Aspirin-intolerant Asthma Research Articles

Urinary Leukotriene E4 as a Biomarker in NSAID-Exacerbated Respiratory Disease (N-ERD): a Systematic Review and Meta-analysis.

Non-steroidal exacerbated respiratory disease (N-ERD) currently requires aspirin challenge testing for diagnosis. Urinary leukotriene E4 (uLTE4) has been extensively investigated as potential biomarker in N-ERD. We aimed to assess the usefulness of uLTE4 as a biomarker in the diagnosis of N-ERD. N-ERD, formerly known as aspirin-intolerant asthma (AIA), is characterised by increased leukotriene production. uLTE4 indicates cysteinyl leukotriene production, and a potential biomarker in N-ERD. Although several studies and have examined the relationship between uLTE4 and N-ERD, the usefulness of uLTE4 as a biomarker in a clinical setting remains unclear. Our literature search identified 38 unique eligible studies, 35 were included in the meta-analysis. Meta-analysis was performed (i.e. pooled standardised mean difference (SMD) with 95% confidence intervals (95% CI)) and risk of bias assessed (implementing Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy (Cochrane DTA)). Data from 3376 subjects was analysed (1354N-ERD, 1420 ATA, and 602 HC). uLTE4 was higher in N-ERD vs ATA (n = 35, SMD 0.80; 95% CI 0.72-0.89). uLTE4 increased following aspirin challenge in N-ERD (n = 12, SMD 0.56; 95% CI 0.26-0.85) but not ATA (n = 8, SMD 0.12; CI - 0.08-0.33). This systematic review and meta-analysis showed that uLTE4 is higher in N-ERD than ATA or HC. Likewise, people with N-ERD have greater increases in uLTE4 following aspirin challenge. However, due to the varied uLTE4 measurement and result reporting practice, clinical utility of these findings is limited. Future studies should be standardised to increase clinical significance and interpretability of the results.

Distinct Gene Set Enrichment Profiles in Eosinophilic and Non-Eosinophilic Chronic Rhinosinusitis with Nasal Polyps by Bulk RNA Barcoding and Sequencing.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease with a high symptom burden, including nasal congestion and smell disorders. This study performed a detailed transcriptomic analysis in CRSwNP classified as eosinophilic CRS (ECRS), nonECRS according to the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) criteria, and a group of ECRS with comorbid aspirin intolerant asthma (Asp). Gene expression profiles of nasal polyps and the uncinate process in CRSwNP patients and normal subjects (controls) were generated by bulk RNA barcoding and sequencing (BRB-seq). A differentially expressed genes (DEGs) analysis was performed using DESeq2 software in iDEP to clarify any relationship between gene expression and disease backgrounds. A total of 3004 genes were identified by DEGs analysis to be associated with ECRS vs control, nonECRS vs control, and Asp vs control. A pathway analysis showed distinct profiles between the groups. A Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) showed distinct phenotype-specific pathways of expressed genes. In the specific pathway of “cytokine–cytokine receptor interaction”, the differentially expressed genes were widely distributed. This study indicates that transcriptome analysis using BRB-seq may be a valuable tool to explore the pathogenesis of type 2 inflammation in CRSwNP.

Development of Monoclonal Antibody-Based EIA for Tetranor-PGDM which Reflects PGD2 Production in the Body.

