Abstract
β2-adrenoceptor agonists are the mainstay therapy for patients with asthma but their effectiveness in cigarette smoke (CS)-induced lung disease such as chronic obstructive pulmonary disease (COPD) is limited. In addition, bronchodilator efficacy of β2-adrenoceptor agonists is decreased during acute exacerbations of COPD (AECOPD), caused by respiratory viruses including influenza A. Therefore, the aim of the present study was to assess the effects of the β2-adrenoceptor agonist salbutamol (SALB) on small airway reactivity using mouse precision cut lung slices (PCLS) prepared from CS-exposed mice and from CS-exposed mice treated with influenza A virus (Mem71, H3N1). CS exposure alone reduced SALB potency and efficacy associated with decreased β2-adrenoceptor mRNA expression, and increased tumour necrosis factor α (TNFα) and interleukin-1β (IL-1β) expression. This impaired relaxation was restored by day 12in the absence of further CS exposure. In PCLS prepared after Mem71 infection alone, responses to SALB were transient and were not well maintained. CS exposure prior to Mem71 infection almost completely abolished relaxation, although β2-adrenoceptor and TNFα and IL-1β expression were unaltered. The present study has shown decreased sensitivity to SALB after CS or a combination of CS and Mem71 occurs by different mechanisms. In addition, the PCLS technique and our models of CS and influenza infection provide a novel setting for assessment of alternative bronchodilators.
Highlights
Small airway dysfunction plays a crucial role in many obstructive lung diseases including chronic obstructive pulmonary disease (COPD) [1,2]
The aim of the present study was to assess the effects of the β2-adrenoceptor agonist salbutamol (SALB) on changes in small airway reactivity using mouse precision cut lung slices (PCLS) prepared from cigarette smoke (CS)-exposed mice and from CS-exposed mice treated with influenza A virus (Mem71, H3N1)
The present study has examined airway reactivity in PCLS prepared from mice exposed to CS (4 days) alone or mice exposed to CS and infected with influenza A virus (Mem71)
Summary
Small airway dysfunction plays a crucial role in many obstructive lung diseases including chronic obstructive pulmonary disease (COPD) [1,2]. Cigarette smoking is a major contributor to COPD and alters immune function to increase susceptibility to subsequent influenza A virus infection [3]. These infections are a major cause of acute exacerbations of COPD (termed AECOPD) [4]. Infection with influenza virus is associated with greater inflammatory responses [7] and loss of lung function compared with exacerbations due to other causes [8]. The greater severity of disease following infection in smokers compared with non-smokers [9,10] is associated with inflammation and injury extending to the smaller airways in the distal lung [11] and increased influenza-related mortality [12,13]
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