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

BACKGROUND: Population-based studies on aspirin-intolerant asthma (AIA) are very few, and no previous population study has investigated risk factors for the condition. OBJECTIVE: To investigate the prevalence and risk factors of AIA in the general population. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Once-daily fluticasone furoate 50 mcg in mild-to-moderate asthma: a 24-week placebo-controlled randomized trial.

BACKGROUND: Inhaled glucocorticosteroids (ICS) are the mainstay of treatment in asthma. Fluticasone furoate (FF) is a novel, once-daily ICS asthma therapy. This study investigated the efficacy and safety of FF 50 mcg in patients with mild-to-moderate persistent asthma. METHODS: A 24-week, multicenter, randomized, placebo-controlled and active-controlled, double-blind, double-dummy, parallel-group phase III study. Three hundred and fifty-one patients (aged ≥12 years; uncontrolled by non-ICS therapy) were randomized to treatment (1 : 1 : 1) with once-daily FF 50 mcg dosed in the evening, twice-daily fluticasone propionate (FP) 100 mcg or placebo. The primary endpoint was change from baseline in evening trough forced expiratory volume in 1 s (FEV1 ) at Week 24. Secondary endpoints were change from baseline in the percentage of rescue-free 24-h periods (powered endpoint), change from baseline in evening and morning peak expiratory flow, change from baseline in the percentage of symptom-free 24-h periods and number of withdrawals due to lack of efficacy. RESULTS: Evening trough FEV1 at Week 24 was not statistically significantly increased with FF 50 mcg once-daily (37 ml [95% CI: -55, 128]; P = 0.430), but was with FP 100 mcg twice daily (102 ml [10, 194]; P = 0.030), vs placebo. No consistent trends were observed across other endpoints, including the powered secondary endpoint. No safety concerns were raised for either active treatment. CONCLUSIONS: FP 100 mcg twice daily improved evening trough FEV1 in patients with mild-to-moderate persistent asthma, but FF 50 mcg once daily did not demonstrate a significant effect. Secondary endpoints showed variable results. No safety concerns were identified for FF or FP.

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.

Cigarette smoking is associated with high prevalence of chronic rhinitis and low prevalence of allergic rhinitis in men.

BACKGROUND: The harmful effects of tobacco smoke on human health, including respiratory health, are extensive and well documented. Previous data on the effect of smoking on rhinitis and allergic sensitization are inconsistent. We sought to investigate how smoking correlates with prevalence of allergic and chronic rhinitis among adults in Sweden. METHODS: The study population comprised 27 879 subjects derived from three large randomly selected cross-sectional population surveys conducted in Sweden between 2006 and 2008. The same postal questionnaire on respiratory health was used in the three surveys, containing questions about obstructive respiratory diseases, rhinitis, respiratory symptoms and possible determinants of disease, including smoking habits. A random sample from one of the cohorts underwent a clinical examination including skin prick testing. RESULTS: Smoking was associated with a high prevalence of chronic rhinitis in both men and women and a low prevalence of allergic rhinitis in men. These associations were dose dependent and remained when adjusted for a number of possible confounders in multiple logistic regression analysis. Prevalence of chronic rhinitis was lowest in nonsmokers and highest in very heavy smokers (18.5% vs 34.5%, P < 0.001). Prevalence of sensitization to common airborne allergens was lower in current smokers (25.9%, P = 0.008) and ex-smokers (28.2%, P = 0.022) than in nonsmokers (38.5%). CONCLUSION: We found that smoking was associated with a high prevalence of chronic rhinitis in both sexes and a low prevalence of allergic rhinitis in men. The associations were dose dependent and remained when adjusting for several possible confounders.

EAACI position statement on asthma exacerbations and severe asthma.

