Leukotriene B4 release by human lung macrophages via receptor- not voltage-operated Ca2+ channels

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 μM (n = 5) versus 0.17±0.12 μM (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.