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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Grassin-delyle, S. Naline, E. Bellamy, J. F. Faisy, C. Guitard, F. Israël-biet, D. Tenor, H. Devillier, P. Sage, E. Buenestado, A. |
| Description | Author Affiliation: Buenestado A ( Laboratory of Pulmonary Pharmacology UPRES EA220, Foch Hospital, University Versailles Saint-Quentin, Suresnes, France.) |
| Abstract | BACKGROUND AND PURPOSE: Lung macrophages are critically involved in respiratory diseases. This study assessed the effects of the PDE4 inhibitor roflumilast and its active metabolite, roflumilast N-oxide on the release of a range of chemokines (CCL2, 3, 4, CXCL1, 8, 10) and of TNF- , from human lung macrophages, stimulated with bacterial lipopolysaccharide LPS. EXPERIMENTAL APPROACH: Lung macrophages isolated from resected human lungs were incubated with roflumilast, roflumilast N-oxide, PGE(2), the COX inhibitor indomethacin, the COX-2 inhibitor NS-398 or vehicle and stimulated with LPS (24 h). Chemokines, TNF- , PGE(2) and 6-keto PGF(1 ) were measured in culture supernatants by immunoassay. COX-2 mRNA expression was assessed with RT-qPCR. PDE activities were determined in macrophage homogenates. KEY RESULTS: Expression of PDE4 in lung macrophages was increased after incubation with LPS. Roflumilast and roflumilast N-oxide concentration-dependently reduced the LPS-stimulated release of CCL2, CCL3, CCL4, CXCL10 and TNF- from human lung macrophages, whereas that of CXCL1 or CXCL8 was not altered. This reduction by the PDE4 inhibitors was further accentuated by exogenous PGE(2) (10 nM) but abolished in the presence of indomethacin or NS-398. Conversely, addition of PGE(2) (10 nM), in the presence of indomethacin restored inhibition by roflumilast. LPS also increased PGE(2) and 6-keto PGF(1 ) release from lung macrophages which was associated with an up-regulation of COX-2 mRNA. CONCLUSIONS AND IMPLICATIONS: Roflumilast and roflumilast N-oxide reduced LPS-induced release of CCL2, 3, 4, CXCL10 and TNF- in human lung macrophages. |
| ISSN | 00071188 |
| e-ISSN | 14765381 |
| Journal | British Journal of Pharmacology |
| Issue Number | 6 |
| Volume Number | 165 |
| Language | English |
| Publisher | Wiley Online Library(on behalf of The British Pharmacological Society) |
| Publisher Date | 2012-03-01 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | Open |
| Subject Keyword | Aminopyridines Pharmacology Benzamides Chemokines Antagonists & Inhibitors Phosphodiesterase 4 Inhibitors Tumor Necrosis Factor-alpha Cells, Cultured Metabolism Cyclopropanes Dinoprostone Epoprostenol Lipopolysaccharides Macrophages, Alveolar Drug Effects Phosphoric Diester Hydrolases Research Support, Non-U.S. Gov't |
| Content Type | Text |
| Resource Type | Article |
| Subject | Pharmacology |
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