Roflumilast inhibits lipopolysaccharide-induced tumor necrosis factor-α and chemokine production by human lung parenchyma.

Abstract

BackgroundRoflumilast is the first phosphodiesterase-4 (PDE4) inhibitor to have been approved for the treatment of COPD. The anti-inflammatory profile of PDE4 inhibitors has not yet been explored in human lung tissues. We investigated the effects of roflumilast and its active metabolite roflumilast-N-oxide on the lipopolysaccharide (LPS)-induced release of tumor necrosis factor-alpha (TNF-α) and chemokines by human lung parenchymal explants. We also investigated roflumilast's interaction with the long-acting β2-agonist formoterol.MethodsExplants from 25 patients undergoing surgical lung resection were incubated with Roflumilast, Roflumilast-N-oxide and formoterol and stimulated with LPS. Levels of TNF-α, chemokines (in the culture supernatants) and cyclic adenosine monophosphate (in tissue homogenates) were determined with appropriate immunoassays.ResultsRoflumilast and Roflumilast-N-oxide concentration-dependently reduced the release of TNF-α and chemokines CCL2, CCL3, CCL4, CXCL9 and CXCL10 from LPS-stimulated human lung explants, whereas CXCL1, CXCL5 and CXCL8 release was not altered. Formoterol (10 nM) partially decreased the release of the same cytokines and significantly increased the inhibitory effect of roflumilast on the release of the cytokines.ConclusionsIn human lung parenchymal explants, roflumilast and roflumilast-N-oxide reduced the LPS-induced release of TNF-α and chemokines involved in the recruitment of monocytes and T-cells but not those involved in the recruitment of neutrophils. Addition of formoterol to roflumilast provided superior in vitro anti-inflammatory activity, which may translate into greater efficacy in COPD.