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Airway Hyperresponsiveness (airway + hyperresponsiveness)

Distribution by Scientific Domains

Medical Sciences	100%

Distribution within Medical Sciences

Allergy & Clinical Immunology	45%
Respiratory Medicine	38%
Immunology	11%

Selected Abstracts

Targeting the allergen to oral dendritic cells with mucoadhesive chitosan particles enhances tolerance induction

ALLERGY, Issue 7 2009
N. Saint-Lu
Background:, Sublingual immunotherapy (SLIT) efficacy could be improved by formulations facilitating allergen contact with the oral mucosa and uptake by antigen-presenting cells (APCs). Methods:, Two types of chitosan microparticles, differing in size and surface charge, were tested in vitro for their capacity to improve antigen uptake and presentation by murine bone marrow-derived dendritic cells (BMDCs) or purified oral APCs. T-cell priming in cervical lymph nodes (LNs) was assessed by intravenous transfer of carboxyfluorescein diacetate succinimidyl ester-labelled ovalbumin (OVA)-specific CD4+ T cells and flow cytometry analysis. Ovalbumin-sensitized BALB/c mice were treated sublingually with soluble or chitosan-formulated OVA twice a week for 2 months. Airway hyperresponsiveness (AHR), lung inflammation and T-cell responses in cervical and mediastinal LNs were assessed by whole-body plethysmography, lung histology and Cytometric Bead Array technology, respectively. Results:, Only a mucoadhesive (i.e. highly positively charged) and microparticulate form of chitosan enhances OVA uptake, processing and presentation by murine BMDCs and oral APCs. Targeting OVA to dendritic cells with this formulation increases specific T-cell proliferation and IFN-,/IL-10 secretion in vitro, as well as T-cell priming in cervical LNs in vivo. Sublingual administration of such chitosan-formulated OVA particles enhances tolerance induction in mice with established asthma, with a dramatic reduction of both AHR, lung inflammation, eosinophil numbers in bronchoalveolar lavages, as well as antigen-specific Th2 responses in mediastinal LNs. Conclusions:, Mucoadhesive chitosan microparticles represent a valid formulation for sublingual allergy vaccines. [source]

Airway hyperresponsiveness and acute chest syndrome in children with sickle cell anemia

PEDIATRIC PULMONOLOGY, Issue 3 2007
Karl P. Sylvester PhD
Abstract To determine the occurrence and magnitude of airway hyperresponsiveness (AHR) in children with sickle cell anemia (SCA) who had or had not had acute chest syndrome (ACS) episodes. A subsidiary aim was to determine whether cold air and exercise challenge testing gave similar results in children with SCA. AHR would be greater in SCA children who had had an ACS episode compared to those who had not. Prospective observational study. Forty-two SCA children (median age of 11.5 [range 6.1,16.8] years); 12 children had been previously hospitalized for an ACS episode. AHR was assessed by the change in forced expiratory volume in 1 sec (FEV1) to a cold air challenge and in a subset of the children to an exercise challenge. A positive result to either challenge was deemed to have occurred if the FEV1 fell by at least 10% from the pre-challenge baseline. The magnitude of change in FEV1 following the cold air challenge was similar in children who had or had not had an ACS episode. Six children had a positive response to the cold air challenge (AHR); none had had an ACS hospitalization. Similar proportions of children responded to the cold air and exercise challenge and the magnitude of response to the two tests was similar. Some children, however, responded only to a cold air challenge and others only to an exercise challenge. SCA children who had had an ACS hospitalization episode compared to those who had not were not more likely to respond to a cold air challenge. Importantly, if AHR is to be correctly diagnosed, some SCA children will require to undergo both cold air and exercise challenge testing. Pediatr Pulmonol. 2007; 42:272,276. © 2007 Wiley-Liss, Inc. [source]

Extrathoracic airway responsiveness in children with asthma-like symptoms, including chronic persistent cough