Asthma exacerbations and severe asthma are linked with high morbidity, significant mortality and high treatment costs. Recurrent asthma exacerbations cause a decline in lung function and, in childhood, are linked to development of persistent asthma. This position paper, from the European Academy of Allergy and Clinical Immunology, highlights the shortcomings of current treatment guidelines for patients suffering from frequent asthma exacerbations and those with difficult-to-treat asthma and severe treatment-resistant asthma. It reviews current evidence that supports a call for increased awareness of (i) the seriousness of asthma exacerbations and (ii) the need for novel treatment strategies in specific forms of severe treatment-resistant asthma. There is strong evidence linking asthma exacerbations with viral airway infection and underlying deficiencies in innate immunity and evidence of a synergism between viral infection and allergic mechanisms in increasing risk of exacerbations. Nonadherence to prescribed medication has been identified as a common clinical problem amongst adults and children with difficult-to-control asthma. Appropriate diagnosis, assessment of adherence and other potentially modifiable factors (such as passive or active smoking, ongoing allergen exposure, psychosocial factors) have to be a priority in clinical assessment of all patients with difficult-to-control asthma. Further studies with improved designs and new diagnostic tools are needed to properly characterize (i) the pathophysiology and risk of asthma exacerbations, and (ii) the clinical and pathophysiological heterogeneity of severe asthma.

Eczema among adults: prevalence, risk factors and relation to airway diseases. Results from a large-scale population survey in Sweden.

BACKGROUND: In contrast to asthma and rhinitis, few studies among adults investigating the prevalence and risk factors of eczema have been published. OBJECTIVES: To investigate the prevalence and risk factors of eczema among adults in West Sweden. A further aim was to study the associations between asthma, rhinitis and eczema. METHODS: A questionnaire on respiratory health was mailed in 2008 to 30,000 randomly selected subjects in West Sweden aged 16-75 years; 62% responded. The questionnaire included questions about eczema, respiratory symptoms and diseases and their possible determinants. A subgroup of 669 subjects underwent skin prick testing against common airborne allergens. RESULTS: 'Eczema ever' was reported by 40·7% and 'current eczema' by 11·5%. Both conditions were significantly more common among women. The prevalence decreased with increasing age. The coexistence of both asthma and rhinitis with eczema was common. The main risk factors were family history of allergy and asthma. The dominant environmental risk factor was occupational exposure to gas, dust or fumes. Smoking increased the risk. Eczema was associated with urbanization, while growing up on a farm was associated with a decreased risk. Added one by one to the multivariate model, asthma, allergic rhinitis and any positive skin prick test were associated with eczema. CONCLUSIONS: Eczema among adults is a common disease with more women than men having and having had eczema. Eczema is associated with other atopic diseases and with airway symptoms. Hereditary factors and exposure to gas, dust and fumes are associated with eczema.

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.

Osteopontin expression and relation to disease severity in human asthma.

Recent studies have associated osteopontin (OPN) with allergic inflammation; however, its role in human asthma remains unclear. The aim of this study was to measure OPN levels in the serum, bronchoalveolar lavage fluid (BALF) and bronchial tissue of healthy controls and asthmatics, identify cellular sources of OPN and examine possible correlations between OPN expression, disease severity and airway remodelling. Serum samples were obtained from 35 mild-to-moderate asthmatics, 19 severe asthmatics and 17 healthy controls in the steady state and in cases of exacerbation. Of these subjects, 29 asthmatics and nine controls underwent bronchoscopy with endobronchial biopsy and BALF collection. OPN expression was determined by ELISA and immunohistochemistry/immunofluorescence. Reticular basement membrane thickness and goblet cell hyperplasia were also determined. Serum and BALF OPN levels were significantly increased in all asthmatics in the steady state, whereas serum levels decreased during exacerbations. OPN was upregulated in the bronchial tissue of all patients, and expressed by epithelial, airway and vascular smooth muscle cells, myofibroblasts, T-lymphocytes and mast cells. OPN expression correlated with reticular basement membrane thickness and was more prominent in subepithelial inflammatory cells in severe compared to mild-to-moderate asthma. OPN expression is upregulated in human asthma and associated with remodelling changes, and its subepithelial expression correlates with disease severity.

Reliability of EP3OS symptom criteria and nasal endoscopy in the assessment of chronic rhinosinusitis--a GA² LEN study.

