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Roflumilast inhibits lipopolysaccharide-induced tumor necrosis factor-α and chemokine production by human lung parenchyma.
PLoS One 2013; 8(9):e74640Plos

Abstract

BACKGROUND

Roflumilast is the first phosphodiesterase-4 (PDE4) inhibitor to have been approved for the treatment of COPD. The anti-inflammatory profile of PDE4 inhibitors has not yet been explored in human lung tissues. We investigated the effects of roflumilast and its active metabolite roflumilast-N-oxide on the lipopolysaccharide (LPS)-induced release of tumor necrosis factor-alpha (TNF-α) and chemokines by human lung parenchymal explants. We also investigated roflumilast's interaction with the long-acting β2-agonist formoterol.

METHODS

Explants from 25 patients undergoing surgical lung resection were incubated with Roflumilast, Roflumilast-N-oxide and formoterol and stimulated with LPS. Levels of TNF-α, chemokines (in the culture supernatants) and cyclic adenosine monophosphate (in tissue homogenates) were determined with appropriate immunoassays.

RESULTS

Roflumilast and Roflumilast-N-oxide concentration-dependently reduced the release of TNF-α and chemokines CCL2, CCL3, CCL4, CXCL9 and CXCL10 from LPS-stimulated human lung explants, whereas CXCL1, CXCL5 and CXCL8 release was not altered. Formoterol (10 nM) partially decreased the release of the same cytokines and significantly increased the inhibitory effect of roflumilast on the release of the cytokines.

CONCLUSIONS

In human lung parenchymal explants, roflumilast and roflumilast-N-oxide reduced the LPS-induced release of TNF-α and chemokines involved in the recruitment of monocytes and T-cells but not those involved in the recruitment of neutrophils. Addition of formoterol to roflumilast provided superior in vitro anti-inflammatory activity, which may translate into greater efficacy in COPD.

Authors+Show Affiliations

Laboratory of Pulmonary Pharmacology UPRES EA220, University of Versailles Saint-Quentin en Yvelines, Suresnes, France.No 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

24066150

Citation

Buenestado, Amparo, et al. "Roflumilast Inhibits Lipopolysaccharide-induced Tumor Necrosis Factor-α and Chemokine Production By Human Lung Parenchyma." PloS One, vol. 8, no. 9, 2013, pp. e74640.
Buenestado A, Chaumais MC, Grassin-Delyle S, et al. Roflumilast inhibits lipopolysaccharide-induced tumor necrosis factor-α and chemokine production by human lung parenchyma. PLoS ONE. 2013;8(9):e74640.
Buenestado, A., Chaumais, M. C., Grassin-Delyle, S., Risse, P. A., Naline, E., Longchampt, E., ... Devillier, P. (2013). Roflumilast inhibits lipopolysaccharide-induced tumor necrosis factor-α and chemokine production by human lung parenchyma. PloS One, 8(9), pp. e74640. doi:10.1371/journal.pone.0074640.
Buenestado A, et al. Roflumilast Inhibits Lipopolysaccharide-induced Tumor Necrosis Factor-α and Chemokine Production By Human Lung Parenchyma. PLoS ONE. 2013;8(9):e74640. PubMed PMID: 24066150.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Roflumilast inhibits lipopolysaccharide-induced tumor necrosis factor-α and chemokine production by human lung parenchyma. AU - Buenestado,Amparo, AU - Chaumais,Marie-Camille, AU - Grassin-Delyle,Stanislas, AU - Risse,Paul-André, AU - Naline,Emmanuel, AU - Longchampt,Elisabeth, AU - Tenor,Hermann, AU - Devillier,Philippe, Y1 - 2013/09/16/ PY - 2013/04/04/received PY - 2013/08/05/accepted PY - 2013/9/26/entrez PY - 2013/9/26/pubmed PY - 2014/5/27/medline SP - e74640 EP - e74640 JF - PloS one JO - PLoS ONE VL - 8 IS - 9 N2 - BACKGROUND: Roflumilast is the first phosphodiesterase-4 (PDE4) inhibitor to have been approved for the treatment of COPD. The anti-inflammatory profile of PDE4 inhibitors has not yet been explored in human lung tissues. We investigated the effects of roflumilast and its active metabolite roflumilast-N-oxide on the lipopolysaccharide (LPS)-induced release of tumor necrosis factor-alpha (TNF-α) and chemokines by human lung parenchymal explants. We also investigated roflumilast's interaction with the long-acting β2-agonist formoterol. METHODS: Explants from 25 patients undergoing surgical lung resection were incubated with Roflumilast, Roflumilast-N-oxide and formoterol and stimulated with LPS. Levels of TNF-α, chemokines (in the culture supernatants) and cyclic adenosine monophosphate (in tissue homogenates) were determined with appropriate immunoassays. RESULTS: Roflumilast and Roflumilast-N-oxide concentration-dependently reduced the release of TNF-α and chemokines CCL2, CCL3, CCL4, CXCL9 and CXCL10 from LPS-stimulated human lung explants, whereas CXCL1, CXCL5 and CXCL8 release was not altered. Formoterol (10 nM) partially decreased the release of the same cytokines and significantly increased the inhibitory effect of roflumilast on the release of the cytokines. CONCLUSIONS: In human lung parenchymal explants, roflumilast and roflumilast-N-oxide reduced the LPS-induced release of TNF-α and chemokines involved in the recruitment of monocytes and T-cells but not those involved in the recruitment of neutrophils. Addition of formoterol to roflumilast provided superior in vitro anti-inflammatory activity, which may translate into greater efficacy in COPD. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/24066150/Roflumilast_inhibits_lipopolysaccharide_induced_tumor_necrosis_factor_α_and_chemokine_production_by_human_lung_parenchyma_ L2 - http://dx.plos.org/10.1371/journal.pone.0074640 DB - PRIME DP - Unbound Medicine ER -