Aspirin-tolerant Patients Research Articles

Variations in expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in nasal mucosa of aspirin-sensitive versus aspirin-tolerant patients with nasal polyposis

Matrix metalloproteinases (MMPs) are key enzymes responsible for extracellular matrix degradation contributing to the progressive histological changes seen in lower airway disease, including asthma. MMP-9 and TIMP-1 have also shown some role in the pathogenesis of chronic rhinosinusitis (CRS) and nasal polyposis (NP). We aim to determine variability in expression of MMP-9 and its inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), in sinus tissue from distinct patient populations presenting with nasal polyposis. The expression of MMP-9 and TIMP-1 was investigated in nasal polyp tissue from 6 aspirin-sensitive (AS) and 6 aspirin-tolerant (AT) patients undergoing endoscopic sinus surgery for chronic rhinosinusitis with nasal polyposis (CRSwNP). Sinus mucosa from 6 patients with chronic rhinosinusitis without nasal polyposis (CRSsNP) was used as control. The MMP-9 and TIMP-1 expression was measured using immunofluorescence technique and graded using manual and computerized methods. Expression of TIMP-1 was significantly reduced in the AS group when compared with both the AT and CRSsNP (control) groups (P < .001). The MMP-9/TIMP-1 ratio was significantly increased in the AS group when compared with other patient groups (P < .001). The MMP- 9 expression was similar between study and control groups. These results support the importance of MMP-9 and TIMP-1 expression in nasal polyp formation. The decreased expression of TIMP-1 in AS patients may promote the effects of MMP-9 expression and thus contribute to tissue remodeling and inflammatory changes. This finding may lead to further understanding of disease severity and resistance to treatment in this group of patients, as well as the pathogenesis of nasal polyps.

Upregulation of RANTES in nasal polyps from patients with cystic fibrosis

Nasal polyps in patients with cystic fibrosis (CF) are believed to be phenotypically different than polyps affecting non-CF patients. The objective of this study was to characterize the expression of inflammatory cytokines within nasal polyps from CF and non-CF, aspirin-tolerant patients. "Regulated on activation, normal T-cell expressed and secreted" (RANTES) is a chemotactic cytokine involved in the recruitment and activation of eosinophils. Multiple molecular studies of non-CF polyps have established that RANTES may play an important role in nasal polyposis. Our study suggests RANTES may be upregulated in CF polyps relative to non-CF polyps. Nasal polyps were prospectively obtained from CF and non-CF, aspirin-tolerant patients. The Quantibody™ Human Cytokine Array I from RayBiotech, Inc., was used to identify differences in cytokine expression between protein extracts of two polyp groups. Four CF polyp extracts and 4 non-CF, aspirin-tolerant polyp extracts were each incubated on identical antibody subarrays, each containing 20 human cytokines in quadruplicate. Western blot analysis confirmed expression of RANTES. The protein microarray suggests a greater than 4-fold upregulation of RANTES in CF polyps relative to non-CF polyps. Western blot analysis confirmed expression of RANTES in CF polyps. Chemokines such as RANTES are responsible for the activation of inflammatory cells within the lamina propria of nasal polyps. We have demonstrated that RANTES may be an important cytokine associated with CF polyps.