BACKGROUND: The European Position Paper on Rhinosinusitis and Nasal Polyps (EP3OS) incorporates symptomatic, endoscopic, and radiologic criteria in the clinical diagnosis of chronic rhinosinusitis (CRS), while in epidemiological studies, the definition is based on symptoms only. We aimed to assess the reliability and validity of a symptom-based definition of CRS using data from the GA(2) LEN European survey. METHODS: On two separate occasions, 1700 subjects from 11 centers provided information on symptoms of CRS, allergic rhinitis, and asthma. CRS was defined by the epidemiological EP3OS symptom criteria. The difference in prevalence of CRS between two study points, the standardized absolute repeatability, and the chance-corrected repeatability (kappa) were determined. In two centers, 342 participants underwent nasal endoscopy. The association of symptom-based CRS with endoscopy and self-reported doctor-diagnosed CRS was assessed. RESULTS: There was a decrease in prevalence of CRS between the two study phases, and this was consistent across all centers (-3.0%, 95% CI: -5.0 to -1.0%, I(2) = 0). There was fair to moderate agreement between the two occasions (kappa = 39.6). Symptom-based CRS was significantly associated with positive endoscopy in nonallergic subjects, and with self-reported doctor-diagnosed CRS in all subjects, irrespective of the presence of allergic rhinitis. CONCLUSION: Our findings suggest that a symptom-based definition of CRS, according to the epidemiological part of the EP3OS criteria, has a moderate reliability over time, is stable between study centers, is not influenced by the presence of allergic rhinitis, and is suitable for the assessment of geographic variation in prevalence of CRS.

IL-5 expression and release from human CD34 cells in vitro; ex vivo evidence from cases of asthma and Churg-Strauss syndrome.

BACKGROUND: Eosinophils develop from hematopoietic CD34(+) progenitor cells in the bone marrow (BM) under the influence of Interleukin-5 (IL-5). The primary source of IL-5 is T-lymphocytes, although other sources may exist. The aims of this study were to determine whether CD34(+) cells from human peripheral blood (PB) and BM have the capacity to produce IL-5 when stimulated in vitro, and secondly, whether an elevated number of IL-5-producing CD34(+) cells can be found in situ in ongoing eosinophilic disease. METHODS: CD34(+) cells from PB and BM were stimulated in vitro, and IL-5 production and release was assessed by ELISA, ELISPOT, flow cytometry and immunocytochemistry. Blood and BM from a patient with Churg-Strauss syndrome were analyzed by flow cytometry for CD34(+)/IL-5(+) cells, and immunohistochemical staining of CD34(+)/IL-5(+) cells in bronchial biopsies from an asthmatic patient was performed. RESULTS: Both PB and BM CD34(+) cells can produce and release IL-5 when stimulated in vitro. In the Churg-Strauss patient, IL-5-producing CD34(+) cells were found in PB and BM. Oral glucocorticoid treatment markedly decreased the number of IL-5-positive CD34 cells in the BM. CD34(+)/IL-5(+) cells were present in a patient with asthma. CONCLUSION: CD34(+) cells in blood and BM are capable of producing IL-5 both in vitro and in vivo in humans, arguing that these cells may have the capacity to contribute to eosinophilic inflammation. Consequently, targeting CD34(+) progenitor cells that produce and release IL-5 may be effective in reducing the mobilization of eosinophil lineage-committed cells in eosinophilic-driven diseases.

Rhinovirus infection and house dust mite exposure synergize in inducing bronchial epithelial cell interleukin-8 release.

