Smooth Muscle Calcium Signaling and Contraction in the Small Airways of the House Dust Mite Asthma Mouse Model

Abstract

The small intrapulmonary airways are the major contributors to reversible airflow limitation in asthma. However, the mechanisms responsible for the increased small‐airway responsiveness to bronchoconstrictors (airway hyperresponsiveness) that characterized asthma pathophysiology are not fully understood. We used precision‐cut lung slices and microscope imaging approaches to investigate the contraction and intracellular calcium signaling in the smooth muscle of small airways from mice chronically challenged with house dust mite extract (HDM) during 3 to 7 weeks. Mice challenged with HDM developed a significant airway inflammation characterized by the presence of eosinophils, lymphocytes, neutrophils, and monocytes that spread through the airway tree and reached the small airways. Superfusion of lung slices with methacholine (MCh) induced a concentration‐dependent airway contraction that was significantly increased in the small airways of the HDM‐challenge mice than in PBS‐challenged mice (controls). MCh stimulation induced intracellular Ca2+ oscillations in the smooth muscle cells on the small airways. The frequency of these Ca2+ oscillations increased with MCh concentration and was higher in airway smooth muscle cells from the HDM‐exposed mice than from controls. The results suggest that airway hyperresponsiveness in asthma is caused by an increased contractility of the airway smooth muscle cells in the small airways which is accompanied by an increased intracellular Ca2+ response to bronchoconstrictors