Serum periostin relates to type-2 inflammation and lung function in asthma: Data from the large population-based cohort Swedish GA(2)LEN.

BACKGROUND: Periostin has been suggested as a novel, phenotype-specific biomarker for asthma driven by type 2 inflammation. However, large studies examining relationships between circulating periostin and patient characteristics are lacking and the suitability of periostin as a biomarker in asthma remains unclear. AIM: To examine circulating periostin in healthy controls and subjects with asthma from the general population with different severity and treatment profiles, both with and without chronic rhinosinusitis (CRS), in relation to other biomarkers and clinical characteristics. METHODS: Serum periostin was examined by ELISA in 1100 subjects aged 17-76 from the Swedish Global Allergy and Asthma European Network (GA(2)LEN) study, which included 463 asthmatics with/without chronic rhinosinusitis (CRS), 98 individuals with CRS only, and 206 healthy controls. Clinical tests included measurement of lung function, Fraction of exhaled NO (FeNO), IgE, urinary eosinophil-derived neurotoxin (U-EDN), and serum eosinophil cationic protein (S-ECP), as well as completion of questionnaires regarding respiratory symptoms, medication, and quality of life. RESULTS: Although median periostin values showed no differences when comparing disease groups with healthy controls, multiple regression analyses revealed that periostin was positively associated with higher FeNO, U-EDN, and total IgE. In patients with asthma, an inverse relationship with lung function was also observed. Current smoking was associated with decreased periostin levels, whereas increased age and lower body mass index (BMI) related to higher periostin levels in subjects both with and without asthma. CONCLUSION: We confirm associations between periostin and markers of type 2 inflammation, as well as lung function, and identify novel constitutional factors of importance to the use of periostin as a phenotype-specific biomarker in asthma.

Assessment of in vivo mast cell reactivity in patients with systemic mastocytosis.

BACKGROUND: Patients with systemic mastocytosis (SM) have clinical signs of mast cell (MC) activation and increased levels of MC mediators. It is unclear whether the increased mediator levels are caused by increased numbers of tissue MCs, or whether these cells in affected individuals have a hyperactive phenotype. OBJECTIVE: To determine reactivity of the skin and the airways to directly acting mediators and indirectly acting mast cell secretagogues in subjects with SM. METHODS: Skin reactivity to morphine and histamine, and airway responsiveness to mannitol and methacholine, was assessed in 15 patients with SM, 11 patients with allergic asthma (A) and 13 healthy controls (HC). Serum tryptase and urinary metabolites of the MC mediators histamine and prostaglandin D2 were measured, as well as ex vivo basophil histamine release. RESULTS: Mast cell mediators in the blood and urine were significantly higher in patients with SM than in HC and A controls. Responsiveness to local activation of skin MCs (by morphine) and airway MCs (by mannitol) was similar in SM and HC groups. Likewise, end-organ responsiveness in the skin to histamine, and in the airways to methacholine, was similar in all three subject groups. There was no evidence of increased basophil reactivity in SM patients. CONCLUSIONS AND CLINICAL RELEVANCE: Mast cells in the skin and airways of subjects with SM do not exhibit hyper-reactivity towards the MC-activating stimuli morphine and mannitol, respectively. Therefore, the highly elevated baseline levels of MC mediators in SM are most likely due to increased MC numbers, rather than altered MC responsiveness. The underlying mechanisms could involve leakage of MC mediators, or dysfunctions in mediator synthesis, storage and release. One clinical implication of our study is that there is no contraindication to perform skin tests using morphine in subjects with mastocytosis.

Simultaneously elevated exhaled nitric oxide and serum-eosinophil cationic protein relate to recent asthma events in asthmatics in a cross-sectional population-based study.