PEDIATRIC PULMONOLOGY, Issue 3 2002
Ipek Turktas MD
Abstract Asthma-like symptoms, including chronic persistent cough, are not always specific for classical asthma. In order to investigate whether assessment of extrathoracic airway hyperresponsiveness (EAHR) during methacholine bronchial challenge helped in the evaluation of pediatric patients with asthma-like symptoms such as chronic cough, we examined 133 consecutive, unselected patients (mean age, 10.06,±,2.16 years) who had neither established asthma nor bronchial obstruction previously. We recorded the forced mid-inspiratory flow (FIF50) as an index of extrathoracic airway narrowing. In addition, a 25% decrease in FIF50 (PD25FIF50) below the cutoff concentration of ,,8 mg/mL methacholine was assumed to indicate EAHR. According to the methacholine response, 81 patients had EAHR, and 41 of them had combined EAHR and bronchial hyperresponsiveness (BHR); 39 patients had only BHR. Airway hyperresponsiveness was not demonstrated in 13 patients and not in any of the control children. When patients with cough as the sole presenting symptom (60.9%) were compared with those with cough and wheeze (20.3%), those with cough alone had a significantly greater probability of having EAHR (OR, 4.16; 95% CI, 1.32,13.13) and a lower probability of having BHR (OR, 0.70; CI, 0.25,1.95) than those with cough and wheeze. Patients with cough, wheeze, and dyspnea (18.8%) had a significantly greater chance of having BHR than those with cough alone (OR, 5.08; CI, 1.55,16.64). Patients with cough and wheeze as compared with those with cough, wheeze, and dyspnea had significantly greater probability of having both EAHR and BHR (OR, 4.71; CI, 1.94,11.47). In order to ascertain the clinical relevance of EAHR, we assessed in the second part of the study whether the effects of treatment of the underlying disease would result in relief of airway hyperresponsiveness. Rhinosinusitis and perennial allergic rhinitis accounted for EAHR in 71 patients, and 34 of them also demonstrated BHR. They received specific therapy for their upper airway diseases for 4 weeks. Compared with values before treatment, FIF50 and forced expiratory volume in 1 sec (FEV1) did not change significantly. The dose of methacholine causing a 20% fall in FEV1 (PD20FEV1) and PD25FIF50 values were significantly increased from 2.40,±,1.39 to 4.22,±,1.13 mg /mL (P,<,0.001) and from 1.03,±,1.75 to 8.71,±,1.21 mg /mL (P,<,0.0001), respectively. We conclude that measurements of EAHR and BHR are the most important ways to evaluate children with asthma-like symptoms, including chronic persistent cough when chest X-rays and pulmonary function tests remain within normal limits. Therefore, empirical treatment is not necessary when these investigations are available. Our results suggest that specific treatment of inflammation in the upper airways reversed persistant cough, and may play an important role in modulating lower airways responsiveness in patients with concomitant BHR. Pediatr Pulmonol. 2002; 34:172,180. © 2002 Wiley-Liss, Inc. [source]

Airway hyperresponsiveness: the usefulness of airway hyperresponsiveness testing in epidemiology, in diagnosing asthma and in the assessment of asthma severity

THE CLINICAL RESPIRATORY JOURNAL, Issue 1 2007
Celeste Porsbjerg MD
Abstract The present PhD thesis was conducted at the Respiratory Research Unit at the Pulmonary Department L in Bispebjerg Hospital, Copenhagen, Denmark and describes airway hyperresponsiveness in asthma patients in four studies. The first study concerned risk factors for the development of asthma in young adults in a 12-year prospective follow-up study of a random population sample of 291 children and adolescents from Copenhagen, who were followed up from the age of 7,17 years (1986) until the age of 19,29 years (1998). During follow-up, 16.1% developed asthma, and in these subjects, the most important predictor of asthma development was airway hyperresponsiveness to histamine at baseline. Airway hyperresponsiveness is associated with more severe asthma and a poorer prognosis in terms of more exacerbations and less chance of remission of the disease. The second study described the relation between airway hyper-responsiveness to methacholine and the quality of life in 691 asthma patients: In asthma patients with airway hyperresponsiveness to methacholine, the quality of life measured with a validated questionnaire (Junipers Asthma Quality of Life Questionnaire) was significantly reduced compared to asthma patients who did not respond to bronchial provocation with methacholine. Airway hyperresponsiveness is not uncommonly observed in non-asthmatics, and the response to bronchial provocation with methacholine is therefore relatively non-specific. The mannitol test is a relatively new bronchial provocation test that acts indirectly on the smooth airway muscle cells through the release of mediators from inflammatory cells in the airways; the mannitol could consequently be a more specific test compared with methacholine. The third study showed that out of 16 non-asthmatics with airway hyperresponsiveness to methacholine, 15 did not respond to bronchial provocation with mannitol Because of the mechanism of action of mannitol, it seems plausible that the response to mannitol is more closely correlated to airway inflammation in asthma compared with the response to methacholine. The fourth study showed that in 53 adult asthma patients, who did not receive treatment with inhaled steroids, there was a positive correlation between the degree of airway inflammation and the degree of airway responsiveness to mannitol as well as to methacholine. The mannitol does, however, have the advantage of being a faster and simpler test to perform, requiring no additional equipment apart from a spirometer. Conclusions:, Airway hyperresponsiveness in children and in adolescents without asthma predicts asthma development in adulthood. Asthma patients with airway hyperresponsiveness to methacholine have a poorer quality of life as well as more severe disease and a poorer prognosis compared with asthma patients without airway hyperresponsiveness. Bronchial provocation with mannitol as well as with methacholine were useful for evaluating the severity of asthma and the degree of airway inflammation, and accordingly for determining the need for steroid statement. The mannitol test does, however, have practical advantages over the methacholine test that make it preferable for clinical use. [source]

