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The modulatory effects of the PDE4 inhibitors CHF6001 and roflumilast in alveolar macrophages and lung tissue from COPD patients.
Cytokine 2019; 123:154739C

Abstract

BACKGROUND

We compared the anti-inflammatory effects of phosphodiesterase type 4 (PDE4) inhibitor roflumilast with CHF6001, a novel PDE4 inhibitor designed for inhaled administration, using human alveolar macrophages (AM) and lung tissue explants models.

METHODS

AM from 13 chronic obstructive pulmonary disease (COPD) patients and 10 smoking controls and lung tissue from 7 COPD patients were stimulated with LPS following preincubation with roflumilast (0.000001-10 µM), CHF6001 (0.000001-0.1 µM), or vehicle. After 24 h, supernatants were analysed for cytokines by ELISA. The effects of both compounds on the phosphorylation and cellular localisation of cAMP response element binding protein (CREB) were assessed by immunofluorescence and Western blot analysis. Extracted RNA was used for quantitative PCR analysis of PDE4 A, B and D mRNA.

RESULTS

PDE4 A, B and D expression were increased in alveolar macrophages and lung tissue of COPD patients compared to controls. Roflumilast and CHF6001 significantly reduced TNF-α production in AM and lung tissue. CHF6001 was more potent than roflumilast with lower EC50s of 0.02, 0.01 and 0.31 nM compared to 0.87, 0.47 and 10.8 nM in respective samples. PDE4 inhibition also inhibited secretion of the chemokines CCL2 and CCL4 from macrophages. Both compounds increased nuclear levels of phosphorylated CREB.

CONCLUSION

PDE4 inhibitors caused a robust anti-inflammatory effect on TNF-α production from COPD AM, with inhibition of selective chemokines also observed. CHF6001 caused more potent inhibition of TNF-α production from COPD AM and lung tissue compared to roflumilast.

Authors+Show Affiliations

University of Manchester, Manchester University Foundation Hospital Trust, Manchester M23 9LT, UK. Electronic address: simon.lea@manchester.ac.uk.University of Manchester, Manchester University Foundation Hospital Trust, Manchester M23 9LT, UK.University of Manchester, Manchester University Foundation Hospital Trust, Manchester M23 9LT, UK.University of Manchester, Manchester University Foundation Hospital Trust, Manchester M23 9LT, UK.University of Manchester, Manchester University Foundation Hospital Trust, Manchester M23 9LT, UK.Corporate Pre-Clinical R&D, CHIESI FARMACEUTICI S.p.A., Largo Belloli 11/A, 43122 Parma, Italy.Corporate Pre-Clinical R&D, CHIESI FARMACEUTICI S.p.A., Largo Belloli 11/A, 43122 Parma, Italy.Corporate Pre-Clinical R&D, CHIESI FARMACEUTICI S.p.A., Largo Belloli 11/A, 43122 Parma, Italy.University of Manchester, Manchester University Foundation Hospital Trust, Manchester M23 9LT, UK.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31319374

Citation

Lea, Simon, et al. "The Modulatory Effects of the PDE4 Inhibitors CHF6001 and Roflumilast in Alveolar Macrophages and Lung Tissue From COPD Patients." Cytokine, vol. 123, 2019, p. 154739.
Lea S, Metryka A, Li J, et al. The modulatory effects of the PDE4 inhibitors CHF6001 and roflumilast in alveolar macrophages and lung tissue from COPD patients. Cytokine. 2019;123:154739.
Lea, S., Metryka, A., Li, J., Higham, A., Bridgewood, C., Villetti, G., ... Singh, D. (2019). The modulatory effects of the PDE4 inhibitors CHF6001 and roflumilast in alveolar macrophages and lung tissue from COPD patients. Cytokine, 123, p. 154739. doi:10.1016/j.cyto.2019.154739.
Lea S, et al. The Modulatory Effects of the PDE4 Inhibitors CHF6001 and Roflumilast in Alveolar Macrophages and Lung Tissue From COPD Patients. Cytokine. 2019;123:154739. PubMed PMID: 31319374.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The modulatory effects of the PDE4 inhibitors CHF6001 and roflumilast in alveolar macrophages and lung tissue from COPD patients. AU - Lea,Simon, AU - Metryka,Alexandra, AU - Li,Jian, AU - Higham,Andrew, AU - Bridgewood,Charles, AU - Villetti,Gino, AU - Civelli,Maurizio, AU - Facchinetti,Fabrizio, AU - Singh,Dave, Y1 - 2019/07/15/ PY - 2019/7/19/pubmed PY - 2019/7/19/medline PY - 2019/7/19/entrez KW - Alveolar macrophages KW - COPD KW - PDE4 SP - 154739 EP - 154739 JF - Cytokine JO - Cytokine VL - 123 N2 - BACKGROUND: We compared the anti-inflammatory effects of phosphodiesterase type 4 (PDE4) inhibitor roflumilast with CHF6001, a novel PDE4 inhibitor designed for inhaled administration, using human alveolar macrophages (AM) and lung tissue explants models. METHODS: AM from 13 chronic obstructive pulmonary disease (COPD) patients and 10 smoking controls and lung tissue from 7 COPD patients were stimulated with LPS following preincubation with roflumilast (0.000001-10 µM), CHF6001 (0.000001-0.1 µM), or vehicle. After 24 h, supernatants were analysed for cytokines by ELISA. The effects of both compounds on the phosphorylation and cellular localisation of cAMP response element binding protein (CREB) were assessed by immunofluorescence and Western blot analysis. Extracted RNA was used for quantitative PCR analysis of PDE4 A, B and D mRNA. RESULTS: PDE4 A, B and D expression were increased in alveolar macrophages and lung tissue of COPD patients compared to controls. Roflumilast and CHF6001 significantly reduced TNF-α production in AM and lung tissue. CHF6001 was more potent than roflumilast with lower EC50s of 0.02, 0.01 and 0.31 nM compared to 0.87, 0.47 and 10.8 nM in respective samples. PDE4 inhibition also inhibited secretion of the chemokines CCL2 and CCL4 from macrophages. Both compounds increased nuclear levels of phosphorylated CREB. CONCLUSION: PDE4 inhibitors caused a robust anti-inflammatory effect on TNF-α production from COPD AM, with inhibition of selective chemokines also observed. CHF6001 caused more potent inhibition of TNF-α production from COPD AM and lung tissue compared to roflumilast. SN - 1096-0023 UR - https://www.unboundmedicine.com/medline/citation/31319374/The_modulatory_effects_of_the_PDE4_inhibitors_CHF6001_and_roflumilast_in_alveolar_macrophages_and_lung_tissue_from_COPD_patients L2 - https://linkinghub.elsevier.com/retrieve/pii/S1043-4666(19)30149-8 DB - PRIME DP - Unbound Medicine ER -