Phosphodiesterase 4 Inhibitors Augment the Ability of Formoterol to Enhance Glucocorticoid-Dependent Gene Transcription in Human Airway Epithelial Cells: A Novel Mechanism for the Clinical Efficacy of Roflumilast in Severe Chronic Obstructive Pulmonary Disease

Abstract

Post-hoc analysis of two phase III clinical studies found that the phosphodiesterase 4 (PDE4) inhibitor, roflumilast, reduced exacerbation frequency in patients with severe chronic obstructive pulmonary disease (COPD) who were taking inhaled corticosteroids (ICS) concomitantly, whereas patients not taking ICS derived no such benefit. In contrast, in two different trials also performed in patients with severe COPD, roflumilast reduced exacerbation rates in the absence of ICS, indicating that PDE4 inhibition alone is sufficient for therapeutic activity to be realized. Given that roflumilast is recommended as an "add-on" medication to patients with severe disease who will inevitably be taking a long-acting b 2 -adrenoceptor agonist (LABA)/ICS combination therapy, we tested the hypothesis that roflumilast augments the ability of glucocorticoids to induce genes with anti-inflammatory activity. Using a glucocorticoid response element (GRE) luciferase reporter transfected into human airway epithelial cells [both bronchial epithelium 1 adenovirus 12 -SV40 hybrid (BEAS-2B) cells and primary cultures], roflumilast enhanced fluticasone propionate-induced GRE-dependent transcription. Roflumilast also produced a sinistral displacement of the concentration-response curves that described the augmentation of GRE-dependent transcription by the LABA formoterol. In BEAS-2B cells and primary airway epithelia, roflumilast interacted with formoterol in a positive cooperative manner to enhance the expression of several glucocorticoid-inducible genes that have anti-inflammatory potential. We suggest that the ability of roflumilast and formoterol to interact in this way supports the concept that these drugs together may impart clinical benefit beyond that achievable by an ICS alone, a PDE4 inhibitor alone, or an ICS/LABA combination therapy. Roflumilast may, therefore, be especially effective in patients with severe COPD.

Anti‐inflammatory effects of the novel inhaled phosphodiesterase type 4 inhibitor CHF6001 on virus‐inducible cytokines

“…In support of this, Moodley et al. (2013) have shown that combined roflumilast and FP treatment enhanced GRE‐dependent reporter activity and several GRE responsive anti‐inflammatory genes. Further studies are required to investigate the potential mechanism responsible for steroid sparing effects of CHF6001.…”

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

“…Via a GRE-dependent molecular mechanism, roflumilast interacted with formoterol in a positive manner to enhance glucocorticoid-dependent transcription of anti-inflammatory genes, including as GILZ and RGS2 (36). Although the gene for MKP-1 (DUSP1) was not examined in the study, our data concur with those from the Giembycz group as they support the concept that "these drugs together may impart clinical benefit beyond that achievable by an ICS alone, a PDE4 inhibitor alone, or an ICS/LABA combination therapy" (36).…”

“…Via a GRE-dependent molecular mechanism, roflumilast interacted with formoterol in a positive manner to enhance glucocorticoid-dependent transcription of anti-inflammatory genes, including as GILZ and RGS2 (36). Although the gene for MKP-1 (DUSP1) was not examined in the study, our data concur with those from the Giembycz group as they support the concept that "these drugs together may impart clinical benefit beyond that achievable by an ICS alone, a PDE4 inhibitor alone, or an ICS/LABA combination therapy" (36). Although our in vitro experimental model of airway inflammation doesn't fully encapsulate the complexity of COPD, these studies, taken together, provide a molecular mechanism that may explain the benefits of adding roflumilast as an "addon" therapy in severe COPD, where patients are likely taking LABA and inhaled corticosteroids.…”

“…Additionally, Milara et al (35) found that in neutrophils from COPD patients, RNO in combination with dexamethasone had an additive/synergistic anti-inflammatory effect. Moodley et al (36) have used lung epithelial cells…”

Roles of roflumilast, a selective phosphodiesterase 4 inhibitor, in airway diseases

“…Adding roflumilast to indacaterol has shown an enhanced antifibrotic effect by inhibiting mediator release from fibroblasts and myofibroblasts. Activation of PKA is the mechanism underlying the additive effect between PDE4 inhibitor and long-acting beta-adrenoceptor agonists (LABAs) (33,34). However, the translation from a scientific basis to a clinical meaning is yet to be proven.…”