The modulatory effects of the PDE4 inhibitors CHF6001 and roflumilast in alveolar macrophages and lung tissue from COPD patients.
Adult
Aged
Aged, 80 and over
Aminopyridines
/ pharmacology
Benzamides
/ pharmacology
Chemokine CCL2
/ immunology
Chemokine CCL4
/ immunology
Cyclopropanes
/ pharmacology
Female
Humans
Macrophages, Alveolar
/ immunology
Male
Middle Aged
Phosphodiesterase 4 Inhibitors
/ pharmacology
Pulmonary Disease, Chronic Obstructive
/ drug therapy
Sulfonamides
/ pharmacology
Tumor Necrosis Factor-alpha
/ immunology
para-Aminobenzoates
/ pharmacology
Alveolar macrophages
COPD
PDE4
Journal
Cytokine
ISSN: 1096-0023
Titre abrégé: Cytokine
Pays: England
ID NLM: 9005353
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
pubmed:
19
7
2019
medline:
9
9
2020
entrez:
19
7
2019
Statut:
ppublish
Résumé
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. 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. 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 EC 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.
Sections du résumé
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 EC
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.
Identifiants
pubmed: 31319374
pii: S1043-4666(19)30149-8
doi: 10.1016/j.cyto.2019.154739
pii:
doi:
Substances chimiques
tanimilast
0
Aminopyridines
0
Benzamides
0
CCL2 protein, human
0
CCL4 protein, human
0
Chemokine CCL2
0
Chemokine CCL4
0
Cyclopropanes
0
Phosphodiesterase 4 Inhibitors
0
Sulfonamides
0
Tumor Necrosis Factor-alpha
0
para-Aminobenzoates
0
Roflumilast
0P6C6ZOP5U
Types de publication
Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
154739Informations de copyright
Copyright © 2019. Published by Elsevier Ltd.