Louis Gélinas’s research while affiliated with Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval) and other places

The role of excessive airway constriction in the hyperresponsiveness to nebulized methacholine in mice with experimental asthma is still contentious. Yet, there have been very few studies investigating whether the increased in vivo response to methacholine caused by experimental asthma is associated with a corresponding increase in ex vivo airway constriction. Herein, the responses to nebulized methacholine in vivo and airway constriction in lung slices ex vivo were studied in 8‐ to 10‐week‐old male mice of two strains, BALB/c and C57BL/6. Experimental asthma was induced by administering house dust mites (HDM) intranasally, once daily, for 10 consecutive days. Complementary ex vivo studies were conducted with excised tracheas to measure and compare isometric force. As expected, the in vivo response to methacholine, and especially the hyperresponsiveness caused by HDM, was greater in BALB/c than in C57BL/6 mice. In contrast, there were no differences in maximal airway constriction between mouse strains, and the hyperresponsiveness to nebulized methacholine caused by HDM in both mouse strains was not associated with a corresponding increase in ex vivo airway constriction. The experiments with excised tracheas demonstrated no differences in isometric force between strains and between mice with and without experimental asthma. It is concluded that the hyperresponsiveness to nebulized methacholine in an acute mouse model of asthma induced by repeated HDM exposures is not associated with excessive airway constriction ex vivo.

The level of airway constriction in thin slices of lung tissue is highly variable. Owing to the labor-intensive nature of these experiments, determining the number of airways to be analyzed in order to allocate a reliable value of constriction in one mouse is challenging. Herein, a new automated device for physiology and image analysis was used to facilitate high throughput screening of airway constriction in lung slices. Airway constriction was first quantified in slices of lungs from male BALB/c mice with and without experimental asthma that were inflated with agarose through the trachea or trans-parenchymal injections. Random sampling simulations were then conducted to determine the number of airways required per mouse to quantify maximal constriction. The constriction of 45 ± 12 airways per mouse in 32 mice were analyzed. Mean maximal constriction was 37.4 ± 32.0%. The agarose inflating technique did not affect the methacholine response. However, the methacholine constriction was affected by experimental asthma (p = 0.003), shifting the methacholine concentration–response curve to the right, indicating a decreased sensitivity. Simulations then predicted that approximately 35, 16 and 29 airways per mouse are needed to quantify the maximal constriction mean, standard deviation and coefficient of variation, respectively; these numbers varying between mice and with experimental asthma.

This study was undertaken to determine whether a smaller lung volume or a stiffer lung tissue accounts for the greater lung elastance of C57BL/6 than BALB/c mice. The mechanical properties of the respiratory system and lung volumes were measured with the flexiVent and compared between male C57BL/6 and BALB/c mice (n = 9). The size of the excised lung was also measured by volume liquid displacement. One lobe was then subjected to sinusoidal strains in vitro to directly assess the mechanical properties of the lung tissue, and another one was used to quantify the content of hydroxyproline. In vivo elastance was markedly greater in C57BL/6 than BALB/c mice based on 5 different readouts. For example, respiratory system elastance was 24.5 ± 1.7 vs. 21.5 ± 2.4 cmH 2 O/mL in C57BL/6 and BALB/c mice, respectively (p = 0.007). This was not due to a different lung volume measured by displaced liquid volume. On the isolated lobes, both elastance and the hydroxyproline content were significantly greater in C57BL/6 than BALB/c mice. These results suggest that the lung elastance of C57BL/6 mice is greater than BALB/c mice not because of a smaller lung volume but because of a stiffer lung tissue due to a greater content of collagen.