BACKGROUND: Human rhinoviruses (HRVs) and house dust mites (HDMs) are among the most common environmental factors able to induce airway inflammation in asthma. Although epidemiological studies suggest that they also synergize in inducing asthma exacerbations, there is no experimental evidence to support this, nor any information on the possible mechanisms involved. OBJECTIVE: To investigate their interaction on the induction of airway epithelial inflammatory responses in vitro. METHODS: BEAS-2B cells were exposed to activated HDM Dermatophagoides pteronyssinus major allergen I (Der p I), HRVs (HRV1b or HRV16) or both in different sequences. IL-8/CXCL8 release, intercellular adhesion molecule (ICAM)-1 surface expression and nuclear factor kappaB (NF-kappaB) translocation were evaluated. Complementary, primary human bronchial epithelial cells (HBECs) exposed to both Der p I and RVs and IL-8, IL-6, IFN-gamma-induced protein (IP)-10/CXCL10, IFN-lambda1/IL-29, regulated upon activation normal T lymphocyte expressed and secreted (RANTES)/CCL5 release were measured. RESULTS: RV and Der p I up-regulated IL-8 release, ICAM-1 expression and NF-kappaB translocation in BEAS-2B cells. Simultaneous exposure to both factors, as well as when cells were initially exposed to HRV and then to Der p I, resulted in further induction of IL-8 in a synergistic manner. Synergism was not observed when cells were initially exposed to Der p I and then to HRV. This was the pattern in ICAM-1 induction although the phenomenon was not synergistic. Concurrent exposure induced an early synergistic NF-kappaB translocation induction, differentiating with time, partly explaining the above observation. In HBECs, both HRV and Der p I induced IL-8, IL-6, IL-29 and IP-10, while RANTES was induced only by HRV. Synergistic induction was observed only in IL-8. CONCLUSION: HRV and enzymatically active Der p I can act synergistically in the induction of bronchial epithelial IL-8 release, when HRV infection precedes or is concurrent with Der p I exposure. Such a synergy may represent an important mechanism in virus-induced asthma exacerbations.

Prolonged eosinophil production after allergen exposure in IFN-gammaR KO mice is IL-5 dependent.

Asthma is a T helper 2 (Th2)-driven inflammatory process characterized by eosinophilia. Prolonged airway eosinophilia is commonly observed in asthma exacerbations. Our aim was to evaluate whether eosinophilia in prolonged allergic inflammation is associated with a continuous supply of new eosinophils to the airways, and how this is regulated. Ovalbumin (OVA)-sensitized interferon-gamma receptor knockout mice (IFN-gammaR KO), known to maintain a long-lasting eosinophilia after allergen exposure, were compared to wild type (wt) controls. Animals were exposed to OVA or phosphate-buffered saline on three consecutive days, and bone marrow (BM), blood and bronchoalveolar lavage (BAL) samples were collected 24 h, 7 and 21 days later. Newly produced cells were labelled using bromodeoxyuridine (BrdU). Serum IL-5 was measured and its role was investigated by administration of a neutralizing anti-IL-5 antibody. In-vitro eosinophilopoiesis was examined in both groups by a colony-forming assay. Allergen challenge increased eosinophils in BM, blood and BAL, in both IFN-gammaR KO and wt mice, both 24 h and 7 days after the last allergen exposure. At 21 days after the last exposure, only IFN-gammaR KO mice maintained significantly increased eosinophil numbers. Approximately 50% of BAL granulocytes in IFN-gammaR KO were produced during the last 6 days. Interleukin (IL)-5 concentration was increased in IFN-gammaR KO mice, and anti-IL-5 reduced eosinophil numbers in all compartments. Increased numbers of eosinophil colonies were observed in IFN-gammaR KO mice after allergen exposure versus controls. In this model of a Th2-driven prolonged allergic eosinophilia, new eosinophils contribute to the extended inflammation in the airways by enhanced BM eosinophilopoiesis in an IL-5-dependent manner.

Regulation of allergen-induced bone marrow eosinophilopoiesis: role of CD4+ and CD8+ T cells.

