The Influence of Aspirin on Release of Eoxin C4, Leukotriene C4 and 15-HETE, in Eosinophilic Granulocytes Isolated from Patients with Asthma

Abstract

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.

Mechanisms of Aspirin-Intolerant Asthma: Identifying Inflammatory Pathways in the Pathogenesis of Asthma

“…Based on the data presented here by James et al [9], it appears that the 15-LO pathway is a potential therapeutic target for AIA and severe aspirin-tolerant asthma. Based on the known biological effects of 15-HETE, it is reasonable to hypothesize that inhibition of 15-LO may reduce inflammatory cell influx and hence lead to improved control in more severe asthma.…”

“…It has been shown that 15-HETE production in the peripheral blood leukocytes from aspirin-intolerant asthmatics is different from that in aspirin-tolerant asthmatics [8]. The study presented by James et al [9] further refines this study by isolating eosinophils from the peripheral blood leukocytes and identifying differences in patients with AIA. It has also been shown that the 15-HETE released from nasal polyps obtained from aspirin-sensitive individuals does not cause activation of eosinophils and/or mast cells [10].…”

“…The eoxins, however, may be involved in the recruitment of inflammatory cells that are then activated by alternative mechanisms. The current study demonstrated the production of these agents by eosinophils [9]; however, further study is required of the ongoing biological effects of the mediators produced by 15-LO.…”

Eosinophilic Drug Allergy

“…There is also a relative increased PGD 2 production (a Th2/ eosinophil chemoattractant) [113]. Additionally, activated eosinophils from AERD patients produce significantly higher amounts of leukotriene C 4 than eosinophils from healthy subjects or mild asthmatics [114]. This may also reflect the overactivity of the 5-LOX pathways in these subjects, that is exaggerated by the administration of aspirin.…”

N-Substituted pyrazole-3-carboxamides as inhibitors of human 15-lipoxygenase

“…11 Recently, it was reported that 15-LOX-1 activity was greater in eosinophils derived from patients with severe asthma or aspirin-intolerant asthma (AIA) compared to eosinophils isolated from patients with mild asthma or healthy controls. 12 There are numerous publications regarding 15-LOX-1 inhibitors, but many studies are conducted using 15-LOX-1 from nonhuman species, most notably soybean (see, e.g., Refs. [13][14][15].…”