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

Depts of ¹ Airways Disease and ³ Histopathology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, ² Novartis Institutes for BioMedical Research, Horsham, and ⁴ Chest Clinic, King Edward King VII Hospital, Windsor, UK.

CORRESPONDENCE: L. E. Donnelly, Airways Disease, National Heart and Lung Institute, Dovehouse St, London, SW3 6LY, UK. Fax: 44 2073518126. E-mail: l.donnelly{at}imperial.ac.uk

Keywords: Ca²⁺ transients, leukotriene B₄, macrophage

Received: August 22, 2008
Accepted December 5, 2008

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)B₄ and is released by macrophages. The present study examines the role and mechanism of Ca²⁺ in platelet-activating factor (PAF)-stimulated LTB₄ 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 LTB₄ release and [Ca²⁺]_i was measured.

Lung macrophages and MDM released LTB₄ 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 LTB₄. Neither smoking nor COPD altered MDM responses. PAF-stimulated LTB₄ release was abrogated by ethylene glycol tetraacetic acid suggesting a role for extracellular Ca²⁺. This was substantiated by using store-operated channel blockers econazole, SK&F96365 and Gd³⁺. 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 B₄ release from human lung macrophages is mediated, in part, by Ca²⁺ influx through receptor- but not voltage-operated Ca²⁺ channels.