Roflumilast improves corticosteroid resistance COPD bronchial epithelial cells stimulated with toll like receptor 3 agonist

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.

Roflumilast N-Oxide in Combination with Formoterol Enhances the Antiinflammatory Effect of Dexamethasone in Airway Smooth Muscle Cells

“…Milara et al (34,35) have demonstrated the influence of RNO in improving the effect of corticosteroids. In bronchial epithelial cells from patients with COPD, RNO, when combined with dexamethasone, increased the expression of MKP-1 and enhanced the inhibitory effects on phospho-p38 MAPK and activity of transcription factors AP-1 and NF-κB (35). Additionally, Milara et al (35) found that in neutrophils from COPD patients, RNO in combination with dexamethasone had an additive/synergistic anti-inflammatory effect.…”

<p>Glucocorticoid Receptor α Mediates Roflumilast’s Ability to Restore Dexamethasone Sensitivity in COPD</p>

“…Furthermore, we found that Rofl stimulates GRα mRNA synthesis and thereby augments Dex's antiinflammatory effects. These findings show that increased GRα expression can reverse glucocorticoid resistance and also clearly reveal a new mechanistic basis of Rofl's therapeutic actions in COPD, 15,16,27 as GRα knockdown blocked the cytokine-inhibitory action of Rofl combined with Dex.…”

Interleukin-1α induced release of interleukin-8 by human bronchial epithelial cellsin vitro: assessing mechanisms and possible treatment options

“…Roflumilast, an anti‐inflammatory drug, has in preclinical models been shown to a broad spectrum of inflammatory cytokines and reactive oxygen species . Low‐dose roflumilast (1 n m and 1 μ m ) reduced the release of IL‐8 in alveolar type II cells .…”