Tetranor-PGDM is a metabolite of PGD2. Urinary tetranor-PGDM levels were reported to be increased in some diseases, including food allergy, Duchenne muscular dystrophy, and aspirin-intolerant asthma. In this study, we developed a monoclonal antibody (MAb) and a competitive enzyme immunoassay (EIA) for measuring tetranor-PGDM. Spleen cells isolated from mice immunized with tetranor-PGDM were utilized to generate Ab-producing hybridomas. We chose hybridomas and purified MAb against tetranor-PGDM to develop competitive EIA. The assay evaluated the optimal ionic strength, pH, precision, and reliability. Specificity was determined by cross-reactivity to tetranor-PGEM, tetranor-PGFM, and tetranor-PGAM. Recovery was determined by spiking experiments on artificial urine. Optimal ionic strength was 150 mM NaCl, and optimal pH was pH 7.5. Metabolites other than tetranor-PGDM did not show any significant cross-reactivity in the EIA. The assay exhibited a half-maximal inhibition concentration (IC50) of 1.79 ng/mL, limit of detection (LOD) of 0.0498 ng/mL, and range of quantitation (ROQ) value of 0.252 to 20.2 ng/mL. The intra- and inter-assay variation for tetranor-PGDM was 3.9–6.0% and 5.7–10.4%, respectively. The linearity-dilution effect showed excellent linearity under dilution when artificial urine samples were applied to solid-phase extraction (SPE). After SPE, recovery of tetranor-PGDM in artificial urine averaged from 82.3% to 113.5% and was within acceptable limits (80%–120%). We successfully generated one monoclonal antibody and developed a sensitive competitive EIA. The established EIA would be useful for routine detection and monitoring of tetranor-PGDM in research or diagnostic body fluids.

Expression of COX-1, COX-2, 5-LOX and hbox {CysLT}_2 in nasal polyps and bronchial tissue of patients with aspirin exacerbated airway disease

BackgroundAspirin exacerbated respiratory disease (AERD) is a disease of the upper and lower airways. It is characterized by severe asthma, chronic sinusitis with nasal polyps (CRSwNP) and intolerance towards nonsteroidal analgesics (NSAR). Arachidonic acid (AA) metabolites play an important role in the pathogenesis of AERD. It is still unknown, whether metabolism of AA is comparable between the upper and lower airways as well as between patients with and without NSAR intolerance.ObjectiveWe sought to analyze differences in the expression of cyclooxygenases type 1 and 2 (COX-1, COX-2), arachidonate 5-lipoxygenase (5-LOX) and cysteinyl leukotriene receptor type 2 (hbox {CysLT}_2) in nasal polyps and the bronchial mucosa of patients with aspirin intolerant asthma (AIA, n=23) as compared to patients with aspirin tolerant asthma (ATA, n=17) and a control group with nasal polyps, but without asthma (NPwA, n=15).MethodsTissue biopsies from nasal polyps and bronchial mucosa were obtained during surgical treatment of nasal polyps by endonasal functional endoscopic sinus surgery (FESS) under general anesthesia from intubated patients. Immunohistochemistry was used to analyze the expression of COX-1, COX-2, 5-LOX and hbox {CysLT}_2 in nasal and bronchial mucosa. Categorization into the different patient groups was performed according to the patient history, clinical and laboratory data, pulmonary function and provocation tests, as well as allergy testing.ResultsWe observed a stronger expression of 5-LOX and hbox {CysLT}_2 in submucosal glands of nasal and bronchial tissue compared to epithelial expression. The expression of COX-1 and COX-2 was stronger in epithelia compared to submucosal glands. There was a similar expression of the enzymes and hbox {CysLT}_2 between upper and lower airways in all patient groups. We did not detect any significant differences between the patient groups.ConclusionsThe AA-metabolizing enzymes and the hbox {CysLT}_2 were expressed in a very similar way in different microscopic structures in samples of the upper and lower airways of individual patients. We did not detect differences between the patient groups indicating the pathogenetic role of AA metabolism in these disorders is independent of the presence of NSAR-intolerance.