Infectious diarrhea: when to test and when to treat

<h3>BACKGROUND</h3> Nasal provocation tests with lysine-aspirin have recently been introduced for assessment of aspirin intolerant asthma. A study was undertaken to evaluate the usefulness of acoustic rhinometry, a new non-invasive technique, in the diagnosis of aspirin intolerant asthma/rhinitis. <h3>METHODS</h3> Fifteen patients with aspirin intolerant asthma/rhinitis (nine women, mean (SD) age 54.7 (14) years), eight patients with aspirin tolerant asthma/rhinitis (three women, mean (SD) age 52.6 (7.8) years), and eight healthy subjects (two women, mean (SD) age 32.5 (9.7) years) were studied. All subjects were challenged with saline (0.9% NaCl) and 25 mg lysine acetylsalicylic acid (L-ASA) instilled into each nostril of the nose on two separate days. The clinical response was evaluated based on nasal symptoms (sneezes, itching, secretion and blockage). The nasal response was measured by acoustic rhinometry. Symptoms and rhinometry curves were recorded at 10 minute intervals for three hours, one hour before challenge and two hours after challenge. <h3>RESULTS</h3> L-ASA challenge induced a significant increase in symptoms in patients with aspirin intolerant asthma/rhinitis. No differences in the clinical response were detected in those with aspirin tolerant asthma/rhinitis or healthy subjects. L-ASA challenge induced a significant decrease in nasal volume measured by acoustic rhinometry in aspirin intolerant patients. No differences were detected between the challenges in aspirin tolerant patients. If a 25% decrease in nasal volume is taken as the cut off point, the specificity of the test was 94% and the sensitivity reached 73%. The nasal challenge was well tolerated by all subjects. <h3>CONCLUSION</h3> Acoustic rhinometry may be used to study the nasal response to L-ASA. Nasal challenge with L-ASA is safe and can be used as a diagnostic test even in asthmatic patients with severe bronchial obstruction.

Protein Microarray Analysis of Nasal Polyps from Aspirin-Sensitive and Aspirin-Tolerant Patients with Chronic Rhinosinusitis

The purpose of this study was to apply protein microarray technology to the study of sinonasal tissue and to identify differential protein expression in nasal polyps from aspirin-sensitive (AS) versus aspirin-tolerant (AT) patients with chronic rhinosinusitis (CRS) and CRS with nasal polyps (CRSwNPs). Nasal polyp specimens were prospectively obtained from two groups of patients with CRSwNP. The test group (AS) consisted of five patients that were diagnosed with CRSwNP and intolerance to aspirin based on medical history and physical exam. The control group (AT) consisted of four AT patients with CRSwNP. Protein was extracted and labeled from harvested polyps and the Sigma Panorama Antibody Microarray-Cell Signaling Kit was used to identify differences in protein expression between the two polyp groups. Western blot analysis was used to validate the results of the protein microarray. The protein microarray showed a greater than twofold change in expression of both beta-adaptin and heat shock protein 70 (HSP70). Western blot analysis confirmed up-regulation of beta-adaptin and HSP70 in nasal polyp tissue from AS patients. Pooled samples of AS and AT nasal polyps evaluated by protein microarray show distinct protein expression profiles in the stress response and receptor-mediated endocytosis pathways. This study establishes the successful application of protein microarray technology to study nasal polyposis, which in turn can be validated by Western blot analysis.

Cellular Allergen Stimulation Test with Acetylsalicylic Acid-Lysine Is Not a Useful Test to Discriminate between Asthmatic Patients with and without Acetylsalicylic Acid Sensitivity

Background: The aspirin provocation test, considered to be the gold standard in the diagnosis of aspirin sensitivity, may be associated with severe adverse reactions; thus, alternative procedures with a higher safety profile are highly desirable. Although the cellular antigen stimulation test (CAST) has been proposed to be such an alternative, there is limited information about its clinical usefulness. Objective: It was the aim of our study to evaluate the clinical usefulness of CAST in the diagnosis of aspirin sensitivity. Material and Methods: Patients with aspirin-sensitive asthma and/or nasal polyps (n = 40), patients with aspirin-tolerant asthma and/or nasal polyps (n = 13) and healthy volunteers (n = 26) were included. A 2-day, single-blind placebo-controlled oral aspirin provocation test was performed. In vitro release of cysteinyl leukotrienes (Cys-LTs) by peripheral blood leukocytes was measured after stimulation with both stimulation buffer and lysine aspirin (2.5 mg/ml) by CAST. Results: Baseline Cys-LT levels were similar among the 3 groups. After lysine aspirin stimulation, the net increase in Cys-LTs was significantly higher in patients with aspirin sensitivity (median 91 pg/ml, interquartile range 22–206) compared with aspirin-tolerant patients (20 pg/ml, range 0–46) and healthy controls (23 pg/ml, range 0–71; p = 0.004). The assay had a sensitivity of 25%, a specificity of 92.3%, and positive and negative predictive values of 28.7 and 90.7%, respectively. Conclusion: Although the leukocytes of patients with aspirin sensitivity produce higher amounts of Cys-LTs as measured by CAST, the low sensitivity and predictive values limit the clinical usefulness of this test in the diagnosis of aspirin sensitivity.

