Roflumilast inhibits lipopolysaccharide-induced tumor necrosis factor-α and chemokine production by human lung parenchyma.

<h4>Background</h4>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 me...

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Autores principales:	Amparo Buenestado, Marie-Camille Chaumais, Stanislas Grassin-Delyle, Paul-André Risse, Emmanuel Naline, Elisabeth Longchampt, Hermann Tenor, Philippe Devillier
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/de9a65066ccf468bb4e118f196475e88
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spelling	oai:doaj.org-article:de9a65066ccf468bb4e118f196475e882021-11-18T08:55:03ZRoflumilast inhibits lipopolysaccharide-induced tumor necrosis factor-α and chemokine production by human lung parenchyma.1932-620310.1371/journal.pone.0074640https://doaj.org/article/de9a65066ccf468bb4e118f196475e882013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24066150/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.Amparo BuenestadoMarie-Camille ChaumaisStanislas Grassin-DelylePaul-André RisseEmmanuel NalineElisabeth LongchamptHermann TenorPhilippe DevillierPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 9, p e74640 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Amparo Buenestado Marie-Camille Chaumais Stanislas Grassin-Delyle Paul-André Risse Emmanuel Naline Elisabeth Longchampt Hermann Tenor Philippe Devillier Roflumilast inhibits lipopolysaccharide-induced tumor necrosis factor-α and chemokine production by human lung parenchyma.
description	<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.
format	article
author	Amparo Buenestado Marie-Camille Chaumais Stanislas Grassin-Delyle Paul-André Risse Emmanuel Naline Elisabeth Longchampt Hermann Tenor Philippe Devillier
author_facet	Amparo Buenestado Marie-Camille Chaumais Stanislas Grassin-Delyle Paul-André Risse Emmanuel Naline Elisabeth Longchampt Hermann Tenor Philippe Devillier
author_sort	Amparo Buenestado
title	Roflumilast inhibits lipopolysaccharide-induced tumor necrosis factor-α and chemokine production by human lung parenchyma.
title_short	Roflumilast inhibits lipopolysaccharide-induced tumor necrosis factor-α and chemokine production by human lung parenchyma.
title_full	Roflumilast inhibits lipopolysaccharide-induced tumor necrosis factor-α and chemokine production by human lung parenchyma.
title_fullStr	Roflumilast inhibits lipopolysaccharide-induced tumor necrosis factor-α and chemokine production by human lung parenchyma.
title_full_unstemmed	Roflumilast inhibits lipopolysaccharide-induced tumor necrosis factor-α and chemokine production by human lung parenchyma.
title_sort	roflumilast inhibits lipopolysaccharide-induced tumor necrosis factor-α and chemokine production by human lung parenchyma.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/de9a65066ccf468bb4e118f196475e88
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Roflumilast inhibits lipopolysaccharide-induced tumor necrosis factor-α and chemokine production by human lung parenchyma.

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