Urinary Leukotriene E4 to Determine Aspirin Intolerance in Asthma: A Systematic Review and Meta-Analysis

Urinary leukotriene E4 (ULTE4) may be a biomarker that distinguishes aspirin-intolerant asthma from other asthma subtypes. To estimate the diagnostic testing accuracy of ULTE4 as a marker of aspirin intolerance in patients with asthma using previously published studies. We identified relevant clinical studies from a systematic review of English and non-English articles using MEDLINE, EMBASE, and CENTRAL (inception to February 10, 2015). Articles were screened at the abstract and full-text level by 2 independent reviewers. We included previously published studies that analyzed ULTE4 in human subjects with asthma characterized as having or not having aspirin intolerance on the basis of a specified definition: convincing history of aspirin intolerance, positive aspirin challenge, or both as the criterion standard. Individual-level data points from all included studies were obtained and analyzed. The search strategy identified 867 potential articles, of which 86 were reviewed at the full-text level and 10 met criteria for inclusion. The sensitivity, specificity, positive predictive value, and negative predictive values of ULTE4 to determine aspirin intolerance in subjects with asthma were 0.55, 0.82, 0.75, and 0.66 (Amersham-enzyme immunoassay); 0.76, 0.77, 0.70, and 0.78 (Cayman-enzyme immunoassay); 0.70, 0.81, 0.86, and 0.79 (mass spectrometry); and 0.81,0.79, 0.65, and 0.88 (radioimmunoassay) at optimal thresholds of 192, 510, 167 to 173, and 66 to 69 pg/mg Cr, respectively. The diagnostic odds ratio for each methodology was 6.0, 11.9, 10.5, and 19.1, respectively. ULTE4 is a marker for aspirin-intolerant asthma and could potentially be used as a clinical test to identify the risk of aspirin intolerance in subjects with asthma.

Differences in urinary leukotriene E4 levels and distribution of eosinophils between chronic rhinosinusitis patients with aspirin-intolerant and -tolerant asthma.

Urinary leukotriene E4 (U-LTE4) concentrations are significantly elevated in patients with aspirin-intolerant asthma (AIA). However, the relationship between the clinicopathogenetic features of eosinophilic rhinosinusitis and U-LTE4 concentration remains unknown. Here we examined the relationship between U-LTE4 level and eosinophil in chronic rhinosinusitis. We measured the U-LTE4 concentrations and eosinophil counts in ethmoidal and maxillary sinuses and peripheral blood in 30 asthmatic patients (including 15 AIA patients). Eosinophil counts in ethmoidal sinuses and peripheral blood were markedly higher in asthmatic patients than in controls. Although there were no significant differences between eosinophil counts in maxillary and ethmoidal sinuses for ATA group, eosinophil counts were higher in ethmoidal sinus compared to that in maxillary sinus in the AIA group (P<.05). Eosinophil counts were higher in the maxillary than in ethmoidal sinuses for control patients (P<.05). Despite low correlation between eosinophil counts in peripheral blood and eosinophil counts in maxillary sinus (rs=0.4323, P<.001), moderate correlation was observed between eosinophil counts in peripheral blood and eosinophil counts in ethmoidal sinus (rs=0.5249, P<.0001). Basal U-LTE4 concentrations were higher in AIA patients than in those with aspirin-tolerant asthma. Despite low correlation between eosinophil counts and U-LTE4 concentration in maxillary sinus (rs=0.3849, P<.01), moderate correlation was observed between eosinophil counts and U-LTE4 concentrations in ethmoidal sinus (rs=0.4736, P<.001). We describe the differences in U-LTE4 and other parameters in AIA compared to ATA, and correlation among parameters. We demonstrate that eosinophil-dominant inflammation starts in ethmoidal sinus clinicopathogenetically in CRS with asthma. U-LTE4 concentration was not exclusively associated with eosinophil counts in ethmoidal sinus. Eosinophils in ethmoidal sinus may be a major production site for CysLTs, particularly in AIA. CRS with AIA is assumed to be characterized by leukotriene-eosinophil cross-interaction in ethmoidal sinus.

