The cyclo-oxygenase (COX) pathway converts arachidonic acid to prostaglandins, prostaBackground -There are two isoforms of cyclin, and thromboxane A 2 . 1 2 There are two cyclo-oxygenase (COX), namely COX-1 isoforms of COX, namely COX-1 and COX-2.3 and COX-2. COX-1 is constitutively ex-COX-1 (PGH synthase-1) was initially purified pressed in most tissues and in blood plateand cloned from sheep vesicular glands and is lets. The metabolites derived from COXconstitutively expressed in most tissues and in 1 are probably involved in cellular houseblood platelets. The metabolites derived from keeping functions. COX-2 is expressed COX-1 are probably involved in cellular houseonly following cellular activation by inkeeping functions such as coordinating the acflammatory stimuli and is thought to be tions of circulating hormones and regulating involved in inflammation. vascular homeostasis. COX-2 (PGH synthaseMethods -The expression of COX-1 and 2) shares approximately 62% amino acid hom-COX-2 isoenzymes has been studied in the ology with COX-1 3 and is expressed only folbronchial mucosa of 10 normal and 18 lowing cellular activation by inflammatory asthmatic subjects, 11 of whom had stimuli such as growth factors, cytokines and aspirin-sensitive asthma (ASA) and mitogens in fibroblasts and by bacterial liposeven had non-aspirin-sensitive asthma polysaccharide in monocytes and macro-(NASA).phages. [4][5][6][7] The observations that the expression Results -There was a significant fourfold of COX-2 is induced by inflammatory meand 14-fold increase, respectively, in the diators in immune cells and that its expression epithelial and submucosal cellular exis inhibited by glucocorticoids suggest that inpression of COX-2, but not of COX-1, in ducible COX-2 may produce prostanoids inasthmatic patients. There was no sigvolved in inflammation. Since enhanced nificant difference in the total number of cytokine expression is a feature of asthmatic cells staining for either COX-1 or COX-2 airways, we reasoned that COX-2 might be between subjects with ASA and NASA, but augmented in this disease. the number and percentage of mast cellsPatients with bronchial asthma form a that expressed COX-2 was significantly inheterogeneous group and asthmatic individuals

The inflammatory cell infiltrate in bronchial biopsies of 12 aspirin-sensitive asthmatic (ASA) subjects and eight non-aspirin-sensitive (non-ASA) control subjects have been compared. Biopsies were taken from a right middle or lower lobe segmental carina using fiberoptic bronchoscopy. The biopsies were snap-frozen in OCT, and sections 5 microns thick were doubled immunostained using a rabbit polyclonal antibody to the enzyme 5-lipoxygenase (5-LO) and with a monoclonal antibody to neutrophils (NP57), macrophages (EMB11), and total (BMK13) and activated eosinophils (EG2), mast cells (AA1), and T-lymphocytes (anti-CD3). There was no significant difference in the total numbers of cells staining for 5-LO between the two groups of subjects. As a percentage of total 5-LO cells, there were significantly more mast cells (12.9 +/- 3.8% versus 3.4 +/- 3.1%; p = 0.039) and total eosinophils (34.7 +/- 9.4% versus 11.1 +/- 3.8%; p = 0.044) and significantly fewer macrophages (23.3 +/- 6.1% versus 39.8% +/- 5.3; p = 0.041) in the bronchial biopsies from ASA subjects as compared with non-ASA patients. The numbers of neutrophils, T-lymphocytes, and activated eosinophils were similar for the two groups. The increased numbers of eosinophils and mast cells identified in the bronchial tissue from aspirin-sensitive asthmatic subjects may be the source of the enhanced cysteinyl leukotriene production observed in these subjects.

The FEV1 and urinary leukotriene E4 (LTE4) concentrations were determined in six aspirin-sensitive and six non-aspirin-sensitive asthmatic subjects before and after inhalation challenge with lysine-aspirin or placebo solution. Lysine-aspirin produced a mean fall in FEV1 of 26.7 +/- 4.9% (mean +/- SEM) in subjects with aspirin sensitivity and of 8.5 +/- 6.5% (mean +/- SEM) in non-aspirin-sensitive asthmatic subjects. The mean baseline urinary LTE4 concentration of 83 pg/mg creatinine (geometric mean [GM], range 15 to 326 pg/mg creatinine) in aspirin-sensitive subjects was significantly higher than the 33.8 pg/mg creatinine (GM, range 10 to 111 pg/mg creatinine) in non-aspirin-sensitive subjects (p = 0.02). In aspirin-sensitive subjects, inhalation challenge with lysine-aspirin produced a significant increase in urinary LTE4 concentration to 240 pg/mg creatinine (GM, range 60 to 1,113 pg/mg creatine), which was not observed after placebo challenge. There was no significant change in urinary LTE4 concentration after inhalation challenge with either lysine-aspirin or placebo solution in non-aspirin-sensitive asthmatic subjects. Thus, sulfidopeptide leukotrienes are released after inhalation of lysine-aspirin in aspirin-sensitive asthmatic patients.

Background -The aspirin-induced bronchoconstriction in patients with aspirinsensitive asthma is caused by cysteinyl leukotriene release. The cellular source of the leukotrienes is unknown. The inflammatory cell infiltrate in bronchial biopsy samples from seven aspirin-sensitive asthmatic (ASA) subjects and eight non-ASA subjects before and after local challenge with lysine aspirin was therefore examined.

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