summary

Introduction

Bronchial thermoplasty (BT) is a non-pharmacological therapy for treating severe asthma by selectively heating conductive airways (3–10 mm in diameter) from within the lumen with a low-power electrical current [1, 2]. During the BT procedure, thermal energy is delivered to the airway wall via a bronchoscope-inserted catheter with a distal basket of four electrodes that expand to make contact with the airway wall, aiming to reach a target temperature of 65°C for 10 s. The primary target of BT is the airway smooth muscle (ASM), a key contributor to airway remodelling, in severe asthma [2–7]. Thermal ablation by radiofrequency energy is commonly used in surgical practice [17, 18], there is a paucity of theoretical [19] and in vitro [20] studies in humans that assess the direct effect of supra-febrile temperatures on ASM cells’ survival and function, or the early effects of BT upon ASM mass and epithelial integrity

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