Association ofTLR3gene polymorphism with IgG subclass deficiency and the severity in patients with aspirin-intolerant asthma

Purpose: Toll-like receptor 3 (TLR3) recognizes to viral double-stranded RNA and is involved in antiviral defenses. A probable role of TLR3 gene variants in the pathogenesis of aspirin-intolerant asthma (AIA) has been suggested. AIA patients present more frequent asthma exacerbations in which respiratory viral infections could be an exacerbating factor. IgG subclass deficiency was commonly present with bronchial asthma. Based on previous findings, we investigated whether TLR3 variants could affect IgG3 subclass deficiency in AIA.Methods: We enrolled 279 AIA patients, 403 aspirin-tolerant asthma (ATA) patients, and 315 normal healthy controls (NC) in this study. TLR3 polymorphism at the promoter region -299698G>T was genotyped. The serum levels of IgG subclasses were determined by the single radial immunodiffusion method. Expressions of IgG3 and TLR3 on Epstein-Barr virus transformed-B cells isolated from asthmatic patients were evaluated by flow cytometry to investigate B-cell functions.Results: The TLR3 -299698 T allele was significantly associated with severity and IgG3 deficiency in the AIA group (P=0.044 and P=0.010, respectively), but not in the ATA group. IgG3 expression on B cells from asthmatics with IgG3 deficiency was significantly lower compared to those without (P=0.025). There was a positive correlation between IgG3 expression levels on B cells and serum IgG3 levels (r2=0.434, P=0.002).Conclusion: These results suggest that the TLR3 -299698G>T polymorphism may be associated with IgG3 subclass deficiency and severity in AIA. (Allergy Asthma Respir Dis 2016:4:264-270)

慢性副鼻腔炎の予後不良因子

Chronic rhinosinusitis (CRS) is a commonly encountered chronic disease that is treated with medications (e.g., corticosteroids or macrolides) and by endoscopic sinus surgery. Although there has been an increase in the cure rate of CRS recently following the introduction of these treatments, a substantial number of patients still have a poor prognosis. Nasal polyps immediately recur after surgery in cases of CRS that present with severe eosinophilic infiltration. We refer to CRS with eosinophilic infiltration as eosinophilic CRS (ECRS). CRS is known to have a multifactorial etiology. Even with the best ESS technique, the clinical course of the disease after the surgery can be challenging on account of several factors, including the postoperative management and the type and the extent of the disease, which may contribute to the natural course of the disease and the surgical outcomes. It has been reported that nasal polyps and asthma are linked by shared inflammation of the entire airway mucosa, and particularly by increased eosinophil infiltration of the mucosa. In addition, mucosal eosinophilia is frequently associated with more severe disease and with recurrence of polyps after surgery. Furthermore, CRS patients with aspirin-intolerant asthma often have particularly severe asthma that is associated with rhinorrhea and recurrent nasal polyps. These findings suggest that concomitant asthma may contribute to the pathophysiology of CRS. Our study revealed that women with CRS have a poorer prognosis than men with CRS. Future studies are needed to elucidate the mechanisms that drive the gender-related difference in disease severity, paving the way for the development of personalized treatments for CRS based on the gender of the patient.

アスピリン不耐性喘息とアスピリン耐性喘息間における尿中-LTE4 と慢性副鼻腔炎副鼻腔粘膜への好酸球分布の違い

アスピリン不耐性喘息とアスピリン耐性喘息間における尿中-LTE4 と慢性副鼻腔炎副鼻腔粘膜への好酸球分布の違い

The whole-genome expression analysis of peripheral blood mononuclear cells from aspirin sensitive asthmatics versus aspirin tolerant patients and healthy donors after in vitro aspirin challenge.