BACKGROUND: We have reported that increased fraction of exhaled nitric oxide (FeNO), a measure of TH2 -driven airway inflammation, and blood eosinophil count, a marker of systemic eosinophil inflammation, correlated with asthma attacks in a population-based study. OBJECTIVE: To investigate the relation between simultaneously elevated FeNO and serum eosinophil cationic protein (S-ECP) levels and asthma events among asthmatics. METHODS: Measurements of FeNO (elevated ≥ 25 ppb) and S-ECP (elevated ≥ 20 ng/mL) were performed in 339 adult asthmatics. Asthma events (attacks and symptoms) were self-reported. RESULTS: Simultaneously normal S-ECP and FeNO levels were found in 48% of the subjects. Subjects with simultaneously elevated S-ECP and FeNO (13% of the population) had a higher prevalence of asthma attacks in the preceding 3 months than subjects with normal S-ECP and FeNO (51% vs. 25%, P = 0.001). This was not found for subjects with singly elevated S-ECP (P = 0.14) or FeNO (P = 0.34) levels. Elevated S-ECP and FeNO levels were independently associated with asthma attacks in the preceding 3 months after adjusting for potential confounders (OR (95% CI) 4.2 (2.0-8.8). CONCLUSIONS: Simultaneously elevated FeNO and S-ECP levels were related to a higher likelihood of asthma attacks in the preceding 3 months. This indicates that there is a value in measuring both FeNO and systemic eosinophilic inflammation in patients with asthma to identify individuals at high risk of exacerbations. CLINICAL RELEVANCE: FeNO and S-ECP are markers for inflammation in asthma, but are dependent on different inflammatory pathways and weakly correlated. Simultaneous measurements of both offer better risk characterization of adult asthmatics.

Important non-disease-related determinants of exhaled nitric oxide levels in mild asthma - results from the Swedish GA(2) LEN study.

BACKGROUND: Fractional exhaled nitric oxide (FeNO) has a potential clinical role in asthma management. Constitutive factors such as age, height and gender, as well as individual characteristics, such as IgE sensitization and smoking, affect the levels of FeNO in population-based studies. However, their effect on FeNO in subjects with asthma has been scarcely studied. OBJECTIVE: To study the effects on FeNO of these commonly regarded determinants, as demonstrated in healthy subjects, as well as menarche age and parental smoking, in a population of asthmatics. MATERIAL AND METHODS: Fractional exhaled nitric oxide was measured in 557 subjects with asthma from the Swedish GA(2) LEN study. Allergic sensitization was assessed by skin prick tests to most common aeroallergens. Upper airway comorbidities, smoking habits, smoking exposure during childhood and hormonal status (for women) were questionnaire-assessed. RESULTS: Male gender (P < 0.001), greater height (P < 0.001) and sensitization to both perennial allergens and pollen (P < 0.001) are related to higher FeNO levels. Current smoking (P < 0.001) and having both parents smoking during childhood, vs. having neither (P < 0.001) or only one parent smoking (P = 0.002), are related to lower FeNO. Women with menarche between 9 and 11 years of age had lower FeNO than those with menarche between 12 and 14 years of age (P = 0.03) or 15 and 17 years of age (P = 0.003). CONCLUSIONS AND CLINICAL RELEVANCE: Interpreting FeNO levels in clinical practice is complex, and constitutional determinants, as well as smoking and IgE sensitisation, are of importance in asthmatic subjects and should be accounted for when interpreting FeNO levels. Furthermore, menarche age and parental smoking during childhood and their effects on lowering FeNO deserve further studies.

Respiratory hypersensitivity reactions to NSAIDs in Europe: the global allergy and asthma network (GA2 LEN) survey.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most prevalent drugs inducing hypersensitivity reactions. The aim of this analysis was to estimate the prevalence of NSAID-induced respiratory symptoms in population across Europe and to assess its association with upper and lower respiratory tract disorders. METHODS: The GA2 LEN survey was conducted in 22 centers in 15 European countries. Each of 19 centers selected random samples of 5000 adults aged 15-74 from their general population, and in three centers (Athens, Munich, Oslo), a younger population was sampled. Questionnaires including questions about age, gender, presence of symptoms of asthma, allergic rhinitis, chronic rhinosinusitis, smoking status, and history of NSAID-induced hypersensitivity reactions were sent to participants by mail. Totally, 62 737 participants completed the questionnaires. RESULTS: The mean prevalence of NSAID-induced dyspnea was 1.9% and was highest in the three Polish centers [Katowice (4.9%), Krakow (4.8%), and Lodz (4.4%)] and lowest in Skopje, (0.9%), Amsterdam (1.1%), and Umea (1.2%). In multivariate analysis, the prevalence of respiratory reactions to NSAIDs was higher in participants with chronic rhinosinusitis symptoms (Odds Ratio 2.12; 95%CI 1.78-2.74), asthma symptoms in last 12 months (2.7; 2.18-3.35), hospitalization due to asthma (1.53; 1.22-1.99), and adults vs children (1.53; 1.24-1.89), but was not associated with allergic rhinitis. CONCLUSION: Our study documented significant variation between European countries in the prevalence of NSAID-induced respiratory hypersensitivity reactions, and association with chronic airway diseases, but also with environmental factors.

