Background: We hypothesize that alternate regulation of cyclooxygenase-2 (COX-2) may predispose patients to aspirin-induced exacerbations.Therefore, we want to examine the dynamics of COX-2 up-regulation in whole blood monocytes in the presence and absence of aspirin. Methods: COX-2 expression was evaluated by flow cytometry through intracellular staining of whole blood monocytes with antiCOX-2 antibodies. Enzyme up-regulation was monitored after in vitrostimulation with lipopolysaccharide (LPS) and/or aspirin in 19 aspirin-intolerant (AI) patients (8 aspirin-sensitive asthmatics and 11 urticaria-angioedema patients) and 14 healthy controls. Results: We found significantly higher COX-2 expression levels after stimulation with LPS and aspirin (mean 78.8, range 44.9–92.3; p = 0.0002) in comparison to LPS alone (mean 65.9%, range 33.6–82.6) in AI patients. A comparable, but lower up-regulation was also observed after aspirin stimulation alone (median 2.1%, range 0.5–15.9; p = 0.004) in comparison with baseline values (median 1%, range 0.1–5.4). There was no significant difference in COX-2 expression between LPS and aspirin stimulation (mean 61.8%, range 26.8–89.2; p = 0.09) and LPS stimulation (mean 55.5%, range 28.1–74.3) nor between aspirin stimulation alone (median 0.5%, range 0–8.6; p = 0.8) and baseline values (median 0.4%, range 0–5.4) in healthy control subjects. Conclusions: The main finding of this study is that COX-2 appears to be differentially regulated in aspirin-sensitive patients. What is really new is the observation that aspirin and LPS increase COX-2 expression on blood monocytes of AI asthmatics, a finding in contrast with the lack of an effect of the same stimuli on COX-2 expression on monocytes from healthy subjects.

Keywords:
Aspirin intolerance, Cyclooxygenase-2 expression, Monocytes
1.
Szczeklik A, Stevenson DD: Aspirin-induced asthma: advances in pathogenesis, diagnosis, and management. J Allergy Clin Immunol 2003;111:913–921.
2.
Jenkins C, Costello J, Hodge L: Systematic review of prevalence of aspirin induced asthma and its implications for clinical practice. BMJ 2004;328:434–440.
3.
Wedi B, Kapp A: Aspirin induced adverse skin reactions: new pathophysiological aspects. Thorax 2000;55:S70–S71.
4.
Cormican LJ, Farooque S, Altmann DR, Lee TH: Improvements in an oral aspirin challenge protocol for the diagnosis of aspirin hypersensitivity. Clin Exp Allergy 2005;35:717–722.
5.
Gyllfors P, Bochenek G, Overholt J, Drupka D, Kumlin M, Sheller J, Nizankowska E, Isakson PC, Mejza F, Lefkowith JB, Dahlén SE, Szczeklik A, Murray JJ, Dahlén B: Biochemical and clinical evidence that aspirin-intolerant asthmatic subjects tolerate the cyclooxygenase 2-selective analgetic drug celecoxib. J Allergy Clin Immunol 2003;111:1116–1121.
6.
KosnikM, Music E, Matjaz F, et al: Relative safety of meloxicam in NSAID-intolerant patients. Allergy 1998;53:1231–1233.
7.
Szczeklik A: The cyclooxygenase theory of aspirin-induced asthma. Eur Respir J 1990;3:558–593.
8.
Bhattacharya M, Peri K, Ribeiro-da-Silva A, et al: Localization of functional prostaglandin E2 receptors EP3 and EP4 in the nuclear envelope. J Biol Chem 1999;274:15719–15724.
9.
Fitzpatrick FA, Soberman R: Regulated formation of eicosanoids. J Clin Invest 2001;107:1347–1351.
10.
Melo CB, Bozza PT, Weller PF: The cellular biology of eosinophil eicosanoid formation and function. J Allergy Clin Immunol 2002;109:393–400.
11.
Schäfer D, Schmid M, Göde UC, Baenkler H-W: Dynamics of eicosanoids in peripheral blood cells during bronchial provocation in aspirin-intolerant asthmatics. Eur Respir J 1999;13:638–646.
12.
Mewes T, Riechelmann H, Klimek L: Increased in vitro cysteinyl leukotriene release from blood leukocytes in patients with asthma, nasal polyps, and aspirin intolerance. Allergy 1996;51:506–510.
13.
Drazen JM. Leukotrienes as mediators of airway obstruction. Am J Respir Crit Care Med 1998;158:S193–S200.
14.
Sousa AR, Parikh A, Scadding G, Corrigan CJ, Lee TH: Leukotriene-receptor expression on nasal mucosal inflammatory cells in aspirin-sensitive rhinosinusitis. N Engl J Med 2002;347:1493–1499.
15.
Picado C, Fernandez-Morata JC, Juan M, Roca-Ferrer J, Fuentes M, Xaubet A, Mullol J: Cyclooxygenase-2 mRNA is downexpressed in nasal polyps from aspirin-sensitive asthmatics. Am J Respir Crit Care Med 1999;160:291–296.
16.
Pujols L, Mullol J, Alobid I, Roca-Ferrer J, Xaubet A, Picado C: Dynamics of COX-2 in nasal mucosa and nasal polyps from aspirin-tolerant and aspirin-intolerant patients with asthma. J Allergy Clin Immunol 2004;114:814–819.
17.
Smith WL, Garavito RM, DeWitt DL: Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and -2. J Biol Chem 1996;271:33157–33160.
18.
Ruitenberg JJ, Waters CA: A rapid flow cytometric method for the detection of intracellular cyclooxygenases in human whole blood monocytes and a COX-2 inducible human cell line. J Immunol Methods 2003;274:93–104.
19.
Hinz B, Brune K, Pahl A: Cyclooxygenase-2 expression in stimulated human monocytes is modulated by cyclic AMP, prostaglandin E2, and nonsteroidal anti-inflammatory drugs. Biochem Biophys Res Commun 2000;278:790–796.
20.
Mitchell JA, Belvisi MG: Too many COX (cyclo-oxygenase) spoil the broth: aspirin-sensitive asthma and 5-lypoxygenase. Thorax 1997;52:933–935.
21.
Holtzman MJ, Turk J, Shornick LP: Identification of a pharmacologically distinct prostaglandin H synthase in cultured epithelial cells. J Biol Chem 1992;267:21438–21445.
22.
Clària J, Serhan CN: Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions. Proc Natl Acad Sci USA 1995;92:9475–9479.
23.
Kowalski ML, Ptasinska A, Jedrzejczak M, Bienkiewicz B, Cieslak M, Grzegorczyk J, Pawliczak R, Dubuske L: Aspirin-triggered 15-HETE generation in peripheral blood leukocytes is a specific and sensitive Aspirin-Sensitive Patients Identification Test (ASPITest). Allergy 2005;60:1139–1145.
24.
Dixon DA, Kaplan CD, McIntyre TM, Zimmerman GA, Prescott SM: Post-transcriptional control of cyclooxygenase-2 gene expression. The role of the 3′-untranslated region. J Biol Chem 2000;275:11750–11757.
25.
Dixon DA, Balch GC, Kedersha N, Anderson P, Zimmerman GA, Beauchamp RD, Prescott SM: Regulation of cyclooxygenase-2 expression by the translational silencer TIA-1. J Exp Med 2003;198:475–481.
26.
Asero R: Oral aspirin challenges in patients with a history of intolerance to single non-steroidal anti-inflammatory drugs. Clin Exp Allergy 2005;35:713.
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2009
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