BackgroundUp to 30 % of adults with severe asthma are hypersensitive to aspirin and no unambiguous theory exists which provides a satisfactory explanation for the occurrence of aspirin-induced asthma (AIA) in some asthmatic patients. Therefore, the aim of this study was to compare the AIA expression profile against aspirin tolerant asthma (ATA) and healthy volunteers (HV) profile in peripheral blood mononuclear cells (PBMCs) after in vitro aspirin challenge in Caucasian population.MethodsPBMCs were separated from blood of three groups of subjects - 11 AIA, 7 ATA and 15 HV and then stimulated by either 2 μM lysine aspirin or 20 μM lysine as a control. Subsequently, RNA was isolated, transcribed into cDNA and subjected to microarray and qPCR studies. Simultaneously, protein was extracted from PBMCs and used in further immunoblotting analysis.ResultsThe validation of results at mRNA level has shown only three genes, whose expression was significantly altered between comprising groups. mRNA expression of CNPY3 in PBMCs in AIA was significantly lower (-0.41 ± 2.67) than in HV (1.04 ± 2.69), (p = 0.02); mRNA expression of FOSL1 in PBMCs in AIA was also significantly decreased (-0.66 ± 2.97) as opposed to HV (0.31 ± 4.83), (p = 0.02). While mRNA expression of ERAS in PBMCs was increased (1.15 ± 0.23) in AIA in comparison to HV (-1.32 ± 0.41), (p = 0.03). At protein level the changed expression of one protein was confirmed. Protein expression of FOSL1 in PBMCs in AIA was both significantly lower (-0.86 ± 0.08) than in ATA (0.39 ± 0.42), (p = 0.046) and in HV (0.9 ± 0.27), (p = 0.007).ConclusionsThis pilot study implies a positive association between CNPY3, ERAS, FOSL1 and aspirin-intolerant asthma, suggesting that these findings would be useful for further investigations of NSAIDs mechanism.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-015-0305-4) contains supplementary material, which is available to authorized users.

Aspirin desensitization for patients with aspirin-exacerbated respiratory disease: A randomized double-blind placebo-controlled trial

The effect of aspirin desensitization (AD) on immunologic profile of patients with AERD has been poorly understood. This study is aimed at investigating the effect of AD on clinical and immunological markers of patients with AERD. This randomized double-blind placebo-controlled trial comprised 34 adult patients (67.6% female) with chronic rhinosinusitis, nasal polyps, and aspirin-intolerant asthma. The active group underwent AD over a 2-day period with increasing doses of aspirin (60, 125, 325, and 625mg), followed by receiving aspirin 625mg twice daily for 6months. Symptom scores and medication needs of patients with AERD who have undergone AD were significantly lower compared to the placebo group after 6months (7.5±3.5 vs. 10.6±3.8 and 9.3±2.0 vs. 11.0±3.1, respectively, all p<0.05). However, no significant difference was observed in serum concentration of IL-10, IFN-γ, and TGF-β between two groups neither at baseline nor at the end of study.

Aspirin-intolerant asthma in the population: prevalence and important determinants.

Population-based studies on aspirin-intolerant asthma (AIA) are very few, and no previous population study has investigated risk factors for the condition. To investigate the prevalence and risk factors of AIA in the general population. A questionnaire on respiratory health was mailed to 30,000 randomly selected subjects aged 16-75 years in West Sweden, 29,218 could be traced and 18,087 (62%) responded. The questionnaire included questions on asthma, respiratory symptoms, aspirin-induced dyspnoea and possible determinants. The prevalence of AIA was 0.5%, 0.3% in men and 0.6% in women (P = 0.014). Sick leave, emergency visits due to asthma and all investigated lower respiratory symptoms were more common in AIA than in aspirin-tolerant asthma (ATA). Obesity was a strong risk factor for AIA (BMI > 35: odds ratio (OR) 12.1; 95% CI 2.49-58.5), and there was a dose-response relationship between increasing body mass index (BMI) and risk of AIA. Obesity, airborne occupational exposure and visible mould at home were considerably stronger risk factors for AIA than for ATA. Current smoking was a risk factor for AIA (OR 2.55; 95% CI 1.47-4.42), but not ATA. Aspirin-intolerant asthma identified in the general population was associated with a high burden of symptoms, uncontrolled disease and a high morbidity. Increasing BMI increased the risk of AIA in a dose-response manner. A number of risk factors, including obesity and current smoking, were considerably stronger for AIA than for ATA.

Risk factors associated with severity of eosinophilic otitis media.

