Grant: Travel Awards - Institute Community Support

Rationale: Airway hyperresponsiveness and elevated airway smooth muscle tone (i.e. sustained contraction) are two common features of asthma. Our previous studies in humans and mice showed that tone increases airway responsiveness by increasing the contractile capacity of airway smooth muscle. This phenomenon was dubbed 'force adaptation'. However, whether there is causal link between force adaptation and the airway hyperresponsiveness in asthma remains to be determined. This project aims to elucidate the role of force adaptation in airway hyperresponsiveness in an allergic mouse model of asthma. Methods: C57BL/6 mice were exposed to house dust mite (HDM) or saline via intranasal instillation once daily during 10 consecutives days. This model is known to induce a Th2 type inflammation with eosinophils in bronchoalveolar lavages. Twenty-four hours after the last instillation, baseline lung functions and the degree of airway responsiveness to methacholine (MCh) were measured with the flexiVent. The delivery of 100 mg/ml of MCh were performed using two different regimens. The group of mice in the first regimen received 4 saline doses 5 minutes apart followed by a high dose of MCh (100 mg/ml). The group of mice in the second regimen received 4 low doses of MCh 5 minutes apart (10 mg/ml, then 3 times 5 mg/ml) to induce tone for 20 minutes followed by a high dose of MCh (75 mg/ml). Results: The degree of airway responsiveness to MCh measured using indices of small airway obstruction, such as G (tissue damping) and H (tissue elastance), was increased in mice pre-exposed to tone. This was further amplified in mice exposed to HDM. Contrastingly, the degree of airway responsiveness to MCh measured using RN (Newtonian resistance), an index of large airway obstruction, was not affected by tone. Conclusion: Force adaptation increases small airway narrowing and this is amplified by inflammation in a mouse model of allergic asthma.