Anti-allergic effects of PG102, a water-soluble extract prepared from Actinidia arguta, in a murine ovalbumin-induced asthma model

CLINICAL & EXPERIMENTAL ALLERGY, Issue 2 2009
D. Kim
Summary Background Asthma is a chronic inflammatory disease of the lung and its incidence has been increasing around the world. We previously reported that oral administration of a water-soluble extract prepared from Actinidia arguta, code-named PG102, could modulate the level of Th1 and Th2 cytokines and suppress the production of immunoglobulin E (IgE) in the ovalbumin (OVA)-immunized murine model as well as in the in vitro cell culture system, and furthermore could significantly improve dermatitis conditions in the NC/Nga murine model. These data suggested that PG102 might have therapeutic effects in a broad range of allergic diseases. Objective To assess the possible anti-allergic effects of PG102 in the OVA-induced murine asthma model. Methods The quality of PG102 was standardized, using its effects on the production of IgE, IL-5, and IL-13, in in vitro cell culture systems. To test effects on asthma, BALB/c mice were orally administrated with PG102, followed by OVA sensitization and challenge to induce asthmatic symptoms. Airway hyperresponsiveness (AHR), bronchoalveolar lavage fluid, serum, and lung tissue were analysed by using various methods. Results PG102 could decrease the level of IgE, IL-5, and IL-13 in in vitro cell culture systems with IC50 being 1.12,1.43 mg/mL. PG102 could ameliorate asthmatic symptoms, including AHR and eosinophilia in the lungs. Such improvement of asthmatic symptoms by PG102 was accompanied by the down-regulation of IL-5 and IgE. In PG102-treated mice, high level expression of heme oxygenase-1, a potent anti-inflammatory enzyme, was observed in alveolar inflammatory cells, while the mRNA levels of foxp3, TGF-,1, and IL-10, important markers for regulatory T cells, were also up-regulated in the lung tissue. Conclusions PG102 may have potential as a safe and effective reagent for the prevention or treatment of asthma. [source]

Serum immunoglobulin E levels predict human airway reactivity in vitro

CLINICAL & EXPERIMENTAL ALLERGY, Issue 2 2000
Schmidt
Background Airway hyperresponsiveness to non-specific stimuli is one characteristic feature of airway diseases such as bronchial asthma and chronic bronchitis. Until now, studies aiming to demonstrate a relationship between in vivo conditions associated with airway hyperreactivity and in vitro airway responsiveness have been inconclusive. Objective Since serum immunoglobulin (Ig) E is believed to be one determinant of airway reactivity in vivo, we studied whether in vitro airway reactivity in lung resection material from patients with elevated levels of serum IgE was increased as compared with patients with undetectable IgE. By this approach, we aimed to elucidate the role of circulating IgE for bronchial smooth muscle reactivity in vitro. Methods Bronchial rings from nine patients with total serum IgE levels above 200 U/mL and 10 patients with total serum IgE levels below 10 U/mL were passively sensitized, i.e. incubated overnight with buffer or sensitizing serum containing high levels of total IgE (> 250 U/mL). Afterwards, contractile responses to histamine were assessed in the organ bath. Results Histamine responsiveness was significantly increased in airways obtained from patients with IgE levels above 200 U/mL as compared with airways from patients with IgE levels below 10 U/mL (P < 0.05). Passive sensitization of bronchi from patients with low IgE significantly increased histamine responsiveness, as compared with non-sensitized controls from the same patients (P < 0.05). In contrast, passive sensitization of airways from patients with elevated IgE did not further increase responsiveness. There was no difference in histamine reactivity between non-passively sensitized and passively sensitized tissue preparations from patients with IgE above 200 U/mL and passively sensitized tissues from patients with IgE below 10 U/mL. Conclusion Our findings reveal that elevated levels of serum IgE predict airway hyperresponsiveness to histamine in vitro. At the same time, they indicate that the in vitro model of passive sensitization, in addition to its ability to induce allergen responses, also mimics conditions of non-specific airway hyperreactivity, which are relevant under in vivo conditions. [source]