A standard, single dose of inhaled terbutaline attenuates hyperpnea-induced bronchoconstriction and mast cell activation in athletes.

Release of bronchoactive mediators from mast cells during exercise hyperpnea is a key factor in the pathophysiology of exercise-induced bronchoconstriction (EIB). Our aim was to investigate the effect of a standard, single dose of an inhaled ß2-adrenoceptor agonist on mast cell activation in response to dry air hyperpnea in athletes with EIB. Twenty-seven athletes with EIB completed a randomized, double-blind, placebo-controlled, crossover study. Terbutaline (0.5 mg) or placebo was inhaled 15 min prior to 8 min of eucapnic voluntary hyperpnea (EVH) with dry air. Pre- and postbronchial challenge, urine samples were analyzed by enzyme immunoassay for 11ß-prostaglandin F2α (11ß-PGF2α). The maximum fall in forced expiratory volume in 1 s of 14 (12-20)% (median and interquartile range) following placebo was attenuated to 7 (5-9)% with the administration of terbutaline (P < 0.001). EVH caused a significant increase in 11ß-PGF2α from 41 (27-57) ng/mmol creatinine at baseline to 58 (43-72) ng/mmol creatinine at its peak post-EVH following placebo (P = 0.002). The rise in 11ß-PGF2α was inhibited with administration of terbutaline: 39 (28-44) ng/mmol creatinine at baseline vs. 40 (33-58) ng/mmol creatinine at its peak post-EVH (P = 0.118). These data provide novel in vivo evidence of mast cell stabilization following inhalation of a standard dose of terbutaline prior to bronchial provocation with EVH in athletes with EIB.

Health-related quality of life in children with objectively diagnosed staple food allergy assessed with a disease-specific questionnaire.

AIM: Among Swedish children of 0-12 years old, we investigated various food allergy-related exposures associated with health-related quality of life using a food allergy-specific questionnaire among children allergic to the staple foods cow's milk, hen's egg and/or wheat, and contextualised worse food allergy-associated health-related quality of life using a generic questionnaire versus controls. METHODS: In total, 85 children with objectively diagnosed allergy to the staple foods were included as cases, and 94 children matched for age and sex were included as controls. We administered a food allergy-specific parent-completed questionnaire originally developed by EuroPrevall to cases only, and a generic health-related quality of life questionnaire (EuroQol Health Questionnaire, 5 Dimensions; EQ 5-D); to both cases and controls. RESULTS: Hen's egg was the most common offending staple food, affecting 76% of cases. Approximately 7% of cases were allergic to all three staple foods. Parent-reported respiratory and cardiovascular symptoms were associated with worse health-related quality of life. Elements of disease severity [previous anaphylaxis (p < 0.001); epinephrine autoinjector prescription (p < 0.003)] were negatively associated with health-related quality of life. Cases had worse health-related quality of life measured by the EQ-5D compared to controls (p < 0.01). CONCLUSION: The use of a disease-specific questionnaire revealed that disease severity in children with objectively diagnosed allergy to the staple foods cow's milk, hen's egg and/or wheat is associated with worse health-related quality of life. The use of a generic questionnaire confirmed that cases have worse health-related quality of life than controls.

Interleukin-33 exacerbates allergic bronchoconstriction in the mice via activation of mast cells.

