Clinical benefits of aspirin desensitization in patients with nonsteroidal anti-inflammatory drug exacerbated respiratory disease are not related to urinary eicosanoid release and are accompanied with decreased urine creatinine.

BACKGROUND: Treatment with acetylsalicylic acid (ASA) after desensitization may be a therapeutic option in patients with nonsteroidal anti-inflammatory drug exacerbated respiratory disease (NERD). The mechanisms that lead to improvement in rhinosinusitis and asthma symptoms remain unknown. AIM: To attribute the documented clinical effects of ASA treatment of chronic rhinosinusitis and/or asthma to the release of eicosanoid metabolites in urine. METHODS: Fourteen patients with NERD were successfully desensitized, and, eventually, eight patients were treated with 650 mg of ASA daily for 3 months. In addition to clinical assessments, nuclear magnetic resonance imaging and smell test were performed before and after treatment with ASA. Venous blood and urine were collected before desensitization and after 1 and 3 months of treatment. The levels of urinary leukotrienes (LT) (cysteinyl LT and LTE4) and tetranor PGDM (metabolite of prostaglandin D2) were measured by enzyme-linked immunosorbent assay. RESULTS: Treatment with ASA after desensitization alleviated symptoms of rhinosinusitis, improved nasal patency (mean, 50% decrease in peak nasal inspiratory flow) and sense of smell (fourfold increase in smell test score) in as early as 4 weeks. Clinical improvements were not accompanied by any change in sinonasal mucosa thickness as assessed with nuclear magnetic resonance. Urinary cysteinyl LTs, LTE4, and prostaglandin D2 metabolite remained relatively stable during ASA treatment and did not correlate with clinical improvements. Desensitization was associated with a progressive decrease of urinary creatinine. CONCLUSION: Clinical improvement in rhinosinusitis and/or asthma after ASA desensitization was not related to concentrations of urinary eicosanoid metabolites. A decrease of urinary creatinine requires further study to determine the renal safety of long-term treatment with ASA after desensitization.

Recruitment of CD34+ progenitor cells into peripheral blood and asthma severity.

BACKGROUND: Previous studies have suggested that the number of progenitor cells is elevated in the peripheral blood of asthmatic patients and that the number of progenitors correlate with the severity of the disease. OBJECTIVE: To evaluate the number of leukocyte progenitor and eosinophil progenitor cells in the peripheral blood of patients with bronchial asthma in relation to disease severity. METHODS: The study involved 51 patients with asthma (25 patients with a mild form and 26 with a severe form of the disease) and a group of 12 healthy controls. Using the flow cytometric method, leukocyte (CD34+ leukocytes) and eosinophil progenitors (CD34+CD125+) were detected in the peripheral blood of both asthmatic patients and healthy controls. RESULTS: Patients with asthma had significantly more leukocyte progenitor cells (median, 0.06% vs 0.016%) and eosinophil progenitor cells (median, 0.046% vs 0.004%) compared with the controls. Patients with severe asthma had more leukocyte progenitor cells (0.12% vs 0.035%) and more eosinophil progenitor cells (0.102% vs 0.019%) than patients with mild asthma. The number of circulating leukocyte and eosinophil progenitor cells inversely correlated with the forced expiratory volume in 1 second percentage of predicted value (r = -0.4 and r = -0.35, respectively) and positively correlated (r = 0.63 and r = 0.65, respectively) with the dose of inhaled steroids used to control asthma. CONCLUSION: These data suggest that the presence of leukocyte precursors and eosinophil progenitor cells in the peripheral blood of asthmatic patients may reflect ongoing airway inflammation.

Systemic responses after bronchial aspirin challenge in sensitive patients with asthma.

BACKGROUND: In aspirin-sensitive patients with asthma, bronchial obstruction induced by oral aspirin may be associated with extrabronchial symptoms, suggesting the systemic character of the response. OBJECTIVE: Go assess potential systemic effects of local aspirin challenge, hemopoietic progenitors were measured in the peripheral blood of challenged patients. METHODS: In 19 patients with a history of aspirin-induced asthma, placebo-controlled bronchial challenges with lysine-aspirin were performed. Peripheral blood was collected before and then 1 hour and 20 hours after challenge (placebo or aspirin). Using the flow-cytometric method, the numbers of leukocyte (CD34+ cells) and eosinophil (CD34+CD125+ cells) progenitors were determined. RESULTS: The challenge was positive in 13 patients; 6 patients had isolated local bronchial reaction, and 7 patients developed systemic symptoms (bronchial and extrabronchial). In patients with positive challenge (n = 13), leukocyte progenitors increased significantly at 1 hour and 20 hours after challenge (mean, 0.04% at baseline, 0.066% at 1 hour after challenge, and 0.073% at 20 hours; P < .05). Eosinophil progenitors raised significantly from mean 0.017% before challenge to 0.04% (P < .05) at 20 hours after the challenge. At 20 hours after the challenge, the increase in leukocyte and eosinophil progenitors was observed only in patients with systemic reactions. Positive aspirin challenge was associated with a significant increase in eotaxin 2 serum concentration. CONCLUSION: This study demonstrated that bronchial challenge with aspirin may involve systemic reactions and is associated with mobilization of leukocyte and eosinophil progenitor cells from the bone marrow.

Differential effects of aspirin and misoprostol on 15-hydroxyeicosatetraenoic acid generation by leukocytes from aspirin-sensitive asthmatic patients.

BACKGROUND: Although the mechanisms of aspirin-induced rhinosinusitis-asthma appear to be related to arachidonic acid abnormalities, only recently has a specific aspirin-triggered enhancement of 15-hydroxyeicosatetraenoic acid (15-HETE) generation in nasal polyp epithelial cells from aspirin-sensitive patients been demonstrated. OBJECTIVE: The aim of this study was to assess generation of 15-HETE and other eicosanoids by peripheral blood leukocytes (PBLs) from aspirin-sensitive and aspirin-tolerant asthmatic patients and modulation of 15-HETE generation by a prostaglandin (PG) E(1) analogue (misoprostol). METHODS: Twenty-four aspirin-sensitive patients with asthma-rhinosinusitis and 18 aspirin-tolerant asthmatic patients were studied, and eicosanoids released from PBLs were assessed by means of enzyme immunoassays. RESULTS: Unstimulated PBLs from aspirin-sensitive and aspirin-tolerant patients generated similar amounts of PGE(2), leukotriene C(4), and 15-HETE, but lipoxin A(4) release was significantly less in aspirin-sensitive patients (300 +/- 70 pg/mL) in comparison with that seen in aspirin-tolerant patients (690 +/- 100 pg/mL, P <.05). Cell incubation with 2, 20, or 200 micromol/L aspirin resulted in a dose-dependent increase in 15-HETE generation (mean change of +85%, +189%, and +284% at each aspirin concentration, respectively) only in aspirin-sensitive asthmatic patients. Naproxen stimulated 15-HETE generation in aspirin-sensitive asthmatic patients, but indomethacin or specific COX-2 inhibitors (NS-398 and celecoxib) did not affect 15-HETE release. A synthetic PGE(1) analogue (misoprostol) inhibited aspirin-induced 15-HETE release but enhanced 15-HETE generation by aspirin in leukocytes from aspirin-tolerant patients. After preincubation with misoprostol, aspirin induced a dose-dependent production of lipoxin A(4) in both groups. CONCLUSION: PBLs from patients with aspirin-sensitive rhinosinusitis-asthma might be specifically triggered by aspirin to generate 15-HETE. Metabolism of 15-HETE is differentially regulated by misoprostol in aspirin-tolerant and aspirin-sensitive asthmatic patients.