β2-agonists induce and augment rhinovirus-induction of pro-inflammatory mediators in bronchial epithelial cells.

<bold>Rationale:</bold> Salmeterol and formoterol induce pro-inflammatory mediators in bronchial epithelial cells (BECs). We investigated whether other β2-agonists or muscarinic antagonists, exhibit similar effects. <bold>Methods:</bold> BEAS-2B BECs were stimulated with vehicle control or 0.1-100nM of short-acting or long-acting β2-agonists (LABAs), ultra-LABAs and short or long-acting muscarinic antagonists; +/- rhinovirus(RV)-A16 infection to mimic use during exacerbations; +/- 10nM fluticasone propionate (furoate with vilanterol). IL-6, IL-11 and brain-derived neurotrophic factor (BDNF) release were quantified by ELISA. <bold>Results:</bold> IL-6 and IL-11 were induced 2-4-fold by all β2-agonists in a dose- and time-dependent manner (all p<0.05). LABAs also induced BDNF (1.6-1.85-fold, P<0.05). Salbutamol mostly induced at 100nM; LABAs induced at concentrations as low as 0.1nM. Salbutamol (100nM) significantly augmented RV-induction of all three mediators by 1.4-1.7-fold and LABAs (10nM) by 1.6-3-fold (P<0.05). Induction potency was salbutamol<fenoterol<formoterol=salmeterol<indacaterol=olodaterol=vilanterol. Adding fluticasone to β2-agonist alone abolished induction of all three mediators and to β2-agonist/RV, suppressed by 72-100% (P<0.05). Ipratropium, tiotropium, aclidinium and umeclidinium did not induce any mediator (all P>0.05). <bold>Conclusion:</bold> β2-agonists, but not muscarinic antagonists, upregulate BEC production of asthma-relevant pro-inflammatory mediators with/without RV. ICS co-administration abolished these pro-inflammatory effects. This may explain the adverse effects associated with β2-agonist use without ICS. In vivo studies need to determine the clinical significance of these findings.