Long-acting bronchodilators improve lipopolysaccharide-induced swine airway hypersecretion as well as the abnormal acidification in pH

Abstract

Recent clinical studies reveal that long-acting bronchodilators (LABDs) alone or in combination provide great reductions in the frequency of COPD exacerbations. Although the mechanisms potentially responsible for these reductions seem to include a significant increase in lung function and improvements in lung hyperinflation, the limited data available from freshly isolated airways have not indicated significant anti-inflammatory effects of LABDs. Here, we investigated the amount of airway secretions from swine tracheal submucosal glands (SMGs) and the pH, using an optical method and a selective pH indicator, SNARF-1. ACh (100nM) caused a gradual increase in the amount of airway secretions (19.1 nl/25mm² at 180sec). Lipopolysaccharides (LPS) further increased ACh-induced secretion 3-fold (7.5 ± 3.3 nl/25mm² for ACh vs. 23.8 ± 4.8 for ACh/LPS) and the pH value of the secretion changed from 6.88±0.08 to 6.68±0.08(ΔpH=-0.20, p=0.005). Indacaterol (IND) attenuated the LPS-induced hypersecretion to one-seventh, and improved the LPS-induced abnormal acidification in the ASL pH (6.66±0.08 for ACh/LPS vs. 6.99±0.09 for ACh/LPS/IND, ΔpH=0.33, p<0.0001). The IND-induced improvement in the abnormal acidification in pH was abolished by CFTR inhibitors. Formoterol and salmeterol also showed almost the same effect on airway secretion. These findings suggest that the improvement in the LPS-induced dysfunction of cAMP-dependent HCO₃^- secretion through CFTR is likely to contribute to reducing the frequency of exacerbations in COPD.