BACKGROUND: Interleukin-33 (IL-33) is implicated as an epithelium-derived danger signal promoting Th2-dependent responses in asthma. We hypothesized that IL-33 might also have direct effects on mast cell-driven allergic airway obstruction. METHODS: The effects of IL-33 on allergic responses in the airways of sensitized mice were assessed both in vivo and ex vivo, as well as on cultured mast cells in vitro. RESULTS: In vivo, the allergen-induced increase in resistance in the conducting airways was enhanced in mice pretreated with IL-33. Also, in the isolated airways, the allergen-induced contractions were increased in preparations from animals subjected to intranasal IL-33 pretreatment. These effects in vivo and ex vivo were blocked by the 5-HT2A receptor antagonist ketanserin and absent in mice without mast cells. Likewise, the IL-33-induced enhancement of the allergen response was absent in isolated airways from mice lacking the IL-33 receptor. Moreover, exposure to IL-33 increased secretion of serotonin from allergen-challenged isolated airways. In cultured mast cells, IL-33 enhanced the expression of tryptophan hydroxylase 1, serotonin synthesis, and storage, as well as the secretion of serotonin following IgE receptor cross-linking. CONCLUSION: These results demonstrate that IL-33 exacerbates allergic bronchoconstriction by increasing synthesis, storage, and secretion of serotonin from the mast cell. This mechanism has implications for the development of airway obstruction in asthma.

Stability of phenotypes defined by physiological variables and biomarkers in adults with asthma.

BACKGROUND: Although asthma is characterized by variable airways obstruction, most studies of asthma phenotypes are cross-sectional. The stability of phenotypes defined either by biomarkers or by physiological variables was assessed by repeated measures over 1 year in the Pan-European BIOAIR cohort of adult asthmatics. METHODS: A total of 169 patients, 93 with severe asthma (SA) and 76 with mild-to-moderate asthma (MA), were examined at six or more visits during 1 year. Asthma phenotype clusters were defined by physiological variables (lung function, reversibility and age of onset of the disease) or by biomarkers (eosinophils and neutrophils in induced sputum). RESULTS: After 1 year of follow-up, the allocation to clusters was changed in 23.6% of all asthma patients when defined by physiological phenotypes and, remarkably, in 42.3% of the patients when stratified according to sputum cellularity (P = 0.034). In the SA cohort, 30% and 48.6% of the patients changed allocation according to physiological and biomarker clustering, respectively. Variability of phenotypes was not influenced by change in oral or inhaled corticosteroid dose, nor by the number of exacerbations. Lower stability of single and repeated measure was found for all evaluated biomarkers (eosinophils, neutrophils and FeNO) in contrast to good stability of physiological variables (FEV1 ), quality of life and asthma control. CONCLUSION: Phenotypes determined by biomarkers are less stable than those defined by physiological variables, especially in severe asthmatics. The data also imply that definition of asthma phenotypes is improved by repeated measures to account for fluctuations in lung function, biomarkers and asthma control.

Socioeconomic evaluation of well-characterized allergy to staple foods in adults.

BACKGROUND: The aim of the present study was to evaluate if total, direct, indirect, and intangible costs differ between a cohort of adults with well-characterized allergy to staple foods ('cases') and controls. METHODS: Swedish adults with objectively diagnosed food allergy to cow's milk, hen's egg, and/or wheat were recruited at an outpatient allergy clinic. Controls age- and sex-matched to cases were recruited from the same geographic area. For assessing the household costs of food allergy, a disease-specific socioeconomic questionnaire, developed within EuroPrevall, was utilized. RESULTS: Overall annual total costs at the household level were significantly higher among adults with food allergy compared with controls (the difference amounted to 8164 €), whereas direct costs did not differ between cases and controls. However, household healthcare costs and costs for medicines were significantly higher for cases vs controls. Furthermore, indirect costs were significantly higher for households with food-allergic adults vs households without food-allergic adults. Specifically, more time was spent on performing domestic tasks due to a family member's food-allergy-related illness, as well as shopping and preparing food, and seeking food-allergy-related information. Presence of food allergy also affected intangible costs. Adults with food allergy experienced overall lower health status compared with controls. CONCLUSIONS: Swedish adults with allergy to staple foods have higher total costs determined as direct, indirect, and intangible costs using the disease-specific socioeconomic questionnaire. Thus, total costs were 8164 € higher per year in households with at least one adult allergic to staple foods compared with controls.

The relation of airway obstruction to asthma, chronic rhinosinusitis and age: results from a population survey of adults.

