Reversal of human neutrophil survival by leukotriene B(4) receptor blockade and 5-lipoxygenase and 5-lipoxygenase activating protein inhibitors.
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)B(4) receptors is being considered as a mode of treating COPD. We examined the capacity for inhibition of leukotriene synthesis and LTB(4) 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 LTB(4) increased neutrophil survival (p < 0. 001). The LTB(4) receptor antagonist SB201146 abolished LPS-induced survival in a concentration-dependent manner (10 pmol to 0.1 microM), with an IC(50) 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 microM), with IC(50) values of 182.0 nM and 63.1 nM, respectively. These findings demonstrate reversal of LPS-, GM-CSF-, and DEX-induced neutrophil survival by LTB(4) 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
E
Institute of Cardiovascular and Respiratory Pharmaceutical Development, School of Sciences, University of Sunderland, Sunderland, UK.
Lindo
T
T
Jackson
N
N
Meng-Choong
L
L
Reynolds
P
P
Hill
A
A
Haswell
M
M
Jackson
S
S
Kilfeather
S
S
D058927:5-Lipoxygenase-Activating Proteins; D000179:Acrylates / Q000494:pharmacology; D000328:Adult; D017209:Apoptosis / Q000187:drug effects*; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D044482:Benzeneacetamides; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002470:Cell Survival; D003907:Dexamethasone / Q000494:pharmacology; D003998:Dicarboxylic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors; D008173:Lung Diseases, Obstructive / Q000097:blood*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors*; D002722:Chlorobenzenes
D058927:5-Lipoxygenase-Activating Proteins; D000179:Acrylates; D001094:Arachidonate 5-Lipoxygenase; D044482:Benzeneacetamides; D002352:Carrier Proteins; D003907:Dexamethasone; D003998:Dicarboxylic Acids; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006877:Hydroxamic Acids; D007211:Indoles; D020024:Leukotriene Antagonists; D007975:Leukotriene B4; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D011725:Pyridines; D018102:Receptors, Leukotriene B4; C548592:ALOX5AP protein, human; C060893:MK-886; D002722:Chlorobenzenes; C056614:N-(3-phenoxycinnamyl)acetohydroxamic acid; C084128:SB 201146; C052393:pobilukast