Submitted on April 13, 2009
Accepted on September 25, 2009
Rhinovirus-induced Exacerbations of Asthma - How is the 
2-adrenoceptor Implicated?
Thomas Trian1*, Qi Ge2, Lyn M Moir3, Janette K Burgess3, Curtis Kuo4, Nicholas J.C King5, Helen K Reddel6, Judith L Black2, Brian G Oliver2, and Brent E McParland4
1 Pharmacology, University of Sydney, Blackburn Building, D06, Sydney, New South Wales, 2006, Australia; Woolcock Institute of Medical Research, Sydney, New South Wales, Australia,
2 Pharmacology, University of Sydney, Sydney, New South Wales, Australia; Woolcock Institute of Medical Research, Sydney, New South Wales, Australia,
3 Pharmacology, University of Sydney, Sydnay, New South Wales, Australia; Woolcock Institute of Medical Research, Sydney, New South Wales, Australia,
4 Pharmacology, University of Sydney, Sydney, New South Wales, Australia,
5 Pathology, Univeristy of Sydney, Sydney, New South Wales, Australia,
6 Woolcock Institute of Medical Research, Sydney, New South Wales, Australia
* To whom correspondence should be addressed. E-mail: thomastrian{at}med.usyd.edu.au.
Rationale: Rhinovirus (RV) infections are the major cause of asthma exacerbations in both children and adults. Under normal circumstances, asthmatic airway obstruction improves either spontaneously or characteristically briskly in response to inhaled ß2-adrenergic receptor (ß2AR) agonists. However during virus associated exacerbations an impaired response to ß2AR agonists is observed and the reason for this is not known.
Objectives: To determine the effect of RV-infected epithelium on airway smooth muscle ß2AR function.
Methods: The human cell line BEAS-2B and primary human bronchial epithelial cells (HBEC) were infected with RV (multiplicity of infection = 1). After 1 or 5 days for primary and Beas-2B cells respectively, cell culture supernatants were harvested, UV-irradiated (to inactivate RV), and applied to human airway smooth muscle cells (HASMC) for 3 days to assess modifications of ß2AR function.
Main Results: RV conditioned medium from both BEAS-2B and HBEC decreased ß2AR agonist- induced cAMP by 50 % and 65% respectively ( n=5 p<0.05) When cAMP was induced independently of the ß2AR using forskolin, no impairment was found. Using flow cytometry we demonstrated that this decrease was likely the result of ß2AR desensitization as membrane but not total cell receptor ß2AR was decreased. Interestingly, pre-treatment of HBEC and Beas-2B but not HASMC with the corticosteroids dexamethasone or fluticasone abolished virus mediated ß2AR loss of function.
Conclusions: This study shows that epithelial infection with RV induces a decrease of ß2AR function on airway smooth muscle cells, potentially explaining the clinical observation of loss of ß2AR agonist function during RV-induced asthma exacerbations.
Key words: asthma •
beta2adrenergic receptor •
rhinovirus •
exacerbation