BACKGROUND: The mechanisms of the distant stimulation of the bone marrow (BM) after airway allergen exposure remain largely obscure. T cells have been implicated in allergic airway inflammation but their role in allergen-induced BM eosinophilopoiesis is poorly understood. The aim of this study was to determine the role of CD4(+) and CD8(+) T cells in allergen-induced BM eosinophilopoiesis. METHODS: Ovalbumin (OVA)-sensitized wild type (WT), CD4 knockout (CD4-/-) and CD8 knockout (CD8-/-) mice were exposed intranasally to OVA or saline. Bromo-deoxyuridine (BrdU) was used to label newly produced cells. Bone marrow, blood and bronchoalveolar lavage (BAL) were sampled 24 h after the final exposure. Immunostaining for newly produced eosinophils (i.e. BrdU(+)/MBP(+)) and BM eosinophil progenitor [CD34(+)/CD45(+)/interleukin-5 (IL-5)Ralpha(+)] cells was performed. RESULTS: The number of newly produced BM eosinophils (BrdU(+)/MBP(+) cells) was significantly reduced in allergen exposed CD4-/- or CD8-/- mice compared with allergen exposed WT mice, which was followed by a subsequent decrease in newly produced blood and airway eosinophils. Furthermore, BM eosinophil progenitors were significantly reduced in allergen exposed CD4-/- and CD8-/- mice compared with WT mice. Finally, serum IL-5 and Bronchoalveolar lavage fluid eotaxin-2 levels were abolished in allergen exposed CD4-/- mice to levels seen in saline exposed WT mice. CONCLUSIONS: These data suggests that both CD4(+) and CD8(+) T cells have a regulatory role in allergen-induced BM eosinophilopoiesis, whereas CD4(+) T cells are obligatory for allergen-induced airway eosinophilia. The subsequent traffic of eosinophils to the airways is likely to be at least partly regulated by a CD4(+) T-cell-dependent local airway eotaxin-2 production.

Allergen stimulates bone marrow CD34(+) cells to release IL-5 in vitro; a mechanism involved in eosinophilic inflammation?

The specific mechanisms that alter bone marrow (BM) eosinophilopoiesis in allergen-induced inflammation are poorly understood. The aims of this study were to evaluate (a) whether the number of BM CD34(+) cells is altered due to allergen sensitization and exposure in vivo and (b) whether BM CD34(+) cells produce and release interleukin (IL)-5, IL-3 and granulocyte macrophage-colony stimulating factor (GM-CSF) after stimulation in vitro. A mouse model of ovalbumin (OVA)-induced airway inflammation was used. Bone marrow CD34(+) cells were cultured in vitro and the cytokine release was measured by enzyme-linked immunosorbent assay. The IL-5-production from CD34(+) cells was confirmed by immunocytochemistry. Airway allergen exposure increased the number of BM CD34(+) cells (P = 0.01). Bone marrow CD34(+) cells produced IL-5 when stimulated with the allergen OVA in vitro, but not IL-3 or GM-CSF. Nonspecific stimulus with calcium ionophore and phorbol-myristate-acetate of BM CD34(+) cells caused release of IL-5, IL-3 and GM-CSF. The induced release of IL-5 was increased in alum-injected vs naive mice (P = 0.02), but was not affected by allergen sensitization and exposure. The release of IL-3 and GM-CSF was increased after allergen sensitization and exposure (P < 0.02). In conclusion, allergen can stimulate BM CD34(+) cells to produce IL-5 protein. It is likely that the CD34(+) cells have autocrine functions and thereby regulate the early stages of BM eosinophilopoiesis induced by airway allergen exposure. Alum, a commonly used adjuvant, enhances the release of IL-5 and may thereby enhance eosinophilopoiesis.

Indirect airway challenges.

Indirect challenges act by causing the release of endogenous mediators that cause the airway smooth muscle to contract. This is in contrast to the direct challenges where agonists such as methacholine or histamine cause airflow limitation predominantly via a direct effect on airway smooth muscle. Direct airway challenges have been used widely and are well standardised. They are highly sensitive, but not specific to asthma and can be used to exclude current asthma in a clinic population. Indirect bronchial stimuli, in particular exercise, hyperventilation, hypertonic aerosols, as well as adenosine, may reflect more directly the ongoing airway inflammation and are therefore more specific to identify active asthma. They are increasingly used to evaluate the prevalence of bronchial hyperresponsiveness and to assess specific problems in patients with known asthma, e.g. exercise-induced bronchoconstriction, evaluation before scuba diving. Direct bronchial responsiveness is only slowly and to a modest extent, influenced by repeated administration of inhaled steroids. Indirect challenges may reflect more closely acute changes in airway inflammation and a change in responsiveness to an indirect stimulus may be a clinically relevant marker to assess the clinical course of asthma. Moreover, some of the indirect challenges, e.g. hypertonic saline and mannitol, can be combined with the assessment of inflammatory cells by induction of sputum.

A role of GM-CSF in the accumulation of neutrophils in the airways caused by IL-17 and TNF-alpha.

