Smooth Muscle Hypocontractility and Airway Normoresponsiveness in a Mouse Model of Pulmonary Allergic Inflammation

Boucher, Magali; Henry, Cyndi; Dufour-Mailhot, Alexis; Khadangi, Fatemeh; Bossé, Ynuk

doi:10.3389/fphys.2021.698019

Cited by 9 publications

(5 citation statements)

References 82 publications

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“…The fact that asthma in the present study increased H and G , which are both sensitive to closure, while leaving airway resistance ( R aw ) unchanged supports the contribution of airway closure. The fact that the increased H and G caused by experimental asthma were almost completely eliminated with recruitment manoeuvres in our previous study (Boucher, Henry, Dufour‐Mailhot et al., 2021 ) also confirms that the main mechanical alteration seen at baseline is attributable to small airway closure.…”

Section: Discussionsupporting

confidence: 79%

“…Mice of each sex were divided into two groups of 20 (Figure 1 ): one group exposed to 25 μL of saline (control mice) and one group exposed to 25 μL of 2 mg of house dust mite (HDM) extract ( Dermatophagoides pteronyssinus ; Greer, Lenoir, NC, USA) per millilitre of saline to induce pulmonary allergic inflammation (asthmatic mice) (Boucher, Henry, Dufour‐Mailhot et al., 2021 , 2021 ; Sahu et al., 2010 ). The endotoxin concentration was 47.3 EU per milligram of HDM extract.…”

Section: Methodsmentioning

confidence: 99%

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More airway smooth muscle in males versus females in a mouse model of asthma: A blessing in disguise?

Gill

Rojas‐Ruiz

Boucher

et al. 2023

Experimental Physiology

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Mouse models are helpful in unveiling the mechanisms underlying sex disparities in asthma. In comparison to their female counterparts, male mice are hyperresponsive to inhaled methacholine, a cardinal feature of asthma that contributes to its symptoms. The physiological details and the structural underpinnings of this hyperresponsiveness in males are currently unknown. Herein, BALB/c mice were exposed intranasally to either saline or house dust mite once daily for 10 consecutive days to induce experimental asthma. Twenty-four hours after the last exposure, respiratory mechanics were measured at baseline and after a single dose of inhaled methacholine that was adjusted to trigger the same degree of bronchoconstriction in both sexes (it was twice as high in females). Bronchoalveolar lavages were then collected, and the lungs were processed for histology. House dust mite increased the number of inflammatory cells in bronchoalveolar lavages to the same extent in both sexes (asthma, P = 0.0005; sex, P = 0.96). The methacholine response was also markedly increased by asthma in both sexes (e.g., P = 0.0002 for asthma on the methacholine-induced bronchoconstriction). However, for a well-matched bronchoconstriction between sexes, the increase in hysteresivity, an indicator of airway narrowing heterogeneity, was attenuated in males for both control and asthmatic mice (sex, P = 0.002). The content of airway smooth muscle was not affected by asthma but was greater in males (asthma, P = 0.31; sex, P < 0.0001). These results provide further insights regarding an important sex disparity in mouse models of asthma. The increased amount of airway smooth muscle in males might contribute functionally to their greater methacholine response and, possibly, to their decreased propensity for airway narrowing heterogeneity.

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Section: Discussionsupporting

confidence: 79%

Section: Methodsmentioning

confidence: 99%

More airway smooth muscle in males versus females in a mouse model of asthma: A blessing in disguise?

Gill

Rojas‐Ruiz

Boucher

et al. 2023

Experimental Physiology

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“…Several strains of mice are used to study lung mechanics and for modeling human respiratory diseases. Yet, C57BL/6 and BALB/c mice are the most widely employed 1 , 2 , 9 . These two strains exhibit different susceptibilities for the development of specific pathogenic traits reminiscent of human respiratory diseases in response to offending triggers.…”

Section: Discussionmentioning

confidence: 99%

“…These two strains exhibit different susceptibilities for the development of specific pathogenic traits reminiscent of human respiratory diseases in response to offending triggers. For example, while C57BL/6 are more prone than BALB/c mice for the development of pulmonary fibrosis upon exposure to bleomycin in models of idiopathic pulmonary fibrosis 2 , 16 , BALB/c are more prone than C57BL/6 mice for the development of methacholine hyperresponsiveness upon exposure to allergen exposure in models of asthma 9 , 17 and for the development of emphysema upon exposure to cigarette smoke or elastase in models of COPD 18 , 19 . Understanding inherent differences in the mechanical properties of the lung between these two mouse strains may help in interpreting these varying strain susceptibilities.…”

Section: Discussionmentioning

confidence: 99%

Lung stiffness of C57BL/6 versus BALB/c mice

Rojas-Ruiz,

Boucher,

Gill

et al. 2023

Sci Rep

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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 cmH2O/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.

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“…Mice were prepared and ventilated with the flexiVent (FX Module 2, SCIREQ, Montreal, Canada) as previously described [23][24][25][26] . Briefly, they were anesthetized and put under systemic analgesia using ketamine (100 mg/kg) and xylazine (10 mg/kg).…”

Section: Respiratory Mechanicsmentioning

confidence: 99%

Airway smooth muscle tone curbs hyperresponsiveness in experimental asthma

Gazzola,

Boucher,

Henry

et al. 2024

Preprint

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Background & ObjectivesA sustained contraction of airway smooth muscle, hereinafter called tone, increases the response to methacholine in healthy mice and humans. However, the effect of tone in the context of an active inflammation remains to be investigated. The objective of the present study was to test the effect of tone on thein vivoresponse to methacholine in mice during an active inflammatory phase of experimental asthma.MethodsMale BALB/c mice were exposed once-daily to either intranasal saline or house dust mite for 10 consecutive days to induce experimental asthma. They then underwent one of two methacholine challenges 24 h after the last exposure. While the same cumulative dose was administered in both challenges, one was preceded by a 20-min period of tone induced by nebulizing low doses of methacholine at 5-min intervals. Respiratory mechanics were monitored before and throughout the methacholine challenge by oscillometry. Bronchoalveolar lavages (BAL) and histology were also performed.ResultsBAL inflammation and histological alterations were consistent with experimental asthma. In accordance with previous studies, tone potentiated the response to methacholine in control mice, mainly by stiffening the lung periphery. The lung was even stiffer upon methacholine challenge during an active phase of inflammation in mice with experimental asthma, but this was not further potentiated by tone. In fact, in mice with experimental asthma, tone mitigated hyperresponsiveness by preventing further airway narrowing and, more importantly, small airway narrowing heterogeneity and closure.ConclusionDuring an active inflammatory phase of experimental asthma, tone protects against hyperresponsiveness.Take-home messageThe effect of airway smooth muscle tone on the methacholine response was investigated in mice with or without experimental asthma. While tone potentiated the methacholine response in control mice, it mitigated hyperresponsiveness in experimental asthma. These results unveiled a protective role of the airway smooth muscle in experimental asthma.

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Smooth Muscle Hypocontractility and Airway Normoresponsiveness in a Mouse Model of Pulmonary Allergic Inflammation

Cited by 9 publications

References 82 publications

More airway smooth muscle in males versus females in a mouse model of asthma: A blessing in disguise?

More airway smooth muscle in males versus females in a mouse model of asthma: A blessing in disguise?

Lung stiffness of C57BL/6 versus BALB/c mice

Airway smooth muscle tone curbs hyperresponsiveness in experimental asthma

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