title: Cysteinyl leukotriene overproduction in aspirin-exacerbated respiratory disease is driven by platelet-adherent leukocytes.
abstract: Cysteinyl leukotriene (cysLT) overproduction is a hallmark of aspirin-exacerbated respiratory disease (AERD), but its mechanism is poorly understood. Because adherent platelets can convert the leukocyte-derived precursor leukotriene (LT)A(4) to LTC(4), the parent cysLT, through the terminal enzyme LTC(4) synthase, we investigated the contribution of platelet-dependent transcellular cysLT production in AERD. Nasal polyps from subjects with AERD contained many extravascular platelets that colocalized with leukocytes, and the percentages of circulating neutrophils, eosinophils, and monocytes with adherent platelets were markedly higher in the blood of subjects with AERD than in aspirin-tolerant controls. Platelet-adherent subsets of leukocytes had higher expression of several adhesion markers than did platelet nonadherent subsets. Adherent platelets contributed more than half of the total LTC(4) synthase activity of peripheral blood granulocytes, and they accounted for the higher level of LTC(4) generation by activated granulocytes from subjects with AERD compared with aspirin-tolerant controls. Urinary LTE(4) levels, a measure of systemic cysLT production, correlated strongly with percentages of circulating platelet-adherent granulocytes. Because platelet adherence to leukocytes allows for both firm adhesion to endothelial cells and augmented transcellular conversion of leukotrienes, a disturbance in platelet-leukocyte interactions may be partly responsible for the respiratory tissue inflammation and the overproduction of cysLTs that characterize AERD.
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Tanya M
authors.initials: TM
authors.lastname: Laidlaw
authors.forename: Molly S
authors.initials: MS
authors.lastname: Kidder
authors.forename: Neil
authors.initials: N
authors.lastname: Bhattacharyya
authors.forename: Wei
authors.initials: W
authors.lastname: Xing
authors.forename: Shiliang
authors.initials: S
authors.lastname: Shen
authors.forename: Ginger L
authors.initials: GL
authors.lastname: Milne
authors.forename: Mariana C
authors.initials: MC
authors.lastname: Castells
authors.forename: Heng
authors.initials: H
authors.lastname: Chhay
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Boyce
mesh_terms: D000328:Adult; D000368:Aged; D001094:Arachidonate 5-Lipoxygenase / Q000276:immunology / Q000378:metabolism; D001241:Aspirin / Q000009:adverse effects* / Q000276:immunology; D055963:Asthma, Aspirin-Induced / Q000276:immunology*; D001792:Blood Platelets / Q000187:drug effects / Q000276:immunology*; D016084:Bronchoconstriction / Q000276:immunology; D003545:Cysteine / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006098:Granulocytes / Q000187:drug effects / Q000276:immunology; D006801:Humans; D016023:Integrins / Q000276:immunology; D007962:Leukocytes / Q000276:immunology*; D017999:Leukotriene E4 / Q000276:immunology; D015289:Leukotrienes / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009298:Nasal Polyps / Q000139:chemically induced* / Q000276:immunology; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000276:immunology; D055815:Young Adult
chemical_list: D016023:Integrins; D015289:Leukotrienes; D010975:Platelet Aggregation Inhibitors; C112381:cysteinyl-leukotriene; D017999:Leukotriene E4; D001094:Arachidonate 5-Lipoxygenase; D003545:Cysteine; D001241:Aspirin