Mast cells play a key role in the developmentof late airway hyperresponsiveness through TNF-,in a murine model of asthma

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2007
Young-Suk Kim
Abstract We have investigated the role of TNF-, in mast cell-mediated late airway hyperresponsiveness (AHR) using mast cell-deficient WBB6F1- W/Wv (W/Wv) mice in a murine model of asthma, which exhibits a biphasic increase in AHR. TNF-, levels in the airway and magnitude of late AHR in response to airway allergen challenge were severely impaired in W/Wv mice compared to their littermates. In addition to TNF-,, cytosolic phospholipase A2 (cPLA2) phosphorylation and enzymatic activity in the lungs were also impaired in W/Wv mice. Either anti-TNF-, antibody or an inhibitor of cPLA2 abolished late AHR in congeneic +/+ mice. Intratracheal administration of TNF-, resulted in increases in late AHR, cPLA2 phosphorylation, cPLA2 activity, and phosphorylation of mitogen-activated protein kinases. Mast cell replacement restored airway TNF-, level, cPLA2 phosphorylation and enzymatic activity in the lungs as well as late AHR in W/Wv mice. These data indicate that mast cells play a key role in the development of late AHR through liberation of TNF-,. [source]

Piperine inhibits eosinophil infiltration and airway hyperresponsiveness by suppressing T cell activity and Th2 cytokine production in the ovalbumin-induced asthma model

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 3 2009
Seung-Hyung Kim
Abstract Objectives This study aimed to investigate the effect of piperine on airway hyper-responsiveness, pulmonary eosinophilic infiltration, various immune cell phenotypes, Th2 cytokine production, immunoglobulin E and histamine production in a murine model of asthma. Methods Asthma was induced in Balb/c mice by ovalbumin sensitization and inhalation. Piperine (4.5 and 2.25 mg/kg) was orally administered 5 times a week for 8 weeks. At 1 day after the last ovalbumin exposure, airway hyperresponsiveness was determined and samples of bronchoalveolar lavage fluid, lung cells and serum were collected for further analysis. Key findings Piperine-treated groups had suppressed eosinophil infiltration, allergic airway inflammation and airway hyperresponsiveness, and these occurred by suppression of the production of interleukin-4, interleukin-5, immunoglobulin E and histamine. Moreover, polymerase chain reaction products for thymus and activation regulated chemokine from lung cell RNA preparations were decreased in the piperine-treated group compared with control groups, although transforming growth factor-, products were increased in the piperine-treated group. Conclusions The results suggest that the therapeutic mechanism by which piperine effectively treats asthma is based on a reduction of Th2 cytokines (interleukin-4, interleukin-5), eosinophil infiltration, and by marked reduction of thymus and activation regulated chemokine, eotaxin-2 and interleukin-13 mRNA expression (especially transcription of nuclear factor-, dependent genes) in lung tissue, as well as reduced interleukin-4, interleukin-5 and eotaxin levels in bronchoalveolar lavage fluid, and histamine and ovalbumin-specific immunoglobulin E production in serum. [source]

Inhaled vs subcutaneous effects of a dual IL-4/IL-13 antagonist in a monkey model of asthma

