title: Endothelin receptor-antagonists suppress lipopolysaccharide-induced cytokine release from alveolar macrophages of non-smokers, smokers and COPD subjects.
abstract: Smoking-induced COPD is characterized by chronic airway inflammation, which becomes enhanced by bacterial infections resulting in accelerated disease progression called exacerbation. Alveolar macrophages (AM) release endothelin-1 (ET-1), IL-6, CCL-2 and MMP-9, all of which are linked to COPD pathogenesis and exacerbation. ET-1 signals via ETA- and ETB-receptors (ETAR, ETBR). This is blocked by endothelin receptor antagonists (ERAs), like bosentan, which targets both receptors, ETAR-selective ambrisentan and ETBR-specific BQ788. Therefore, ERAs could have anti-inflammatory potential, which might be useful in COPD and other inflammatory lung diseases. We hypothesized that ERAs suppress cytokine release from AM of smokers and COPD subjects induced by lipopolysaccharide (LPS), the most important immunogen of gram-negative bacteria. AM were isolated from the broncho-alveolar lavage (BAL) of n=29 subjects (11 non-smokers, 10 current smokers without COPD, 8 smokers with COPD), cultivated and stimulated with LPS in the presence or absence of ERAs. Cytokines were measured by ELISA. Endothelin receptor expression was investigated by RT-PCR and western blot. AM expressed ETAR and ETBR mRNA, but only ETBR protein was detected. LPS and ET-1 both induced IL-6, CCL-2 and MMP-9. LPS-induced IL-6 release was increased in COPD versus non-smokers and smokers. Bosentan, ambrisentan and BQ788 all partially reduced all cytokines without differences between cohorts. Specific ETBR inhibition was most effective. LPS induced ET-1, which was exclusively blocked by BQ788. In conclusion, LPS induces ET-1 release in AM, which in turn leads to CCL-2, IL-6 and MMP-9 expression rendering AM sensitive for ERAs. ERAs could have anti-inflammatory potential in smoking-induced COPD.
authors.affiliation: Department of Internal Medicine III for Pneumology, Allergology, Sleep- and Respiratory Medicine, University Hospital Bergmannsheil, Bochum, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Gerlach
authors.affiliation: Department of Internal Medicine III for Pneumology, Allergology, Sleep- and Respiratory Medicine, University Hospital Bergmannsheil, Bochum, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Köhler-Bachmann
authors.affiliation: Department of Internal Medicine III for Pneumology, Allergology, Sleep- and Respiratory Medicine, University Hospital Bergmannsheil, Bochum, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Jungck
authors.affiliation: Department of Internal Medicine III for Pneumology, Allergology, Sleep- and Respiratory Medicine, University Hospital Bergmannsheil, Bochum, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Körber
authors.affiliation: Department of Internal Medicine III for Pneumology, Allergology, Sleep- and Respiratory Medicine, University Hospital Bergmannsheil, Bochum, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Yanik
authors.affiliation: Department of Internal Medicine III for Pneumology, Allergology, Sleep- and Respiratory Medicine, University Hospital Bergmannsheil, Bochum, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Knoop
authors.affiliation: Department of Internal Medicine III for Pneumology, Allergology, Sleep- and Respiratory Medicine, University Hospital Bergmannsheil, Bochum, Germany.
authors.forename: Deborah
authors.initials: D
authors.lastname: Wehde
authors.affiliation: Department of Internal Medicine III for Pneumology, Allergology, Sleep- and Respiratory Medicine, University Hospital Bergmannsheil, Bochum, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Rheinländer
authors.affiliation: Department of Internal Medicine III for Pneumology, Allergology, Sleep- and Respiratory Medicine, University Hospital Bergmannsheil, Bochum, Germany.
authors.forename: Jörg W
authors.initials: JW
authors.lastname: Walther
authors.affiliation: Department of Internal Medicine III for Pneumology, Allergology, Sleep- and Respiratory Medicine, University Hospital Bergmannsheil, Bochum, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Kronsbein
authors.affiliation: Department of Internal Medicine III for Pneumology, Allergology, Sleep- and Respiratory Medicine, University Hospital Bergmannsheil, Bochum, Germany. Electronic address: juergen.knobloch@ruhr-uni-bochum.de.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Knobloch
authors.affiliation: Department of Internal Medicine III for Pneumology, Allergology, Sleep- and Respiratory Medicine, University Hospital Bergmannsheil, Bochum, Germany. Electronic address: andrea.koch@bergmannsheil.de.
authors.forename: Andrea
authors.initials: A
authors.lastname: Koch
mesh_terms: D000368:Aged; D000077300:Bosentan; D016207:Cytokines / Q000378:metabolism*; D065128:Endothelin Receptor Antagonists / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology / Q000378:metabolism*; D012907:Smoking / Q000276:immunology / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D016207:Cytokines; D065128:Endothelin Receptor Antagonists; D008070:Lipopolysaccharides; D013449:Sulfonamides; D000077300:Bosentan
keywords: Alveolar macrophages; COPD; Cytokines; Endothelin receptor antagonists; Endothelin-1