RATIONALE: There is conflicting evidence on whether patients with asthma experience an accelerated decline in lung function with age. We examined the association between postbronchodilator lung function, asthma, chronic rhinosinusitis (CRS), and atopy with age using a large European sample. METHODS: In 17 centers in 11 European countries, case-control studies were nested within representative cross-sectional surveys of adults aged less than 75 years. Representative samples of participants with asthma, CRS or both and controls were assessed for postbronchodilator ventilatory function, smoking history, atopy, and treatment. Multiple regression was used to assess the interactive effects of age and diagnostic group on decline in postbronchodilator ventilatory function. RESULTS: A total of 3337 participants provided adequate data (778 with asthma, 399 with CRS, 244 with both asthma and CRS and 1916 controls who had neither asthma nor CRS). Participants with asthma had lower FEV1 /FVC (-4.09% (95% CI: -5.02, -3.15, P < 0.001) and a steeper slope of FEV1 /FVC against age (-0.14%/annum [95%CI: -0.19, -0.08]) equivalent to smoking 1-2 packs of cigarettes per day. Those with atopy had a slope equivalent to controls. CONCLUSIONS: People with asthma have a steeper decline in postbronchodilator lung function with age, but neither CRS nor atopy alone were associated with such decline.

Geographical variation in the prevalence of sensitization to common aeroallergens in adults: the GA(2) LEN survey.

BACKGROUND: Geographical variation in the prevalence of sensitization to aeroallergens may reflect differences in exposure to risk factors such as having older siblings, being raised on a farm or other unidentified exposures. OBJECTIVE: We wanted to measure geographical variation in skin prick test positivity and assess whether it was explained by differences in family size and/or farm exposure. We also compared prevalence in younger and older subjects. METHODS: Within the Global Allergy and Asthma European Network (GA(2) LEN) survey, we measured the prevalence of skin prick positivity to a panel of allergens, and geometric mean serum total immunoglobulin E (IgE), in 3451 participants aged 18-75 years in 13 areas of Europe. Estimated prevalence was standardized to account for study design. We compared prevalence estimates in younger and older subjects and further adjusted for age, gender, smoking history, farm exposure, number of older siblings and body mass index (BMI). RESULTS: Skin prick test positivity to any one of the measured allergens varied within Europe from 31.4% to 52.9%. Prevalence of sensitization to single allergens also varied. Variation in serum total IgE was less marked. Younger participants had higher skin prick sensitivity prevalence, but not total IgE, than older participants. Geographical variation remained even after adjustment for confounders. CONCLUSION: Geographical variation in the prevalence of skin prick test positivity in Europe is unlikely to be explained by geographical variation in gender, age, smoking history, farm exposure, family size and BMI. Higher prevalence in younger, compared to older, adults may reflect cohort-associated increases in sensitization or the influence of ageing on immune or tissue responses.

Frequent exacerbators--a distinct phenotype of severe asthma.

BACKGROUND: Exacerbations represent a major source of morbidity and mortality in asthma and are a prominent feature of poorly controlled, difficult-to-treat disease. OBJECTIVE: The goal of our study was to provide a detailed characterization of the frequent exacerbator phenotype and to identify risk factors associated with frequent and seasonal exacerbations. METHODS: Ninety-three severe asthmatics (SA) and 76 mild-to-moderate patients (MA) were screened and prospectively followed up for 1 year (NCT00555607). Medical history, baseline clinical data and biomarkers were used to assess risk factors for frequent exacerbations. RESULTS: During the study, 104 exacerbations were recorded in the SA group and 18 in the MA. Frequent exacerbators were characterized by use of higher doses of inhaled (1700 vs. 800 µg) and oral (6.7 vs. 1.7 mg) glucocorticosteroids, worse asthma control (ACQ score 2.3 vs. 1.4), lower quality of life (SGRQ score 48.5 vs. 33.3), higher sputum eosinophils (25.7% vs. 8.2%) and a more rapid decline in FEV1 /FVC ratio (-0.07 vs. -0.01 ΔFEV1 /FVC, frequent vs. non-frequent, respectively, P < 0.05). Exhaled NO > 45 p.p.b. and a history of smoking were associated with an increased risk of frequent exacerbations (odds ratios: 4.32 and 2.90 respectively). CONCLUSION AND CLINICAL RELEVANCE: We were able to distinguish and characterize a subphenotype of asthma subjects--frequent exacerbators--who are significantly more prone to exacerbations. Patients with FeNO > 45 p.p.b. and a history of smoking are at increased risk of frequent exacerbations and require careful monitoring in clinical practice.

