Expression of 5-lipoxygenase and cyclooxygenase pathway enzymes in nasal polyps of patients with aspirin-intolerant asthma.
In aspirin-intolerant subjects, adverse bronchial and nasal reactions to cyclooxygenase (COX) inhibitors are associated with over-production of cysteinyl-leukotrienes (cys-LTs) generated by the 5-lipoxygenase (5-LO) pathway. In the bronchi of patients with aspirin-intolerant asthma, we previously linked cys-LT over-production and aspirin hyper-reactivity with elevated immunoexpression in eosinophils of the terminal enzyme for cys-LT production, LTC4 synthase. We investigated whether this anomaly also occurs in the nasal airways of these patients. Immunohistochemical expression of 5-LO and COX pathway proteins was quantified in nasal polyps from 12 patients with aspirin-intolerant asthma and 13 with aspirin-tolerant asthma. In the mucosa of polyps from aspirin-intolerant asthmatic patients, cells immunopositive for LTC4 synthase were four-fold more numerous than in aspirin-tolerant asthmatic patients (p=0.04). There were also three-fold more cells expressing 5-LO (p=0.037), with no differences in 5-LO activating protein (FLAP), COX-1 or COX-2. LTC4 synthase-positive cell counts correlated exclusively with mucosal eosinophils (r=0.94, p<0.001, n=25). Co-localisation confirmed that five-fold higher eosinophil counts (p=0.007) accounted for the increased LTC4 synthase expression in polyps from aspirin-intolerant asthmatic patients, with no alterations in mast cells or macrophages. Within the epithelium, increased counts of eosinophils (p=0.006), macrophages (p=0.097), and mast cells (p=0.034) in aspirin-intolerant asthmatic polyps were associated only with 2.5-fold increased 5-LO-positive cells (p<0.05), while the other enzymes were not different. Our results indicate that a marked over-representation of LTC4 synthase in mucosal eosinophils is closely linked to aspirin intolerance in the nasal airway, as in the bronchial airways.
Adamjee
J
J
Allergy and Inflammation Research (IIR Division), Southampton University School of Medicine, Southampton SO16 6YD, UK.
Suh
Y-J
YJ
Park
H-S
HS
Choi
J-H
JH
Penrose
J F
JF
Lam
B K
BK
Austen
K F
KF
Cazaly
A M
AM
Wilson
S J
SJ
Sampson
A P
AP
D000293:Adolescent; D000328:Adult; D000368:Aged; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D001241:Aspirin / Q000009:adverse effects*; D001249:Asthma / Q000150:complications / Q000201:enzymology* / Q000276:immunology; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects; D004802:Eosinophilia / Q000201:enzymology; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009297:Nasal Mucosa / Q000201:enzymology / Q000276:immunology; D009298:Nasal Polyps / Q000150:complications / Q000201:enzymology* / Q000276:immunology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*
D016861:Cyclooxygenase Inhibitors; D001094:Arachidonate 5-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase; D001241:Aspirin