Urinary leukotrienes in patients with nasal polyposis

To compare urinary leukotriene E4 (ULT) level in patients with nasal polyposis (NP) with and without aspirin intolerance and allergic rhinitis (AR), and correlate it with disease severity. Prospective study from November 2005 to November 2006. Patients with NP (n = 30) and AR (n = 35) were included. The concentration of ULT was measured in both groups. Oral provocation test with aspirin was performed to patients with NP. ULT level between both groups was compared and correlated with NP disease severity. ULT concentration was elevated on NP and AR. The patients with NP and aspirin intolerance (n = 4) presented higher levels of ULT compared to aspirin-tolerant patients. Leukotriene concentration was not correlated with NP severity. Patients with NP and aspirin intolerance have increased ULT excretion; thus their measurement can be used as an indicator of arachidonic acid metabolism alteration.

Prostaglandin E2 systemic production in patients with asthma with and without aspirin hypersensitivity

Background:A special regulatory role for prostaglandin E2 has been postulated in aspirin-induced asthma. A study was undertaken to investigate the effects of aspirin on the systemic production of prostaglandin E2...

PGE2 suppresses excessive anti‐IgE induced cysteinyl leucotrienes production in mast cells of patients with aspirin exacerbated respiratory disease

Aspirin causes bronchospasm in patients with aspirin exacerbated respiratory disease (AERD). The contribution of mast cells to the increased cysteinyl-leucotrienes (cys-LTs) detected in AERD patients is however not defined. Effects of prostaglandin (PG) E(2) and inhibitors of cyclooxygenase (COX) and lipoxygenase (LO) pathways on mediator release from cultured mast cells of normal subjects, aspirin tolerant asthma (ATA) and AERD patients were compared to better define the role of mast cells in AERD. Mast cells were cultured from peripheral blood progenitors and were activated by anti-IgE. Histamine, PGD(2) and cys-LTs released were then determined. Basal release of all three mediators was similar in all subjects. Although the release of all three mediators was increased by anti-IgE, mast cells from AERD patients produced significantly more cys-LTs (6.9 +/- 2.0 ng/10(6) cells) than normal and ATA subjects (2.3 +/- 0.8 and 1.7 +/- 0.5 ng/10(6) cells, respectively). While COX and LO pathway inhibitors did not affect anti-IgE induced histamine release, they significantly suppressed the production of PGD(2) and cys-LTs, respectively, in all patients. PGE(2) significantly enhanced anti-IgE induced histamine and PGD(2) release from mast cells of normal subjects but not those of ATA and AERD patients. In contrast, PGE(2) suppressed only anti-IgE induced cys-LTs release from mast cells of AERD patients. We speculate that overproduction of cys-LTs is unique to mast cells of AERD patients and is particularly sensitive to suppression by PGE(2). Consequently reduction of PGE(2) production by aspirin removes this endogenous control of cys-LTs overproduction, resulting in asthma attack.

Expression of Cyclooxygenase and Lipoxygenase Enzymes in Nasal Polyps of Aspirin-Sensitive and Aspirin-Tolerant Patients

To evaluate the expression of cyclooxygenase (COX) and lipoxygenase (LO) enzymes in nasal polyp specimens from aspirin-sensitive (AS) and aspirin-tolerant (AT) patients. Immunohistochemical staining of archived tissue. Subjects Specimens from 26 patients (11 AS and 15 AT) with nasal polyps were analyzed; specimens from 4 patients were used as controls. Immunohistochemical techniques were used to evaluate the expression of the enzymes COX-1, COX-2, 5-LO, 12-LO, and 15-LO in nasal polyp tissue specimens from AS and AT patients. The results were compared with those of a control group of patients without a history of nasal polyposis or rhinosinusitis. Characteristic staining patterns of epithelium and submucosal glands were noted for each enzyme. Statistically significant (P<.05) differences in staining of columnar epithelium were noted for COX-1 (basal cell layer cytoplasm), COX-2 (apical cell layer cytoplasm), and 12-LO (full-thickness cytoplasm and nucleus). Increased 15-LO (full-thickness cytoplasm) expression in columnar epithelium was noted only in the AT group. Significant differences in the staining of submucosal glands were noted for COX-2 (plasma membrane and cytoplasm), 12-LO (cytoplasm), and 15-LO (cytoplasm) between control and AS patients as well as between control and AT patients (P<.05). The only significant difference noted between the AS and AT groups was cytoplasm staining for 5-LO in submucosal glands, which was greater in the AS group. No epithelial staining differences were noted between AT and AS patients. There were significant differences in the expression of COX and LO enzymes between patients with nasal polyps and controls, irrespective of aspirin sensitivity. With 1 exception, there were no significant differences between AS and AT groups.

