Clinical Relevance of the Anti-inflammatory Effects of Roflumilast on Human Bronchus: Potentiation by a Long-Acting Beta-2-Agonist

Abstract

Background: Roflumilast is an option for treating patients with severe COPD and frequent exacerbations despite optimal therapy with inhaled drugs. The present study focused on whether the phosphodiesterase (PDE) 4 inhibitor roflumilast and its active metabolite roflumilast N-oxide affect the release of tumor necrosis factor (TNF)-α and chemokines by lipopolysaccharide (LPS)-stimulated human bronchial explants. We also investigated the interactions between roflumilast, roflumilast N-oxide and the β2-agonist formoterol with regard to cytokine release by the bronchial preparations.Methods: Bronchial explants from resected lungs were incubated with roflumilast, roflumilast N-oxide and/or formoterol and then stimulated with LPS. An ELISA was used to measure levels of TNF-α and chemokines in the culture supernatants.Results: At a clinically relevant concentration (1 nM), roflumilast N-oxide and roflumilast consistently reduced the release of TNF-α, CCL2, CCL3, CCL4, CCL5 and CXCL9 (but not CXCL1, CXCL5, CXCL8 and IL-6) from human bronchial explants. Formoterol alone decreased the release of TNF-α, CCL2, and CCL3. The combination of formoterol with roflumilast (1 nM) was more potent than roflumilast alone for inhibiting the LPS-induced release of TNF-α, CCL2, CCL3, CCL4, and CXCL9 by the bronchial explants.Conclusions: At a clinically relevant concentration, roflumilast N-oxide and its parent compound, roflumilast, reduced the LPS-induced production of TNF-α and chemokines involved in monocyte and T-cell recruitment but did not alter the release of chemokines involved in neutrophil recruitment. The combination of formoterol with roflumilast enhanced the individual drugs’ anti-inflammatory effects.

Apremilast in Recalcitrant Cutaneous Dermatomyositis

“…To evaluate the association of apremilast with downstream JAK/STAT signaling, we evaluated changes in levels of activated (phosphorylated) STAT1 and STAT3 before and after therapy using immunohistochemistry. In addition, we evaluated changes in levels of CCL5, a known PDE-4 target and an inflammatory marker in DM . After therapy, phosphorylation of STAT1 decreased by a mean (SD) of 22.3% (28.3%) positive cells ( P = .09), with a mean (SD) H score decrease of 46.1 (54.9) ( P = .07) (Figure 4A-D).…”

“…In addition, we evaluated changes in levels of CCL5, a known PDE-4 target and an inflammatory marker in DM. 27,28 After therapy, phosphorylation of STAT1 decreased by a mean (SD) of 22.3% (28.3%) positive cells (P = .09), with a mean (SD) H score decrease of 46.1 (54.9) (P = .07) (Figure 4A-D). Similarly, pSTAT3 levels decreased by a mean (SD) of 13.4% (11.6%) positive cells (P = .03), with a mean (SD) H score decrease of 26.9 (22.9) (P = .02) (Figure 4E-H).…”

Pre-Clinical Assessment of Roflumilast Therapy in a Thoracic Model of Spinal Cord Injury

“…This immune response is associated with the expression of pro-inflammatory cytokines, fibrosis, oxidative damage and neurodegeneration, contributing to wound-healing failure [ 37 ]. The reduction in ameboid microglia/macrophages is probably due to a direct effect on inflammation by Rof since it has previously been demonstrated that Rof has an anti-inflammatory effect [ 48 , 49 ]. For instance, as seen in the lung, Rof consistently minimizes the release of TNF-α, CCL2, CCL3, CCL4, CCL5 and CXCL9 from human bronchial explants [ 49 ].…”

“…The reduction in ameboid microglia/macrophages is probably due to a direct effect on inflammation by Rof since it has previously been demonstrated that Rof has an anti-inflammatory effect [ 48 , 49 ]. For instance, as seen in the lung, Rof consistently minimizes the release of TNF-α, CCL2, CCL3, CCL4, CCL5 and CXCL9 from human bronchial explants [ 49 ]. The accumulation of microglia/macrophages in the lesion epicenter plays a significant role in the inflammatory response during secondary injury.…”