The association of asthma, nasal allergies, and positive skin prick tests with obesity, leptin, and adiponectin.

BACKGROUND: Cross-sectional and longitudinal reports show that obese adults have more asthma than non-obese adults. A proposed mechanism is via effects of adipokines (leptin and adiponectin) on the immune system. OBJECTIVE: We wished to measure the associations of asthma and other atopic diseases with serum adipokine levels and to find whether the associations with asthma were strong enough to rule out the possibility that they are secondary to the association of fatness measures with asthma. METHODS: The Global Asthma and Allergy Network of Excellence (GA(2) LEN) clinical follow-up survey is a clinical survey, embedded in a larger multi-centre cross-sectional postal survey, involving, with a case/control design, enrichment of the sample with subjects with asthma and chronic rhinosinusitis (CRS). We recorded serum leptin or adiponectin in 845 men and 1110 women in 15 centres and also anthropometric measures of fatness including body mass index and waist/hip ratio, current asthma, and specific skin prick and IgE sensitisation. We used inverse sampling-probability-weighted rank and regression statistics to measure population associations of disease outcomes with adipokines in males and females, adjusting for confounders (area, age, smoking history, and number of elder siblings) and also mutually adjusting associations with adipokines and fatness measures. RESULTS: One thousand nine hundred and fifty-five subjects aged 16-77 years had information on leptin or adiponectin levels. Leptin and leptin/adiponectin ratio were positively associated with the level of asthma, especially in females (Somers' D of leptin by asthma score, 0.20; 95% CI, 0.08-0.30; P = 0.00079). These associations were attenuated after adjusting for confounders and became non-significant after additionally adjusting for fatness measures and multiple comparisons. CONCLUSIONS AND CLINICAL RELEVANCE: Asthma levels are positively associated with serum leptin. However, we cannot rule out the possibility that this association is secondary to associations of both with fatness measures.

Chronic rhinosinusitis in asthma is a negative predictor of quality of life: results from the Swedish GA(2)LEN survey.

BACKGROUND: Asthma and chronic rhinosinusitis (CRS) both impair quality of life, but the quality-of-life impact of comorbid asthma and CRS is poorly known. The aim of this study was to evaluate the impact of CRS and other relevant factors on quality of life in asthmatic subjects. METHODS: This Swedish cohort (age 17-76 years) consists of 605 well-characterized asthmatics with and without CRS, 110 individuals with CRS only, and 226 controls and is part of the Global Allergy and Asthma European Network (GA(2) LEN) survey. The Mini Asthma Quality of Life Questionnaire (mAQLQ), the Euro Quality of Life (EQ-5D) health questionnaire, spirometry, skin prick test (SPT), exhaled nitric oxide (FeNO), smell test, and peak nasal inspiratory flow were used. RESULTS: Subjects having both asthma and CRS have lower mAQLQ scores in all domains (P < 0.001) and a lower EQ-5D index value and EQ-5D VAS value (P < 0.001) compared to those with asthma only. Asthmatics with CRS have significantly lower FEV1%pred and FVC%pred (88.4 [85.1-91.7] and 99.9 [96.7-103.0], respectively) compared with asthma only (91.9 [90.3-93.4] and 104.0 [102.5-105.5], respectively P < 0.05). Multiple regression analysis shows that low asthma quality of life is associated with having CRS (P < 0.0001), lower lung function (P = 0.008), current smoking (P = 0.01), BMI > 30 kg/m2 (P = 0.04), high age (P = 0.03), and a negative SPT (P = 0.04). CONCLUSIONS: Comorbid CRS was a significant and independent negative predictor of quality of life in asthmatics. Other negative factors were lower lung function, current smoking, obesity, advanced age, and having nonatopic asthma.

PGE2 maintains the tone of the guinea pig trachea through a balance between activation of contractile EP1 receptors and relaxant EP2 receptors.