Lipoxin A4 (LXA4) and Leukotriene C4 (LTC4) Levels in Nasal Lavages after Intranasal Provocation with Aspirin in Aspirin Sensitive and Aspirin Tolerant Patients

Lipoxin A4 (LXA4) and Leukotriene C4 (LTC4) Levels in Nasal Lavages after Intranasal Provocation with Aspirin in Aspirin Sensitive and Aspirin Tolerant Patients

Aspirin‐triggered 15‐HETE generation in peripheral blood leukocytes is a specific and sensitive Aspirin‐Sensitive Patients Identification Test (ASPITest)*

We have previously demonstrated that aspirin triggers specific generation of 15-hydroxyeicosateraenoic acid (15-HETE) from nasal polyp epithelial cells and peripheral blood leukocytes (PBL) from aspirin-sensitive (AS) but not aspirin-tolerant (AT) patients with asthma/rhinosinusitis. The goal of this study was to assess the diagnostic value of ASA-induced 15-HETE generation measurement to identify AS patients. PBL were obtained from 43 AS patients with asthma and rhinosinusitis, 35 AT asthmatics and 17 healthy control (HC) subjects. PBL were incubated with 2-200 muM aspirin (ASA) and 15-HETE release was measured in cell supernatants with competitive ELISA. Unstimulated PBL from all three groups of patients generated similar amount of 15-HETE. Incubation with 200 microM ASA resulted in an increase in an 15-HETE generation (mean increase +421%) in AS-asthmatics but small and nonsignificant response in AT-asthmatics or control subjects. Receiver operating curve (ROC) analysis revealed that the sensitivity of the test for confirmation of ASA-sensitivity was 83% and the specificity 82%. Positive predictive value was 0.79 and negative predictive value was 0.86. Naproxen induced a significant increase in 15-HETE only in some AS-asthmatics, but not in AT-asthmatics. Our data demonstrate that ASA-induced 15-HETE generation by PBL is a specific and sensitive aspirin-sensitive patients identification test (ASPITest).

Cyclooxygenase-1 gene polymorphisms in patients with different asthma phenotypes and atopy

Cyclooxygenase-1 (COX-1) regulates the biosynthesis of prostaglandins, which are important mediators in asthma. The possible association of COX-1 gene polymorphisms with asthma has not been investigated. The allele frequencies of 20 COX-1 polymorphisms were determined in a random Australian Caucasian population using MassARRAY technology. Informative and potentially functional promoter (c.8592C > T, c.1676C > T) and coding region (c.22C > T, c.50C > T) polymorphisms were investigated in carefully phenotyped patients with mild (n = 316), moderate (n = 241), severe (n = 86) or aspirin-intolerant asthma (AIA) (n = 58), and in nonasthmatic subjects (n = 477). There were no allelic, genotypic or haplotypic associations between these four polymorphisms and asthma or asthma severity. Over-representation of the c.50TT genotype among AIA patients (3.4%) compared with aspirin-tolerant patients (0.8%), and a global haplotype association with AIA did not reach statistical significance. The c.22TT genotype was less frequent among atopic (0.1%) rather than nonatopic individuals (1.2%; odds ratio = 9.05, 95% confidence interval 1.01-81.29). In conclusion, the present investigation of cyclooxygenase-1 polymorphisms in asthma indicates that they do not appear to play a substantial role in genetic pre-disposition for asthma or asthma severity. However, the c.22TT genotype confers a small protective effect against atopy. Potential associations with aspirin-intolerant asthma were identified and warrant further investigation in a larger population of aspirin-intolerant asthma patients.

