Abstract
BackgroundChronic obstructive pulmonary disease (COPD) is characterised by chronic pulmonary inflammation punctuated by periods of viral exacerbations. Recent evidence suggests that the combination of roflumilast with corticosteroids may improve the compromised anti-inflammatory properties of corticosteroids in COPD. We analyzed differential and combination anti-inflammatory effects of dexamethasone and roflumilast N-oxide in human bronchial epithelial cells (HBECs) stimulated with viral toll like receptor (TLR) agonists.MethodsLung tissue and HBECs were isolated from healthy (n = 15), smokers (n = 12) and smokers with COPD (15). TLR3 expression was measured in lung tissue and in HBECs. IL-8 secretion was measured in cell cultures after TLR3 stimulation with poly I:C 10 μg/mL.ResultsWe found that TLR3 expression was increased by 1.95 fold (protein) and 2.5 fold (mRNA) in lung tissues from smokers with COPD and inversely correlated with lung function. The TLR3 agonist poly I:C 10 μg/mL increased the IL-8 release in HBECs that was poorly inhibited by dexamethasone in smokers (24.5%) and smokers with COPD (21.6%). In contrast, roflumilast showed similar inhibitory effects on IL-8 release in healthy (58.8%), smokers (56.6%) and smokers with COPD (50.5%). The combination of roflumilast N-oxide and dexamethasone showed additive inhibitory effects. Mechanistically, roflumilast N-oxide when combined with dexamethasone increased the expression of MKP1, and enhanced the inhibitory effects on phospho-p38, AP1 and NFκB activities which may explain the additive anti-inflammatory effects.ConclusionsAltogether, our data provide in vitro evidence for a possible clinical utility to add roflumilast on top of inhaled corticosteroid in COPD.
Highlights
Chronic obstructive pulmonary disease (COPD) is characterised by chronic pulmonary inflammation punctuated by periods of viral exacerbations
toll like receptor 3 (TLR3) immunostaining was significantly elevated in alveolar macrophages and bronchial epithelial cells from smokers and smokers with COPD compared with non-smokers (Figure 1D, E, and F)
While TLR8 showed a marked expression in all lung structures of non-smokers, the immunohistochemical staining of TLR8 showed a weak distribution in alveolar macrophages and bronchial epithelial cells from smokers and smokers with COPD (Figure 3C, D, and E)
Summary
Chronic obstructive pulmonary disease (COPD) is characterised by chronic pulmonary inflammation punctuated by periods of viral exacerbations. Recent evidence suggests that the combination of roflumilast with corticosteroids may improve the compromised anti-inflammatory properties of corticosteroids in COPD. Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow obstruction, inflammation, and a progressive decline in lung function [1]. In contrast to other inflammatory diseases, corticosteroids are less effective in improving lung function and have little or no effect on controlling the underlying chronic inflammation in COPD patients [2]. The poor anti-inflammatory properties of corticosteroids in COPD have increased the development of other anti-inflammatory drugs. This is the case of roflumilast, the first phosphodiesterase–4 (PDE4) inhibitor
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