Eosinophilic otitis media (EOM) is an intractable otitis media associated with bronchial asthma. Clinical characteristics of EOM are apparent, but severe EOM, which is unresponsive to ongoing treatments, can occur. The present study aimed to investigate potential risk factors associated with the severity of EOM. We scored the EOM severity of 26 patients according to quantity of middle ear effusion (MEE), thickness of the middle ear mucosa, use of topical and oral corticosteroids, and use of antibiotics, all measured over a 3-month period. The scores for four 3-month periods (1 year) were averaged. We analyzed the prevalence of clinical variables by partial regression: sex, age, body mass index (BMI), duration of bronchial asthma, association of aspirin-intolerant asthma, Lund-Mackay score for sinusitis, mastoid pneumatization, width of the bony Eustachian tube at the tympanic orifice, percentage of eosinophils and immunoglobulin E in peripheral blood, and association of allergic rhinitis. Duration of bronchial asthma was defined as the period from onset of bronchial asthma to the age of first consultation at our hospital. Samples of MEE were taken for bacterial culture. The average severity score was 6.6 (out of 16). The severity score in the pathogen-positive MEE group was significantly higher than that in the pathogen-negative MEE group (p<0.05). The score was not significantly different between the seasons. Linear multiple regression analysis showed that BMI and the duration of bronchial asthma significantly affected the EOM severity score (p<0.05). The presence of aspirin intolerant asthma tended to be correlated with the severity score. The Lund-Mackay score tended to be negatively correlated with it. There is a significant association between the severity of EOM and obesity, as well as with the duration of bronchial asthma.

Myeloid-derived suppressor cell function is diminished in aspirin-triggered allergic airway hyperresponsiveness in mice

Myeloid-derived suppressor cells (MDSCs) have recently been implicated in the pathogenesis of asthma, but their regulation in patients with aspirin-intolerant asthma (AIA) remains unclear. We sought to characterize MDSC accumulation and pathogenic functions in allergic airway inflammation mediated by COX-1 deficiency or aspirin treatment in mice. Allergic airway inflammation was induced in mice by means of ovalbumin challenge. The distribution and function of MDSCs in mice were analyzed by using flow cytometry and pharmacologic/gene manipulation approaches. CD11b(+)Gr1(high)Ly6G(+)Ly6C(int) MDSCs (polymorphonuclear MDSCs [PMN-MDSCs]) recruited to the lungs are negatively correlated with airway inflammation in allergen-challenged mice. Aspirin-treated and COX-1 knockout (KO) mice showed significantly lower accumulation of PMN-MDSCs in the inflamed lung and immune organs accompanied by increased TH2 airway responses. The TH2-suppressive function of PMN-MDSCs was notably impaired by COX-1 deletion or inhibition, predominantly through downregulation of arginase-1. COX-1-derived prostaglandin E2 promoted PMN-MDSC generation in bone marrow through E prostanoid 2 and 4 receptors (EP2 and EP4), whereas the impaired arginase-1 expression in PMN-MDSCs in COX-1 KO mice was mediated by dysregulation of the prostaglandin E2/EP4/cyclic AMP/protein kinase A pathway. EP4 agonist administration alleviated allergy-induced airway hyperresponsiveness in COX-1 KO mice. Moreover, the immunosuppressive function of PMN-MDSCs from patients with AIA was dramatically decreased compared with that from patients with aspirin-tolerant asthma. The immunosuppressive activity of PMN-MDSCs was diminished in both allergen-challenged COX-1 KO mice and patients with AIA, probably through an EP4-mediated signaling pathway, indicating that activation of PMN-MDSCs might be a promising therapeutic strategy for asthma, particularly AIA.

