Bronchodilator responsiveness is impaired in a mouse model of cigarette smoke exposure and influenza infection

Abstract

Introduction: Influenza infections commonly cause acute exacerbations of chronic obstructive pulmonary disease (AECOPD). AECOPD trigger an accelerated decline in lung function, leading to hospitalisation and in some cases death. The majority of COPD patients have small airway obstruction, which contributes to dyspnea and decreased efficacy of current medication. However, the contribution of the small airways to AECOPD is poorly understood. Aim: To characterise small airway reactivity in a mouse model of AECOPD using the lung slice technique. Methods: Male Balb/C mice were exposed to cigarette smoke (CS) generated from 9 cigarettes/day (or air for sham) for 4 days. On day 5, mice were infected with 1x10 4.5 PFU of Mem71 influenza A virus (flu, H3N1) or PBS. Lung slices were prepared from mice 7 days post-infection for phase-contrast microscopy analysis of airway reactivity. Results: Contraction to methacholine (MCh) or serotonin (5HT) was unchanged between sham+PBS, sham+flu, CS+PBS or CS+flu treated mice. However, the dilator potency of salbutamol (SALB) and isoprenaline was higher in lung slices from sham mice than CS or flu treated mice. Airway relaxation was abolished by CS+flu treatment, but the maximum response was not significantly impaired by CS or flu alone (10 μM SALB % relaxation; sham+PBS: 31±5, sham+flu: 12±5, CS+PBS: 44±8, n=4/group). There was no change in the β 2 -adrenoceptor expression between groups. Discussion: These data indicate that bronchodilator responsiveness is impaired in a mouse model of influenza A-induced COPD exacerbation. The lung slice technique is a means by which to assess novel dilators and mechanisms of impaired dilator responsiveness.