Peripheral Airway Smooth Muscle, but Not the Trachealis, Is Hypercontractile in an Equine Model of Asthma

Abstract

Heaves is a naturally occurring equine disease that shares many similarities with human asthma, including reversible antigen-induced bronchoconstriction, airway inflammation, and remodeling. The purpose of this study was to determine whether the trachealis muscle is mechanically representative of the peripheral airway smooth muscle (ASM) in an equine model of asthma. Tracheal and peripheral ASM of heaves-affected horses under exacerbation, or under clinical remission of the disease, and control horses were dissected and freed of epithelium to measure unloaded shortening velocity (Vmax), stress (force/cross-sectional area), methacholine effective concentration at which 50% of the maximum response is obtained, and stiffness. Myofibrillar Mg(2+)-ATPase activity, actomyosin in vitro motility, and contractile protein expression were also measured. Horses with heaves had significantly greater Vmax and Mg(2+)-ATPase activity in peripheral airway but not in tracheal smooth muscle. In addition, a significant correlation was found between Vmax and the time elapsed since the end of the corticosteroid treatment for the peripheral airways in horses with heaves. Maximal stress and stiffness were greater in the peripheral airways of the horses under remission compared with controls and the horses under exacerbation, potentially due to remodeling. Actomyosin in vitro motility was not different between controls and horses with heaves. These data demonstrate that peripheral ASM is mechanically and biochemically altered in heaves, whereas the trachealis behaves as in control horses. It is therefore conceivable that the trachealis muscle may not be representative of the peripheral ASM in human asthma either, but this will require further investigation.

Science‐in‐brief: Equine asthma diagnosis: Beyond bronchoalveolar lavage cytology

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Gene set enrichment analysis of the bronchial epithelium implicates contribution of cell cycle and tissue repair processes in equine asthma

“…We detected here significantly enriched gene sets associated with wound healing, hemostasis, blood coagulation and regulation of body fluid levels in the asthmatic group following challenge, lending support to linkage and importance of these pathways in equine asthma. Smooth muscle cells of the bronchioles are hypercontractile in human asthmatics 35 , and SRF and its co-factor MYOCD are thought to contribute to airway remodeling in severe equine asthma 19 . Several other genes previously identified as differentially expressed between asthmatic and non-asthmatic horses are involved in wound healing, coagulation, hemostasis and regulation of body fluids, including thrombospondin 1 (THBS1) , oncostatin (OSM) , pleckstrin (PLEK) and others 28 .…”

CD151, a laminin receptor showing increased expression in asthmatic patients, contributes to airway hyperresponsiveness through calcium signaling

“…This focus relates to control of airway conductance, of which ASM contraction is a principal determinant. A number of studies suggest that ASM from asthmatic patients can be hypercontractile [15][16][17][18][19][20] or can display altered contractile properties. 21 However, full agreement is yet to be reached, 23,24 and the mechanism for such a change in function remains to be confirmed.…”