ALLERGY, Issue 1 2010
A. Tomkinson
Abstract Background:, Pitrakinra is a recombinant protein derived from human interleukin-4 (IL-4) that binds to IL-4R, and acts as a competitive antagonist of IL-4 and IL-13. The studies reported here compare the dose-ranging effects of pitrakinra on allergen-induced airway hyperresponsiveness (AHR) and airway eosinophilia when administered subcutaneously (s.c.) or by inhalation to the Ascaris suum -sensitive cynomolgus monkey for the purpose of elucidating the primary site of pitrakinra's anti-asthmatic action. Methods:, Airway responsiveness to inhaled methacholine and bronchoalveolar lavage cell composition was determined before and after three allergen exposures with a 1-week course of twice-daily (b.i.d.) s.c. or inhaled pitrakinra or placebo treatment. Results:, Treatment with s.c. pitrakinra significantly reduced allergen-induced AHR, with a maximum effect of a 2.8- to 3.8-fold increase in methacholine PC100 relative to control (P < 0.05) observed at b.i.d. s.c. doses of 0.05,0.5 mg/kg. Inhaled pitrakinra also significantly reduced AHR with a similar maximum effect of a 2.8- to 3.2-fold increase in methacholine PC100 relative to control (P < 0.05) at nominal b.i.d. doses of 3,100 mg. The maximal effect on AHR following inhalation was observed at a plasma concentration which exhibited no efficacy via the subcutaneous route. The effect of pitrakinra on lung eosinophilia was not statistically significant following either route of administration, although lung eosinophil count was reduced in all studies relative to control. Conclusion:, Local administration of pitrakinra to the lung is sufficient to inhibit AHR, one of the cardinal features of asthma, indicating the therapeutic potential of inhaled pitrakinra in the treatment of atopic asthma. [source]

Airway wall geometry in asthma and nonasthmatic eosinophilic bronchitis

ALLERGY, Issue 6 2009
S. Siddiqui
Background:, Variable airflow obstruction and airway hyperresponsiveness (AHR) are features of asthma, which are absent in nonasthmatic eosinophilic bronchitis (EB). Airway remodelling is characteristic of both conditions suggesting that remodelling and airway dysfunction are disassociated, but whether the airway geometry differs between asthma and nonasthmatic EB is uncertain. Methods:, We assessed airway geometry by computed tomography (CT) imaging in asthma vs EB. A total of 12 subjects with mild,moderate asthma, 14 subjects with refractory asthma, 10 subjects with EB and 11 healthy volunteers were recruited. Subjects had a narrow collimation (0.75 mm) CT scan from the aortic arch to the carina to capture the right upper lobe apical segmental bronchus (RB1). In subjects with asthma and EB, CT scans were performed before and after a 2-week course of oral prednisolone (0.5 mg/kg). Results:, Mild,moderate and refractory asthma were associated with RB1 wall thickening in contrast to subjects with nonasthmatic EB who had maintained RB1 patency without wall thickening [mean (SD) % wall area and luminal area mild-t0-moderate asthma 67.7 (7.3)% and 6.6 (2.8) mm2/m2, refractory asthma 67.3 (5.6)% and 6.7 (3.4) mm2/m2, healthy control group 59.7 (6.3)% and 8.7 (3.8) mm2/m2, EB 61.4 (7.8)% and 11.1 (4.6) mm2/m2 respectively; P < 0.05]. Airway wall thickening of non-RB1 airways generation three to six was a feature of asthma only. There was no change in airway geometry of RB1 after prednisolone. Proximal airway wall thickening was associated with AHR in asthma (r = ,0.56; P = 0.02). Conclusions:, Maintained airway patency in EB may protect against the development of AHR, whereas airway wall thickening may promote AHR in asthma. [source]

Distinct association of genetic variations of vascular endothelial growth factor, transforming growth factor-,, and fibroblast growth factor receptors with atopy and airway hyperresponsiveness

