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.
Allergy and Inflammation Research (IIR Division), Southampton University School of Medicine, Southampton SO16 6YD, UK.
J
J
Adamjee
Y-J
YJ
Suh
H-S
HS
Park
J-H
JH
Choi
J F
JF
Penrose
B K
BK
Lam
K F
KF
Austen
A M
AM
Cazaly
S J
SJ
Wilson
A P
AP
Sampson
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