title: Leukotriene B4 release by human lung macrophages via receptor- not voltage-operated Ca2+ channels.
abstract: Increased numbers of macrophages and neutrophils in the lung is a key feature of chronic obstructive pulmonary disease (COPD). The major neutrophil chemotactic agent in the airways of COPD patients is leukotriene (LT)B(4) and is released by macrophages. The present study examines the role and mechanism of Ca(2+) in platelet-activating factor (PAF)-stimulated LTB(4) release from human lung macrophages. Macrophages were isolated from lung tissue of subjects undergoing lung resection surgery and monocyte-derived macrophages (MDM) were obtained from nonsmokers, smokers without obstruction and COPD patients. Cells were stimulated with PAF and LTB(4) release and [Ca(2+)](i) was measured. Lung macrophages and MDM released LTB(4) following stimulation with PAF (mean effective concentration: 0.08+/-0.06 microM (n = 5) versus 0.17+/-0.12 microM (n = 17), respectively). Compared with MDM, lung macrophages released approximately eight-fold more LTB(4). Neither smoking nor COPD altered MDM responses. PAF-stimulated LTB(4) release was abrogated by ethylene glycol tetraacetic acid suggesting a role for extracellular Ca(2+). This was substantiated by using store-operated channel blockers econazole, SK&F96365 and Gd(3+). However, econazole and SK&F96365 were more effective in MDM than lung macrophages. Neither LOE908 nor nifedipine could attenuate this response. These data suggest that platelet-activating factor-stimulated leukotriene B(4) release from human lung macrophages is mediated, in part, by Ca(2+) influx through receptor- but not voltage-operated Ca(2+) channels.
authors.affiliation: Department of Airways Disease, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK.
authors.forename: T K
authors.initials: TK
authors.lastname: Finney-Hayward
authors.forename: P
authors.initials: P
authors.lastname: Bahra
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.forename: C T
authors.initials: CT
authors.lastname: Poll
authors.forename: A G
authors.initials: AG
authors.lastname: Nicholson
authors.forename: R E K
authors.initials: RE
authors.lastname: Russell
authors.forename: P A
authors.initials: PA
authors.lastname: Ford
authors.forename: J
authors.initials: J
authors.lastname: Westwick
authors.forename: P S
authors.initials: PS
authors.lastname: Fenwick
authors.forename: P J
authors.initials: PJ
authors.lastname: Barnes
authors.forename: L E
authors.initials: LE
authors.lastname: Donnelly
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001681:Biological Assay / Q000379:methods; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D007975:Leukotriene B4 / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism* / Q000503:physiopathology; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*; D012907:Smoking / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D044169:Receptors, Calcium-Sensing; D007975:Leukotriene B4