BACKGROUND AND PURPOSE: The guinea pig trachea (GPT) is commonly used in airway pharmacology. The aim of this study was to define the expression and function of EP receptors for PGE(2) in GPT as there has been ambiguity concerning their role. EXPERIMENTAL APPROACH: Expression of mRNA for EP receptors and key enzymes in the PGE(2) pathway were assessed by real-time PCR using species-specific primers. Functional studies of GPT were performed in tissue organ baths. KEY RESULTS: Expression of mRNA for the four EP receptors was found in airway smooth muscle. PGE(2) displayed a bell-shaped concentration-response curve, where the initial contraction was inhibited by the EP(1) receptor antagonist ONO-8130 and the subsequent relaxation by the EP(2) receptor antagonist PF-04418948. Neither EP(3) (ONO-AE5-599) nor EP(4) (ONO-AE3-208) selective receptor antagonists affected the response to PGE(2). Expression of COX-2 was greater than COX-1 in GPT, and the spontaneous tone was most effectively abolished by selective COX-2 inhibitors. Furthermore, ONO-8130 and a specific PGE(2) antibody eliminated the spontaneous tone, whereas the EP(2) antagonist PF-04418948 increased it. Antagonists of other prostanoid receptors had no effect on basal tension. The relaxant EP(2) response to PGE(2) was maintained after long-term culture, whereas the contractile EP(1) response showed homologous desensitization to PGE(2), which was prevented by COX-inhibitors. CONCLUSIONS AND IMPLICATIONS: Endogenous PGE(2), synthesized predominantly by COX-2, maintains the spontaneous tone of GPT by a balance between contractile EP(1) receptors and relaxant EP(2) receptors. The model may be used to study interactions between EP receptors.

Corticosteroid treatment selectively decreases mast cells in the smooth muscle and epithelium of asthmatic bronchi.

BACKGROUND: Mast cells are important in the pathophysiology of airway inflammation and evidence suggests their sub-localisation within the airway is altered in asthma. Little is known about the effect of corticosteroids on mast cell localisation within the bronchi. METHODS: We therefore performed an immunohistochemical analysis of mast cell numbers within the smooth muscle, epithelium and submucosa of healthy subjects (n = 10) and well-characterised asthmatic patients, using either ß(2)-agonists alone (n = 10) or ß(2)-agonists and inhaled corticosteroids (n = 10). RESULTS: Patients using inhaled corticosteroids displayed significantly lower numbers of mast cells within their epithelium and smooth muscle compared to those not treated with inhaled corticosteroids. Submucosal mast cells were not affected by corticosteroid treatment. Numbers of smooth muscle mast cells correlated with bronchial responsiveness and epithelial mast cells with exhaled NO. CONCLUSION: We demonstrate that glucocorticosteroids differentially affect mast cell numbers within specific airway sub-locations highlighting the importance of mast cell and smooth muscle/epithelial interactions in asthma pathogenesis.

Asthma in adults and its association with chronic rhinosinusitis: the GA2LEN survey in Europe.

BACKGROUND: The prevalence of asthma and its association with chronic rhinosinusitis (CRS) have not been widely studied in population-based epidemiological surveys. METHODS: The Global Allergy and Asthma Network of Excellence (GA(2) LEN) conducted a postal questionnaire in representative samples of adults living in Europe to assess the presence of asthma and CRS defined by the European Position Paper on Rhinosinusitis and Nasal Polyps. The prevalence of self-reported current asthma by age group was determined. The association of asthma with CRS in each participating centre was assessed using logistic regression analyses, controlling for age, sex and smoking, and the effect estimates were combined using standard methods of meta-analysis. RESULTS: Over 52,000 adults aged 18-75 years and living in 19 centres in 12 countries took part. In most centres, and overall, the reported prevalence of asthma was lower in older adults (adjusted OR for 65-74 years compared with 15-24 years: 0.72; 95% CI: 0.63-0.81). In all centres, there was a strong association of asthma with CRS (adjusted OR: 3.47; 95% CI: 3.20-3.76) at all ages. The association with asthma was stronger in those reporting both CRS and allergic rhinitis (adjusted OR: 11.85; 95% CI: 10.57-13.17). CRS in the absence of nasal allergies was positively associated with late-onset asthma. CONCLUSION: Geographical variation in the prevalence of self-reported asthma was observed across Europe, but overall, self-reported asthma was more common in young adults, women and smokers. In all age groups, men and women, and irrespective of smoking behaviour, asthma was also associated with CRS.