Am. J. Respir. Crit. Care Med., Volume 160, Number 6, December 1999, 2079-2085

Reversal of Human Neutrophil Survival by Leukotriene B₄ Receptor Blockade and 5-Lipoxygenase and 5-Lipoxygenase Activating Protein Inhibitors

ELAINE LEE, TRISHA LINDO, NICHOLAS JACKSON, LEE MENG-CHOONG, PAULA REYNOLDS, ANTHONY HILL, MALCOLM HASWELL, STEPHEN JACKSON, and STEPHEN KILFEATHER

Institute of Cardiovascular and Respiratory Pharmaceutical Development, School of Sciences, University of Sunderland, Sunderland; and Clinical Age Research Unit, Department of Health Care of the Elderly, King's College School of Medicine and Dentistry, London, United Kingdom

Persistent neutrophilia is a feature of chronic obstructive pulmonary disease (COPD). Leukotriene synthesis inhibitors and cysteinyl leukotriene receptor antagonists have shown efficacy in the treatment of asthma. Antagonism of leukotriene (LT)B₄ receptors is being considered as a mode of treating COPD. We examined the capacity for inhibition of leukotriene synthesis and LTB₄ receptor antagonism to reduce survival of neutrophils from patients with COPD and those from normal subjects. The basal apoptosis level of these cells was 55.4 ± 2.4% (mean ± SEM) of total cells. Separate exposure to lipopolysaccharide (LPS), granulocyte-macrophage colony-stimulating factor (GM-CSF), dexamethasone (DEX), and LTB₄ increased neutrophil survival (p < 0.001). The LTB₄ receptor antagonist SB201146 abolished LPS-induced survival in a concentration-dependent manner (10 pmol to 0.1 µM), with an IC₅₀ of 1.9 nM. Combined exposure to SB201146 and to the cysteinyl leukotriene antagonist SKF104353 did not have a greater effect on survival than did exposure to SB201146 alone. Inhibition of 5-lipoxygenase (5-LO) with BWA4C and of 5-LO-activating protein (FLAP) with MK886 abolished GM-CSF- and DEX-induced neutrophil survival. BWA4C and MK886 abolished GM-CSF- induced neotrophil survival in a concentration-dependent manner (1 nM to 10 µM), with IC₅₀ values of 182.0 nM and 63.1 nM, respectively. These findings demonstrate reversal of LPS-, GM-CSF-, and DEX-induced neutrophil survival by LTB₄ receptor antagonism and inhibitors of 5-LO and FLAP. They also suggest a potential additional antiinflammatory mode of action of these compounds through reduction of cell survival. Lee E, Lindo T, Jackson N, Meng-Choong L, Reynolds P, Hill A, Haswell M, Jackson S, Kilfeather S. Reversal of human neutrophil survival by leukotriene B₄ receptor blockade and 5-lipoxygenase and 5-lipoxygenase activating protein inhibitors.

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