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A phosphodiesterase 4 inhibitor, roflumilast N-oxide, inhibits human lung fibroblast functions in vitro.
Pulm Pharmacol Ther 2010; 23(4):283-91PP

Abstract

The PDE4 inhibitor roflumilast mitigates bleomycin-induced lung fibrotic remodeling in rodents. In the current study it was explored whether roflumilast N-oxide, the active metabolite of roflumilast influences functions of cultured lung fibroblasts. Cells of the human foetal lung fibroblast strain GM06114 were stimulated with TNF-alpha (5 ng ml(-1)) and cell surface ICAM-1 and eotaxin release were assessed. [methyl-(3)H] thymidine incorporation was measured following stimulation with bFGF (10 ng ml(-1)). alpha-Smooth muscle actin (protein), CTGF (mRNA) and fibronectin (mRNA) were determined secondary to TGFbeta1 (1 ng ml(-1)). In the presence of PGE(2) (1 nM), roflumilast N-oxide reduced TNF-alpha-induced ICAM-1 and eotaxin by about 70% and >90% with half-maximum inhibition at 0.9 nM and 0.5 nM, respectively. Roflumilast N-oxide also attenuated [methyl-(3)H] thymidine incorporation secondary to bFGF by about 75% with half-maximum inhibition at 0.7 nM when cells were co-incubated with IL-1beta (10 pg ml(-1)). In the presence of this cytokine roflumilast N-oxide (1 microM) diminished TGFbeta1-induced expression of alpha-smooth muscle actin and transcripts of CTGF and fibronectin. In addition, IL-1beta up-regulated PDE4 activity in the lung fibroblasts. Taken together, these findings indicate that roflumilast N-oxide directly targets human lung fibroblasts, which may at least partially explain the efficacy of roflumilast to mitigate a pulmonary fibrotic response in vivo.

Authors+Show Affiliations

Pulmonary Disease Unit, G Gaslini Institute, Largo G Gaslini 5, 16147 Genoa, Italy. federicasabatini@ospedale-gaslini.ge.itNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20226872

Citation

Sabatini, F, et al. "A Phosphodiesterase 4 Inhibitor, Roflumilast N-oxide, Inhibits Human Lung Fibroblast Functions in Vitro." Pulmonary Pharmacology & Therapeutics, vol. 23, no. 4, 2010, pp. 283-91.
Sabatini F, Petecchia L, Boero S, et al. A phosphodiesterase 4 inhibitor, roflumilast N-oxide, inhibits human lung fibroblast functions in vitro. Pulm Pharmacol Ther. 2010;23(4):283-91.
Sabatini, F., Petecchia, L., Boero, S., Silvestri, M., Klar, J., Tenor, H., ... Rossi, G. A. (2010). A phosphodiesterase 4 inhibitor, roflumilast N-oxide, inhibits human lung fibroblast functions in vitro. Pulmonary Pharmacology & Therapeutics, 23(4), pp. 283-91. doi:10.1016/j.pupt.2010.02.004.
Sabatini F, et al. A Phosphodiesterase 4 Inhibitor, Roflumilast N-oxide, Inhibits Human Lung Fibroblast Functions in Vitro. Pulm Pharmacol Ther. 2010;23(4):283-91. PubMed PMID: 20226872.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A phosphodiesterase 4 inhibitor, roflumilast N-oxide, inhibits human lung fibroblast functions in vitro. AU - Sabatini,F, AU - Petecchia,L, AU - Boero,S, AU - Silvestri,M, AU - Klar,J, AU - Tenor,H, AU - Beume,R, AU - Hatzelmann,A, AU - Rossi,G A, Y1 - 2010/03/11/ PY - 2009/07/28/received PY - 2010/01/27/revised PY - 2010/02/28/accepted PY - 2010/3/16/entrez PY - 2010/3/17/pubmed PY - 2010/9/14/medline SP - 283 EP - 91 JF - Pulmonary pharmacology & therapeutics JO - Pulm Pharmacol Ther VL - 23 IS - 4 N2 - The PDE4 inhibitor roflumilast mitigates bleomycin-induced lung fibrotic remodeling in rodents. In the current study it was explored whether roflumilast N-oxide, the active metabolite of roflumilast influences functions of cultured lung fibroblasts. Cells of the human foetal lung fibroblast strain GM06114 were stimulated with TNF-alpha (5 ng ml(-1)) and cell surface ICAM-1 and eotaxin release were assessed. [methyl-(3)H] thymidine incorporation was measured following stimulation with bFGF (10 ng ml(-1)). alpha-Smooth muscle actin (protein), CTGF (mRNA) and fibronectin (mRNA) were determined secondary to TGFbeta1 (1 ng ml(-1)). In the presence of PGE(2) (1 nM), roflumilast N-oxide reduced TNF-alpha-induced ICAM-1 and eotaxin by about 70% and >90% with half-maximum inhibition at 0.9 nM and 0.5 nM, respectively. Roflumilast N-oxide also attenuated [methyl-(3)H] thymidine incorporation secondary to bFGF by about 75% with half-maximum inhibition at 0.7 nM when cells were co-incubated with IL-1beta (10 pg ml(-1)). In the presence of this cytokine roflumilast N-oxide (1 microM) diminished TGFbeta1-induced expression of alpha-smooth muscle actin and transcripts of CTGF and fibronectin. In addition, IL-1beta up-regulated PDE4 activity in the lung fibroblasts. Taken together, these findings indicate that roflumilast N-oxide directly targets human lung fibroblasts, which may at least partially explain the efficacy of roflumilast to mitigate a pulmonary fibrotic response in vivo. SN - 1522-9629 UR - https://www.unboundmedicine.com/medline/citation/20226872/A_phosphodiesterase_4_inhibitor_roflumilast_N_oxide_inhibits_human_lung_fibroblast_functions_in_vitro_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1094-5539(10)00020-9 DB - PRIME DP - Unbound Medicine ER -