The influence of aspirin on release of eoxin C4, leukotriene C4 and 15-HETE, in eosinophilic granulocytes isolated from patients with asthma.
BACKGROUND
The effect of aspirin on the release of key arachidonic acid metabolites in activated eosinophils from subjects with aspirin-intolerant asthma (AIA) has not been investigated previously, despite the characteristic eosinophilia in AIA.


METHODS
Peripheral blood eosinophils were isolated from four groups of subjects: healthy volunteers (HV; n = 8), mild asthma (MA; n = 8), severe asthma (SA; n = 9) and AIA (n = 7). In the absence or presence of lysine-aspirin, eosinophils were stimulated with arachidonic acid or calcium ionophore to trigger the 15-lipoxygenase-1 (15-LO) and 5-lipoxygenase (5-LO) pathways, respectively. 15(S)-hydroxy-eicosatetraenoic acid (15-HETE) and eoxin C4 (EXC4) were measured as 15-LO products and leukotriene (LT)C4 as a product of the 5-LO pathway.


RESULTS
Activated eosinophils from patients with SA and AIA produced approximately five times more 15-HETE than eosinophils from HV or MA patients. In the presence of lysine-aspirin, eosinophils from AIA, MA and SA patients generated higher levels of 15-HETE than in the absence of lysine-aspirin. Furthermore, in the presence of lysine-aspirin, formation of EXC4 was also significantly increased in eosinophils from AIA patients, and LTC4 synthesis was increased both in AIA and SA patients.


CONCLUSIONS
Taken together, this study shows an increased release of the recently discovered lipid mediator EXC4, as well as the main indicator of 15-LO activity, 15-HETE, in activated eosinophils from severe and aspirin-intolerant asthmatics, and also elevated EXC4 and LTC4 formation in eosinophils from AIA patients after cellular activation in the presence of lysine-aspirin. The findings support a pathophysiological role of the 15-LO pathway in SA and AIA.
The Centre for Allergy Research, Stockholm, Sweden.
Anna
A
James
Kameran
K
Daham
Linda
L
Backman
Asa
A
Brunnström
Tove
T
Tingvall
Maria
M
Kumlin
Charlotte
C
Edenius
Sven-Erik
SE
Dahlén
Barbro
B
Dahlén
Hans-Erik
HE
Claesson
D000328:Adult; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism; D001241:Aspirin / Q000009:adverse effects* / Q000276:immunology; D055963:Asthma, Aspirin-Induced / Q000276:immunology* / Q000378:metabolism; D004804:Eosinophils / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D017997:Leukotriene C4 / Q000378:metabolism*; D015289:Leukotrienes / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D055815:Young Adult
D006893:Hydroxyeicosatetraenoic Acids; D015289:Leukotrienes; C526311:eoxin C4; D016718:Arachidonic Acid; D017997:Leukotriene C4; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; C515716:ALOX15 protein, human; D001093:Arachidonate 15-Lipoxygenase; D001094:Arachidonate 5-Lipoxygenase; D001241:Aspirin