title: Interleukin-1α induced release of interleukin-8 by human bronchial epithelial cells in vitro: assessing mechanisms and possible treatment options.
abstract: Survival after lung transplantation is hampered by chronic lung allograft dysfunction (CLAD). Persistently elevated BAL-neutrophilia is observed in some patients despite treatment with azithromycin, which may be induced by IL-1α. Our aim is to establish an in vitro model, assess mechanistic pathways and test different therapeutic strategies of IL-1α-induced release of IL-8 by human bronchial epithelial cells. Bronchial epithelial cells (16HBE) were stimulated with IL-1α with or without azithromycin or dexamethasone. IL-8 protein was analyzed in cell supernatant. Different MAP kinases (p38, JNK, ERK1/2, Iκβ) and targets known to be involved in tumor formation (PI3K, Akt) were investigated. Finally, different treatment options were tested for their potential inhibitory effect. IL-1α induced IL-8 in bronchial epithelial cells, which was dose-dependently inhibited by dexamethasone but not by azithromycin. IL-1α induced p38 and Akt phosphorylation, but activation of these MAPK was not inhibited by dexamethasone. JNK, ERK1/2, Iκβ and PI3K were not activated. None of the tested drugs reduced the IL-1α induced IL-8 production. We established an in vitro model wherein steroids inhibit the IL-1α-induced IL-8 production, while azithromycin was ineffective. Despite using this simple in vitro model, we could not identify a new treatment option for azithromycin-resistant airway neutrophilia.
authors.affiliation: Lung Transplant Unit, Department of Clinical and Experimental Medicine, Division of Respiratory Disease, KU Leuven, Leuven, Belgium.
authors.forename: Hannelore
authors.initials: H
authors.lastname: Bellon
authors.affiliation: Lung Transplant Unit, Department of Clinical and Experimental Medicine, Division of Respiratory Disease, KU Leuven, Leuven, Belgium.
authors.forename: Elly
authors.initials: E
authors.lastname: Vandermeulen
authors.affiliation: Lung Transplant Unit, Department of Clinical and Experimental Medicine, Division of Respiratory Disease, KU Leuven, Leuven, Belgium.
authors.forename: Carolien
authors.initials: C
authors.lastname: Mathyssen
authors.affiliation: Lung Transplant Unit, Department of Clinical and Experimental Medicine, Division of Respiratory Disease, KU Leuven, Leuven, Belgium.
authors.forename: Annelore
authors.initials: A
authors.lastname: Sacreas
authors.affiliation: Lung Transplant Unit, Department of Clinical and Experimental Medicine, Division of Respiratory Disease, KU Leuven, Leuven, Belgium.
authors.forename: Stijn E
authors.initials: SE
authors.lastname: Verleden
authors.affiliation: Lung Transplant Unit, Department of Clinical and Experimental Medicine, Division of Respiratory Disease, KU Leuven, Leuven, Belgium.
authors.forename: Tobias
authors.initials: T
authors.lastname: Heigl
authors.affiliation: Environment and Health, KU Leuven, Leuven, Belgium.
authors.forename: Hanne
authors.initials: H
authors.lastname: Vriens
authors.affiliation: Lung Transplant Unit, Department of Clinical and Experimental Medicine, Division of Respiratory Disease, KU Leuven, Leuven, Belgium.
authors.forename: Elise
authors.initials: E
authors.lastname: Lammertyn
authors.affiliation: Institute of Experimental & Clinical Research - Pole of Pneumology, ENT and Dermatology, Université Catholique de Louvain (UCL), Brussels, Belgium.
authors.forename: Charles
authors.initials: C
authors.lastname: Pilette
authors.affiliation: Environment and Health, KU Leuven, Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Hoet
authors.affiliation: Lung Transplant Unit, Department of Clinical and Experimental Medicine, Division of Respiratory Disease, KU Leuven, Leuven, Belgium.
authors.forename: Robin
authors.identifier: http://orcid.org/0000-0002-3468-9251
authors.initials: R
authors.lastname: Vos
authors.affiliation: Lung Transplant Unit, Department of Clinical and Experimental Medicine, Division of Respiratory Disease, KU Leuven, Leuven, Belgium.
authors.forename: Bart M
authors.initials: BM
authors.lastname: Vanaudenaerde
authors.affiliation: Lung Transplant Unit, Department of Clinical and Experimental Medicine, Division of Respiratory Disease, KU Leuven, Leuven, Belgium.
authors.forename: Geert M
authors.initials: GM
authors.lastname: Verleden
mesh_terms: D000085:Acetates / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology; D000631:Aminopyridines; D000890:Anti-Infective Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017963:Azithromycin / Q000737:chemistry; D001549:Benzamides; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D003521:Cyclopropanes; D003622:Dapsone / Q000494:pharmacology; D003907:Dexamethasone / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000378:metabolism*; D024841:Fluoroquinolones / Q000494:pharmacology; D006801:Humans; D053582:Interleukin-1alpha / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D000077266:Moxifloxacin; D009504:Neutrophils / Q000378:metabolism; D010766:Phosphorylation; D011728:Pyridones / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D013440:Sulfides; D013806:Theophylline / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D000085:Acetates; D000631:Aminopyridines; D000890:Anti-Infective Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001549:Benzamides; C508606:CXCL8 protein, human; D003521:Cyclopropanes; D024841:Fluoroquinolones; C508584:IL1A protein, human; D053582:Interleukin-1alpha; D016209:Interleukin-8; D011728:Pyridones; D011804:Quinolines; D013440:Sulfides; C424423:Roflumilast; D003907:Dexamethasone; D017963:Azithromycin; D003622:Dapsone; D013806:Theophylline; C093844:pirfenidone; C093875:montelukast; D000077266:Moxifloxacin; D000111:Acetylcysteine
keywords: immunosuppression; lung transplantation; rejection