Aspirin induces IL-4 mRNA expression via activation of MAPKs pathway (HYP6P.272)

Abstract Aspirin-exacerbated respiratory disease is characterized by asthma, nasal polyps, and intolerance to aspirin. IL-4 is mainly produced by allergic cells, including Th2 cells, mast cells, and eosinophils, and plays a central role in pathogenesis of allergic diseases such as asthma. In the present study, we demonstrated that aspirin induced IL-4 expression. Aspirin dose-dependently induced IL-4 mRNA and IL-4 promoter reporter activity in these three cell types. Treatment with pharmacologic inhibitors showed that the aspirin-induced IL-4 expression occurred through the MAPK ERK1/2 pathway, which was consistent with the observation that aspirin induced ERK phosphorylation. Analysis of serially deleted IL-4 promoter reporter showed that aspirin elevated the promoter activities regardless of the deleted constructs. When nuclear extract from these cells treated with aspirin were reacted with the probes harboring P0, P1, P2, P3, P4, P5 elements, and a region between P1 and P2 elements, DNA-protein complexes were remarkably augmented in the probes. Some of the DNA-protein complexes were supershifted by anti-NFAT. Collectively, these data indicate that aspirin induces IL-4 expression via ERK1/2 activation and availability of transcription factors that bind critical cis-acting elements in IL-4 promoter, thereby contributing to pathogenesis of aspirin-intolerant asthma.

Fatty acids, inflammation, and asthma

Fatty acids and consequently diet play an essential role in the formation of inflammatory mediators involved in the pathogenesis of asthma. Because intake variations of omega-6 (n-6) and omega-3 (n-3) fatty acids ultimately determine cell membrane incorporation, changes in diet have the potential to modify downstream production of inflammatory mediators derived from these compounds. It has long been hypothesized that decreasing the n-6/n-3 ratio could reduce the production of more proinflammatory mediators while increasing the formation of downstream metabolites that can serve to limit or resolve inflammation. In turn, these changes would result in improved asthma outcomes or would lower the risk for asthma incidence. This review will focus on the role of fatty acid inflammatory and resolving mediators and will summarize the clinical and epidemiologic data on how diet and obesity alter fatty acid profiles that can contribute to asthma.

The Influence of Aspirin on Release of Eoxin C4, Leukotriene C4 and 15-HETE, in Eosinophilic Granulocytes Isolated from Patients with Asthma

Background: The effect of aspirin on the release of key arachidonic acid metabolites in activated eosinophils from subjects with aspirin-intolerant asthma (AIA) has not been investigated previously, despite the characteristic eosinophilia in AIA. Methods: Peripheral blood eosinophils were isolated from four groups of subjects: healthy volunteers (HV; n = 8), mild asthma (MA; n = 8), severe asthma (SA; n = 9) and AIA (n = 7). In the absence or presence of lysine-aspirin, eosinophils were stimulated with arachidonic acid or calcium ionophore to trigger the 15-lipoxygenase-1 (15-LO) and 5-lipoxygenase (5-LO) pathways, respectively. 15(S)-hydroxy-eicosatetraenoic acid (15-HETE) and eoxin C₄ (EXC₄) were measured as 15-LO products and leukotriene (LT)C₄ as a product of the 5-LO pathway. Results: Activated eosinophils from patients with SA and AIA produced approximately five times more 15-HETE than eosinophils from HV or MA patients. In the presence of lysine-aspirin, eosinophils from AIA, MA and SA patients generated higher levels of 15-HETE than in the absence of lysine-aspirin. Furthermore, in the presence of lysine-aspirin, formation of EXC₄ was also significantly increased in eosinophils from AIA patients, and LTC₄ synthesis was increased both in AIA and SA patients. Conclusions: Taken together, this study shows an increased release of the recently discovered lipid mediator EXC₄, as well as the main indicator of 15-LO activity, 15-HETE, in activated eosinophils from severe and aspirin-intolerant asthmatics, and also elevated EXC₄ and LTC₄ formation in eosinophils from AIA patients after cellular activation in the presence of lysine-aspirin. The findings support a pathophysiological role of the 15-LO pathway in SA and AIA.