New Immunohistologic Findings on the Differential Role of Cyclooxygenase 1 and Cyclooxygenase 2 in Nasal Polyposis

Cyclooxygenase 1 (Cox-1) plays a key role in arachidonic acid metabolism and in the pathophysiology and immunology of nasal polyposis in patients suffering from aspirin intolerance. We hypothesize that Cox-2 also might be relevant in the etiology of nasal polyps of aspirin-tolerant patients by their effects on inflammatory mediators as well as on microvascular permeability. Fifty-two surgical specimens were immunohistochemically labeled for Cox-1 and Cox-2. Specimens were taken from chronically inflamed mucosa (n = 19) and from nasal polyps (n = 19) during endonasal sinus surgery. Controls were obtained from healthy nasal respiratory mucosa (n = 14), harvested during turbinate surgery in patients with nasal obstruction without inflammatory disease. Staining intensities were semiquantitatively assessed and statistically analyzed. In chronically inflamed tissue the expression of Cox-1 and Cox-2 was strongly labeled. However, in nasal polyps the staining pattern of Cox-1 was similar, but Cox-2 expression in epithelial cells was significantly less than in inflamed, nonpolypous specimens. These data suggest that while Cox-1 is strongly up-regulated, Cox-2 expression is significantly lower in epithelial cells of nasal polyps than in those of chronic sinusitis without polyps. The relevance of this finding has to be discussed with respect to the regulatory function of Cox on the inflammatory reaction in nasal respiratory mucosa and its hypothetical role in alterations of capillary permeability via vascular permeability factor/vascular endothelial growth factor.

Expression of the cysteinyl leukotriene receptors cysLT 1 and cysLT 2 in aspirin-sensitive and aspirin-tolerant chronic rhinosinusitis

Cysteinyl leukotrienes play a disease-regulating role in rhinosinusitis and asthma, particularly aspirin-sensitive disease. They act through 2 G-protein coupled receptors termed cysteinyl leukotriene type 1 receptor (cysLT 1 ) and cysteinyl leukotriene type 2 receptor (cysLT 2 ). We previously compared expression of cysLT 1 on mucosal leukocytes in patients with aspirin-sensitive and aspirin-tolerant rhinosinusitis. To compare expression of cysLT 1 and cysLT 2 on leukocytes, mucus glands, and epithelium in 32 patients with chronic polypoid rhinosinusitis (21 aspirin-sensitive, 11 aspirin-tolerant) and 9 normal controls. Total numbers of CD45 + leukocytes, percentages of these cells expressing cysLT 1 or cysLT 2 , and percentages of the total epithelial and glandular areas expressing cysLT 1 or cysLT 2 were measured in sections of nasal biopsies by using immunohistochemistry and image analysis. The percentages of mucosal CD45 + leukocytes expressing cysLT 1 were significantly ( P < .0001) elevated in the aspirin-sensitive but not the aspirin-tolerant patients compared with the controls. In contrast, the percentages of leukocytes expressing cysLT 2 did not differ significantly in the 3 groups. On epithelial and glandular cells, expression of cysLT 2 significantly exceeded that of cysLT 1 in both the patients with rhinosinusitis and the controls ( P < or = .004), although there was no significant difference in the expression of either receptor in the patients with rhinosinusitis (aspirin-sensitive or aspirin-tolerant) and the controls. Although cysLT 1 expression predominates on inflammatory leukocytes in patients with aspirin-sensitive rhinosinusitis, the effects of cysteinyl leukotrienes on glands and epithelium may be mediated predominantly through cysLT 2. This has potentially important therapeutic implications.