The T-cell cytokine interleukin (IL)-17 selectively accumulates neutrophils in murine airways in vivo and may thus constitute a link between activation of T-lymphocytes and accumulation of neutrophils. In this study, the authors evaluated the role of granulocyte macrophage-colony stimulating factor (GM-CSF) in accumulation of neutrophils in the airways caused by IL-17 and tumour necrosis factor (TNF)-alpha. In vitro, human (h) IL-17 concentration-dependently stimulated the release of GM-CSF protein (enzyme-linked immunosorbent assay) in human bronchial epithelial cells (16HBE). IL-17 also time-dependently stimulated the release of GM-CSF protein in venous endothelial (human umbilical vein endothelial cells) cells in vitro. Co-stimulation with IL-17 plus the pro-inflammatory cytokine TNF-alpha potentiated the release of GM-CSF protein in 16HBE cells. hIL-17 also enhanced the expression of GM-CSF messenger ribonucleic acid in 16HBE cells (reverse transcriptase polymerase chain reaction), with a similar order of magnitude as TNF-alpha. Conditioned cell medium from bronchial epithelial cells co-stimulated with hIL-17 plus TNF-alpha prolonged survival (trypan blue exclusion) of human neutrophils in vitro and this effect was blocked by an anti-GM-CSF antibody. In vivo, local co-stimulation with mouse IL-17 plus TNF-alpha caused an additive potentiation of the accumulation of neutrophils in bronchoalveolar lavage fluid from mouse airways and this effect was blocked by an anti-GM-CSF antibody given systemically. In conclusion, granulocyte macrophage-colony stimulating factor is involved in the accumulation of neutrophils in the airways caused by interleukin-17 and tumour necrosis factor-alpha, probably via effects on both recruitment and survival of neutrophils.

Bronchodilation by an inhaled VPAC(2) receptor agonist in patients with stable asthma.

BACKGROUND: The synthetic vasoactive intestinal peptide (VIP) analogue Ro 25-1553 is a selective VIP-PACAP type 2 (VPAC(2)) receptor agonist that causes a bronchodilatory effect in guinea pigs in vivo. The effect of Ro 25-1553 given by inhalation to patients with asthma was studied and compared with that of a long acting beta(2) adrenoceptor agonist. METHODS: Twenty four patients with moderate stable asthma participated in a double blind, randomised, placebo controlled, crossover study. The primary variable was bronchodilatory effect (increase in forced expiratory volume in 1 second, FEV(1)) after inhalation of Ro 25-1553 (100 microg or 600 microg) and formoterol (4.5 microg), respectively. Putative side effects were characterised by monitoring sitting blood pressure, serum potassium, electrocardiography and echocardiography. RESULTS: Inhalation of 600 microg Ro 25-1553 caused a rapid bronchodilatory effect (geometric mean increase in FEV(1) compared with placebo) within 3 minutes of 6% (95% CI 4 to 9), as did inhalation of formoterol (8% (95% CI 5 to 10)). The corresponding maximum bronchodilatory effect during 24 hours was similar for 600 microg Ro 25-1553 (7% (95% CI 4 to 10)) and the reference bronchodilator formoterol (10% (95% CI 7 to 12)). However, for both doses of Ro 25-1553 the bronchodilatory effect was attenuated 5 hours after inhalation whereas formoterol still had a bronchodilatory effect 12 hours after inhalation. Neither Ro 25-1553 nor formoterol produced any clinically relevant side effects. No drug related difference in adverse events was observed. CONCLUSION: Inhalation of a synthetic selective VPAC(2) receptor agonist constitutes a promising approach for bronchodilation in patients with asthma.

Effect of seasonal allergen exposure on mucosal IL-16 and CD4+ cells in patients with allergic rhinitis.