Increased CXCL10 Expression in Nasal Fibroblasts from Patients with Refractory Chronic Rhinosinusitis and Asthma

Chronic rhinosinusitis (CRS) is characterized by local inflammation of the sinonasal tissues. CRS patients with nasal polyps and asthma often develop acute exacerbation of sinonasal symptoms after upper respiratory tract infections. However, the influence of concomitant asthma on the nasal immune response to viral infection remains unclear. Specimens of nasal polyp and mucosal tissues were obtained from 3 groups of CRS patients (n = 14 per group): 1) patients without asthma (CRS group), 2) patients with aspirin-tolerant asthma (ATA group), and 3) patients with aspirin-intolerant asthma (AIA group). Nasal fibroblasts isolated from the specimens were stimulated with poly I:C. CXCL10 expression was analyzed by the quantitative real-time polymerase chain reaction and enzyme-linked immunoadsorbent assay. Biopsy specimens from CRS patients without asthma were subjected to immunohistochemistry for detection of T-bet and GATA-3 expression in CD3+ T cells by double labeling. Nasal fibroblasts from the ATA and AIA groups showed significantly enhanced expression of CXCL10 mRNA and protein after poly I:C stimulation compared with cells from the CRS group and the control group (normal nasal mucosa). In addition to T helper (Th)2 cells, there was more abundant infiltration of Th1 cells into tissues from the AIA and ATA groups. Our findings suggest that CRS associated with asthma may become intractable through the over-production of CXCL10 in response to viral infection.

Age-Specific Characteristics of Inpatients with Severe Asthma Exacerbation

The characteristics of inpatients with severe asthma exacerbation remain unclear. It is considered that the characteristics of inpatients with severe asthma vary depending on age. However, these are rarely investigated. The objective of this study is to investigate the differences in characteristics among different age groups. We considered that it is necessary to understand the characteristics of each age group so that we can establish strategies in preventing severe asthma exacerbation. All asthma inpatients who were hospitalized between 2004 and 2011 with SpO2 <90% (in room air), were breathless at rest, and showed increased respiratory rate and pulse rate were examined. We compared the characteristics among the young age group, middle age group, and advanced age group. The total number of patients was 204. In the young age group, the percentages of patients with irregular visits and non visits to a medical institution were high. This group showed high percentages of smokers and pet owners. The percentage of continuous ICS users in this group was 25.9%. The middle age group had high rates of aspirin-intolerant asthma. The percentage of continuous ICS users in this group was 60.2%. In the advanced age group, the percentages of patients with hypertension/heart disease, diabetes mellitus, and COPD were high. This group showed good treatment adherence. The percentage of continuous ICS users in this group was 77.4%. The characteristics of inpatients with severe asthma vary depending on age. We need to establish countermeasures for asthma exacerbation according to the characteristics of patients depending on age.

Aspirin-Intolerant Asthma: A Comprehensive Review of Biomarkers and Pathophysiology

Aspirin-exacerbated respiratory disease is a tetrad of nasal polyps, chronic hypertrophic eosinophilic sinusitis, asthma, and sensitivity to aspirin. Unawareness of this clinical condition by patients and physicians may have grave consequences because of its association with near-fatal asthma. The pathogenesis of aspirin-intolerant asthma is not related with an immunoglobin E mechanism, but with an abnormal metabolism of the lipoxygenase (LO) and cyclooxygenase (COX) pathways. At present, a diagnosis of aspirin sensitivity can be established only by provocative aspirin challenge, which represents a health risk for the patient. This circumstance has encouraged the search for aspirin intolerance-specific biomarkers. Major attempts have focused on mediators related with inflammation and eicosanoid regulation. The use of modern laboratory techniques including high-throughput methods has facilitated the detection of dozens of biological metabolites associated with aspirin-intolerant asthma disease. Not surprisingly, the majority of these is implicated in the LO and COX pathways. However, substantial amounts of data reveal the participation of many genes deriving from different ontologies. Biomarkers may represent a powerful, noninvasive tool in the diagnosis of aspirin sensitivity; moreover, they could provide a new way to classify asthma phenotypes.