Dynamics of COX-2 in nasal mucosa and nasal polyps from aspirin-tolerant and aspirin-intolerant patients with asthma

Only dynamic studies can elucidate the discrepancies concerning the expression of the inducible COX-2 gene in inflammatory airway diseases. To quantify the expression and spontaneous regulation of COX-1 and COX-2 mRNAs in nasal polyps and nasal mucosa by real-time PCR. Nasal polyps were obtained from 16 aspirin-tolerant patients with asthma/rhinitis (ATAR) and 18 aspirin-intolerant patients with asthma/rhinitis (AIAR) undergoing nasal polypectomy. Nasal mucosa was obtained from 12 subjects undergoing nasal corrective surgery. All specimens were cut into 3 pieces. One was immediately snap-frozen in liquid nitrogen, and the remaining 2 were left at room temperature for 30 or 60 minutes before freezing. Data are presented as medians and 25th to 75th percentiles of 10 6 cDNA molecules/microg total RNA. Baseline COX-2 mRNA levels were significantly lower in both ATAR (0.45; 0.13-1.20; P <.05) and AIAR (0.24; 0.12-0.41; P <.001) nasal polyps than in nasal mucosa (1.35; 0.52-3.90). COX-2 mRNA expression did not change over time in nasal mucosa but increased significantly in ATAR nasal polyps ( P <.05), reaching similar levels to nasal mucosa after 60 minutes. In contrast, COX-2 mRNA showed no significant change over time in AIAR nasal polyps. COX-1 mRNA was higher in nasal polyps than in nasal mucosa, and its expression was not modified over time in any group of patients. These results suggest differential kinetics of COX-2 mRNA between nasal mucosa and nasal polyps. AIAR nasal polyps appear to have a greater abnormality of the COX-2 pathway than ATAR.

Effect of inhalation aspirin challenge on exhaled nitric oxide in patients with aspirin-inducible asthma.

A complex relationship between arachidonic acid metabolites and nitric oxide (NO) synthesis has been reported in asthma. The effects of inhaled aspirin on fractional exhaled NO (FENO) in patients with aspirin-tolerant (ATA) and aspirin-inducible (AIA) asthma compared with normal controls have been investigated. The FENO was measured baseline, after saline and lysine-aspirin (L-ASA) bronchial challenge in 10 patients with ATA and in 10 patients with AIA [mean (PD(20)FEV(1) L-ASA): 14.7 +/- 12.7 mg], who had comparable age and baseline FEV(1). Ten healthy subjects served as controls. Sputum eosinophils were counted after saline and after L-ASA challenge in the two groups of asthmatics. Asthmatic patients had baseline FENO significantly higher than controls (29.7 +/- 6.8 vs 9.8 +/- 2.05 p.p.b. respectively, P < 0.0001). No difference was observed in methacholine PD(20)FEV(1) and baseline FENO between ATA and AIA patients. After L-ASA inhalation, FENO increased significantly only in patients with AIA, reaching the peak value 4 h after bronchoconstriction (from 31.1 +/- 6 to 43 +/- 4.8 p.p.b., P < 0.001), while no change was observed in patients with ATA and in controls. Sputum eosinophils increased significantly after L-ASA inhalation only in patients with AIA (from 8.1 +/- 2.7 to 11.1 +/- 2.8%, P < 0.005) and there was a significant relationship between the increase in sputum eosinophils and the increase in FENO after ASA challenge. Exhaled NO may indicate eosinophilic airway inflammation during ASA exposure in patients with ASA inducible asthma.

Lymphocyte subpopulations and cytokines in nasal polyps: is there a local immune system in the nasal polyp?

Purpose The pathogenesis of chronic hyperplastic rhinosinusitis with massive nasal polyposis is still not entirely known. The present study evaluates the lymphocyte subpopulations and their production of cytokines using a technique for detection of intracytoplasmic cytokines by flow cytometry. This information may allow us to determine whether the source of these lymphocytes is from peripheral blood, the common mucosal immune system, or both. Methods Detection of intracytoplasmic cytokines by flow cytometry was performed using a fluoresceinated monoclonal antibody directed against CD4+ and CD8+ lymphocytes and a rhodamine-labeled intracytoplasmic monoclonal antibody directed against four cytokines. In this way, the percentage of lymphocytes synthesizing TH1 and TH2 cytokines were identified in nasal polyp lymphocytes and the corresponding peripheral blood lymphocytes of 13 patients. Results Lymphocytes producing interferon-gamma and IL-2, as well as IL-4 and IL-5, were found in the nasal polyps, suggesting that the nasal polyp possesses both TH1 and TH2 cytokine expression. There are also significant differences between the percentage of lymphocytes producing these cytokines between nasal polyps and peripheral blood, suggesting that nasal polyp lymphocytes derive from at least another source than only peripheral blood lymphocytes. Statistical analysis of four groups of patients demonstrated that no statistically significant difference in the lymphocyte subpopulations in atopic versus non-atopic patients, nor aspirin-intolerant versus aspirin-tolerant patients. In general, CD8 cells always produce more interferon-gamma than IL-2 in both peripheral blood and nasal polyps. In contrast with this data, CD4 cells produce more IL-2 in the peripheral blood than in nasal polyps. Conclusions Data support the concept that nasal polyp lymphocyte subpopulations may be derived from both the local mucosal immune system as well as from random migration of peripheral blood lymphocytes secondary to adhesion molecules and chemokines, which are known to be present in nasal polyps.

