title: Roflumilast n-oxide associated with PGE2 prevents the neutrophil elastase-induced production of chemokines by epithelial cells.
abstract: Neutrophil chemotaxis is involved in the lung inflammatory process in conditions such as chronic obstructive pulmonary disease (COPD). Neutrophil elastase (NE), one of the main proteases produced by neutrophils, has an important role in the inflammatory process via the release of chemokines from airway epithelial cells. It was recently shown that roflumilast N-oxide has therapeutic potential in COPD. The aim of the present study was to investigate roflumilast N-oxide's effect on NE-induced chemokine production and signaling pathways in A549 epithelial cells. A549 cells were incubated with NE for 30min, washed with PBS and then cultured for 2h (for measurement of mRNA expression) and 24h (for chemokine release) or for 5 to 30min (for protein phosphorylation assays). Prior to the addition of NE, cells were also pre-incubated with prostaglandin E2 (PGE2), alone and in combination with roflumilast N-oxide. Addition of NE was associated with elevated chemokine production by A549 cells and induction of the p38α pathway. In contrast when combined with PGE2, the roflumilast N-oxide had an additive effect on the inhibition of NE-induced chemokine release and p38α and other kinases activation. In conclusion, we demonstrated that NE is able to increase the release of chemokines from epithelial cells via the activation of p38α MAP-kinase and that roflumilast N-oxide when combined with PGE2 lowers NE-induced kinase activation and chemokine production.
authors.affiliation: UMR991 INSERM/Université de Rennes 1, Rennes, France; Laboratório de Reparo Tecidual, DHE/IBRAG/UERJ Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil. Electronic address: tatianavictoni@hotmail.com.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Victoni
authors.affiliation: UMR991 INSERM/Université de Rennes 1, Rennes, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gicquel
authors.affiliation: UMR991 INSERM/Université de Rennes 1, Rennes, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Bodin
authors.affiliation: UMR991 INSERM/Université de Rennes 1, Rennes, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Daude
authors.affiliation: Nycomed GmbH, Konstanz, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Tenor
authors.affiliation: Laboratório de Reparo Tecidual, DHE/IBRAG/UERJ Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil; Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Samuel
authors.initials: S
authors.lastname: Valença
authors.affiliation: Hôpital Foch, UPRES EA220, Université de Versailles Saint-Quentin-en-Yvelines, Suresnes, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Devillier
authors.affiliation: Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Luis Cristovão
authors.initials: LC
authors.lastname: Porto
authors.affiliation: UMR991 INSERM/Université de Rennes 1, Rennes, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Lagente
authors.affiliation: UMR991 INSERM/Université de Rennes 1, Rennes, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Boichot
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D003521:Cyclopropanes / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D004359:Drug Therapy, Combination; D004847:Epithelial Cells / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007111:Immunity, Cellular; D019272:Leukocyte Elastase / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009504:Neutrophils / Q000276:immunology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000276:immunology
chemical_list: D000631:Aminopyridines; D000893:Anti-Inflammatory Agents; D001549:Benzamides; D018925:Chemokines; D003521:Cyclopropanes; D019272:Leukocyte Elastase; C517734:roflumilast N-oxide; D015232:Dinoprostone
keywords: COPD; Chemokine; Neutrophil elastase; Roflumilast N-oxide