Ensifentrine inhibits lipopolysaccharide-induced production of cytokines by human lung macrophages: a comparison with roflumilast, and an interaction with adenosine.

BACKGROUND AND PURPOSE: The dual phosphodiesterase (PDE) 3/4 inhibitor ensifentrine was recently approved for the maintenance treatment of chronic obstructive pulmonary disease in adults. Ensifentrine anti-inflammatory effects have not been studied in human lung macrophages (LMs), which are critically involved in respiratory disease. The main objectives of the present study were to compare the inhibitory effects of ensifentrine, the PDE4 inhibitor roflumilast, and the non-selective PDE inhibitor theophylline on the lipopolysaccharide (LPS)-induced production of cytokines by LMs and to assess interactions with the adenosine analogue 5´-N-ethyl-carboxamidoadenosine (NECA).

EXPERIMENTAL APPROACH: LMs isolated from resected human lungs were incubated with a range of concentrations of ensifentrine, roflumilast, theophylline, NECA, and formoterol, and stimulated with LPS for 24 h. The levels of tumour necrosis factor-alpha (TNF-α), CCL2, CCL3, and CCL4 in the culture supernatants were measured using ELISAs.

KEY

RESULTS

Ensifentrine reduced the LPS-stimulated production of TNF-α by LMs in a concentration-dependent manner, with a 100-fold lower potency but a 20-30% higher efficacy than roflumilast. Theophylline and formoterol were essentially inactive. The relative reductions in the LPS-induced production of TNF-α and the three CCL chemokines associated with treatment with the two selective inhibitors was further accentuated by NECA and resulted in similar levels of cytokine production inhibition (between 65% and 95%) with the two PDE inhibitors.

CONCLUSION

Clinically relevant concentrations of ensifentrine and roflumilast partially inhibited the LPS-induced production of cytokines by LMs - cytokine production that might be enhanced during inflammatory flare-ups of respiratory diseases.