Prostaglandin EP receptor agonists differentially modulate aspirin-induced generation of 15-HETE in aspirin-sensitive asthmatics

Rationale Aspirin triggers generation of 15-hydroxyeicosaterraenoic acid (15-HETE) in peripheral blood leukocytes from aspirin-sensitive (AS) but not aspirin-tolerant (AT) patients with asthma/rhinosinusitis. The aim of this study was to determine the effect of prostaglandin EP receptor agonists (misoprostol and sulprostone) on aspirin-induced 15-HETE generation. Methods Peripheral blood leukocytes (PBLs) were isolated from AS and AT patients with asthma, and the 15-HETE release into the cell supernatant was measured with a specific immunoassay (Assay Design, MA). Results Incubation of PBLs from AS asthmatics with 200μM of lysine-aspirin significantly increased generation of 15-HETE (mean increase +260%) but lysine-aspirin did not affect 15-HETE generation in PBLs from AT asthmatics. Preincubation of cells with misoprostol or sulprostone did not affect basal 15-HETE in AS or AT patients. However, both misoprostol and sulprostone inhibited in a dose-dependent manner the ASA-induced increase in 15-HETE generation in AS asthmatics (maximal inhibition being 89% and 80% after misoprostol and sulprostone respectively). In contrast in AT patients preincubation of PBLs with misoprostol or sulprostone resulted in a significant increase in generation of 15-HETE after addition of 200μM lysine-aspirin. The maximal increase of 15-HETE generation was observed with 10 μg/ml of misoprostol or sulprostone (+73% and +86% respectively). Conclusions Our data suggest that aspirin-triggered 15-HETE release is differentially regulated by prostaglandin EP receptors in PBLs from AS and AT asthmatics.

Outcome analysis of endoscopic sinus surgery in patients with nasal polyps and asthma.

To investigate the efficacy of endoscopic sinus surgery (ESS) in the management of chronic sinusitis and asthma in patients with nasal polyps and steroid-dependent asthma. Retrospective chart review. The study included 17 patients who underwent ESS with nasal polyps, steroid-dependent asthma with or without aspirin sensitivity and a minimum of 1 year postoperative follow-up. Nine patients were ASA sensitive, and eight patients were ASA tolerant. Chronic sinusitis and asthma were evaluated using subjective (patient complaints) and objective (computed tomography scans, pulmonary function tests, steroid doses) criteria. Preoperative data were compared with data obtained 12 to 18 months postESS. Tissue samples were graded for degree of inflammation and edema. Thirteen of the 17 (76.5%) patients reported improved clinical symptoms postESS. The postoperative Lund-Mackay scores were statistically lower for the 17 patients (P <.0001). The group experienced improvement in postoperative forced expiratory volume at 1 second (FEV1) (P <.014). Twelve of 17 (70.6%) experienced reduction in systemic steroid usage (P <.048). The ASA sensitive patients did not have a statistical improvement in postoperative FEV1 (P >.08) and sinonasal symptoms (P >.16) compared with the ASA tolerant group. Polyp tissue from the ASA sensitive patients demonstrated more edema and more inflammation on average than ASA tolerant polyps, but the results were not statistically significant. ESS demonstrates a beneficial effect on the sinonasal and asthma symptomatology in patients with nasal polyps and asthma using objective measures. Subset of aspirin-tolerant patients have statistically better outcome for sinonasal symptoms and pulmonary function testing than aspirin-sensitive patients.

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 μmol/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.