BACKGROUND: CD4+ T cells constitute a major source of cytokines in allergic diseases such as allergic rhinitis. Interleukin (IL)-16 selectively recruits CD4+ cells. METHODS: We evaluated the effect of natural allergen exposure during a grass-pollen season on IL-16 expression and number of CD4+ cells in nasal mucosa. Patients with allergic rhinitis (n=16) were treated with either a nasal glucocorticoid beclomethasone (BDP; 400 microg/day) or placebo, and gave nasal biopsies prior to and during the grass-pollen season. The evaluated markers in allergic rhinitis patients were also compared to those in healthy control subjects (n=5). RESULTS: Prior to the pollen season, the expression of IL-16, but not the number of CD4+ cells, was significantly higher in patients with allergic rhinitis than in healthy control subjects. The grass-pollen season further increased IL-16 expression and also increased the number of CD4+ cells in placebo-treated, but not in BDP-treated, allergic rhinitis patients. The pollen-season-induced change in IL-16 expression and in CD4+ cells was significantly more pronounced in placebo- than in BDP-treated patients. There was a significant correlation between the change in IL-16 expression and the number of CD4+ cells. CONCLUSIONS: These data suggest that local upregulation of IL-16 expression contributes to the inflammation observed in seasonal allergic rhinitis. Hypothetically, inhibition of IL-16 expression can be one of several mechanisms by which nasal glucocorticoids achieve their anti-inflammatory effect in allergic rhinitis.

Exudation of plasma and production of thromboxane in human bronchi after local bradykinin challenge.

Plasma exudation has been suggested to be an important component of the inflammatory response in asthma. Bradykinin elicits many of the features of asthma, including bronchoconstriction, cough, plasma exudation and mucus secretion. In an attempt to quantify local plasma exudation, we have employed a novel low-trauma technique with the aim of challenging and lavaging a central part of the bronchial tree, by selecting a medium sized bronchus. A fibreoptic bronchoscopy was performed in non-smoking healthy volunteers. The instrument was placed proximally in the right upper lobe bronchus. A plastic catheter, equipped with an inflatable latex balloon, was inflated with air (2-4 cmH2O). A solution (100 microl of either two different concentrations of bradykinin: 0.09 and 0.9 mg ml(-1) or normal saline) was instilled through the catheter and distal to the balloon. Eight minutes later a lavage procedure with 10 ml of saline was performed through the catheter. The procedure was then repeated twice, with the other solutions, but from the lingular and middle lobe bronchi. All solutions were given in a blinded fashion, and two different studies were performed. Lavage concentrations of albumin and IgG were quantified as measurements of plasma exudation. In our first study we found that bradykinin challenge significantly increased concentrations of albumin and IgG. In study two, there was no numeric increase in plasma proteins after local bradykinin challenge, but the concentration of thromboxane was significantly increased in lavages from bradykinin-challenged bronchi. Thus, local bronchial administration of bradykinin has the capacity to induce exudation of large plasma macromolecules into the bronchial lumen, as well as local thromboxane production.

IL-17-induced cytokine release in human bronchial epithelial cells in vitro: role of mitogen-activated protein (MAP) kinases.

1. Recent data indicate that interleukin (IL)-17 may contribute to neutrophilic airway inflammation by inducing the release of neutrophil-mobilizing cytokines from airway cells. The aim of this study was to evaluate the role of mitogen activated protein kinases in IL-17 induced release of IL-8 and IL-6 in bronchial epithelial cells. 2. Transformed human bronchial epithelial cells (16HBE) were stimulated with either IL-17 or vehicle. Both groups were treated either with SB202190 (inhibitor of p38 MAP kinase), PD98059 (inhibitor of extracellular-signal-regulated kinase [ERK] pathway), Ro-31-7549 (protein kinase C [PKC] inhibitor), LY 294002 (a phosphatidylinositol 3-kinase [PI 3-kinase] inhibitor) or vehicle. IL-6 and IL-8 levels were measured in conditioned media by ELISA. 3. The IL-17-induced release of IL-6 and IL-8 was concentration-dependently inhibited by SB202190 and by PD98059 in bronchial epithelial cells without affecting cell proliferation or survival. 4. Ro-31-7549 and LY294002 had no significant effect on IL-17-induced IL-6 or IL-8 release in bronchial epithelial cells. 4. Taken together, these data indicate a role for p38 and ERK kinase pathways in IL-17-induced release of neutrophil-mobilizing cytokines in human bronchial epithelial cells. These mechanisms constitute potential pharmacotherapeutical targets for inhibition of the IL-17-mediated airway neutrophilia.