title: Influenza A virus infection and cigarette smoke impair bronchodilator responsiveness to β-adrenoceptor agonists in mouse lung.
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 12 in 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.
authors.affiliation: Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Chantal
authors.initials: C
authors.lastname: Donovan
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria 3010, Australia School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria 3083, Australia.
authors.forename: Huei Jiunn
authors.initials: HJ
authors.lastname: Seow
authors.affiliation: Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Bourke
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria 3010, Australia School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria 3083, Australia ross.vlahos@rmit.edu.au.
authors.forename: Ross
authors.initials: R
authors.lastname: Vlahos
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001993:Bronchodilator Agents / Q000627:therapeutic use*; D009980:Influenza A virus; D008168:Lung / Q000378:metabolism / Q000821:virology*; D008297:Male; D051379:Mice; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000378:metabolism; D011941:Receptors, Adrenergic / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects*; D014026:Nicotiana / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000318:Adrenergic beta-Agonists; D001993:Bronchodilator Agents; D011941:Receptors, Adrenergic; D014409:Tumor Necrosis Factor-alpha
keywords: acute exacerbations of COPD (AECOPD); chronic obstructive pulmonary disease (COPD); influenza; respiratory virus; small airways; β-adrenoceptor