ALLERGY, Issue 4 2008
H.-K. Park
Background:, Recent studies showed that high levels of transforming growth factor (TGF)-,1 in the airways reduced airway responsiveness, which was reversed in conditions of basic fibroblast growth factor (FGF2) deficiency, whereas high levels of vascular endothelial growth factor (VEGF) enhanced airway sensitization to allergens and airway hyperresponsiveness (AHR). Objective:, We investigated the effect of single-nucleotide polymorphisms (SNPs) in the VEGF, TGF-,1, and FGF2 receptors on the expression of atopy and AHR in the general population. Methods:, Atopy and AHR were evaluated in a cohort of 2055 children and adolescents. Direct sequencing was used to identify informative SNPs (minor allele frequency >5%) in the receptors of candidate genes. Tagging SNPs were scored using the high-throughput single-base pair extension method, and the statistical significance of these scores was assessed via haplotype analysis. Results:, Informative SNPs were identified for VEGF receptors 1 (Flt-1); TGF-, receptor 3 (TGFBR3); and FGR receptors 1, 2, and 4 (FGFR1, FGFR2, and FGFR4), and 13 tagging SNPs were scored in the cohort. Atopy was significantly associated with haplotypes of TGFBR3, FGFR1, and FGFR2. Meanwhile, AHR was significantly associated with haplotypes of Flt-1, FGFR1, and FGFR4. However, atopy was not associated with genetic variations of Flt-1 and FGFR4, whereas AHR not associated with TGFBR3 and FGFR2. Conclusion:, The expression of atopy and AHR is distinctly associated with genetic variations in VEGF, TGF-,1, and FGFR in the Korean population. [source]

Increased prostaglandin E2 levels in the airway of patients with eosinophilic bronchitis

ALLERGY, Issue 1 2008
B. Sastre
Background:, Eosinophilic bronchitis is a common cause of chronic cough, which like asthma is characterized by sputum eosinophilia, but unlike asthma there is no variable airflow obstruction or airway hyperresponsiveness. We tested the hypothesis that the different airway function in patients with eosinophilic bronchitis and asthma could be caused by an imbalance in the production of bronchoconstrictor (LTC4) and bronchoprotective (prostaglandin E2; PGE2) lipid mediators. Methods:, We measured cytokines levels, proinflammatory mediators and eicosanoids concentration in sputum from 13 subjects with nonasthmatic eosinophilic bronchitis, 13 subjects with asthma, and 11 healthy control subjects. Cytokines mRNA levels were measured by real time PCR, proinflammatory mediators, PGE2, and LTC4 were measured by enzyme immunoassays. Results:, The median sputum eosinophil count was not statistically different in patients with asthma (7.95%) and eosinophilic bronchitis (15.29%). The levels of mRNA specific to interleukin-5 (IL-5), IL-4, IL-10, IL-13, interferon , (IFN-,), IL-2, vascular endothelial growth factor and transforming growth factor , were similar in both conditions. In addition, no differences were found between asthma and eosinophilic bronchitis in proinflammatory cytokines, such as IL-8, IFN-, and tumor necrosis factor , (TNF-,) levels. Sputum cysteinyl-leukotrienes concentration was raised both in eosinophilic bronchitis and asthma patients. We found that induced sputum PGE2 concentrations were significantly increased in subjects with eosinophilic bronchitis (838.3 ± 612 pg/ml) when compared with asthmatic (7.54 ± 2.14 pg/ml) and healthy subjects (4 ± 1.3 pg/ml). Conclusion:, This data suggest that the difference in airway function observed in subjects with eosinophilic bronchitis and asthma could be due to differences in PGE2 production in the airways. [source]

Mechanisms of virus-induced asthma exacerbations: state-of-the-art.

ALLERGY, Issue 5 2007
A GA2LEN, InterAirways document
Viral infections of the respiratory tract are the most common precipitants of acute asthma exacerbations. Exacerbations are only poorly responsive to current asthma therapies and new approaches to therapy are needed. Viruses, most frequently human rhinoviruses (RV), infect the airway epithelium, generate local and systemic immune responses, as well as neural responses, inducing inflammation and airway hyperresponsiveness. Using in vitro and in vivo experimental models the role of various proinflammatory or anti-inflammatory mediators, antiviral responses and molecular pathways that lead from infection to symptoms has been partly unravelled. In particular, mechanisms of susceptibility to viral infection have been identified and the bronchial epithelium appeared to be a key player. Nevertheless, additional understanding of the integration between the diverse elements of the antiviral response, especially in the context of allergic airway inflammation, as well as the interactions between viral infections and other stimuli that affect airway inflammation and responsiveness may lead to novel strategies in treating and/or preventing asthma exacerbations. This review presents the current knowledge and highlights areas in need of further research. [source]

Omalizumab decreases nonspecific airway hyperresponsiveness in vitro

ALLERGY, Issue 2 2007
P. Berger
Background:, In asthmatic patients, both symptoms and hyperresponsiveness are related to immunoglobulin E (IgE) concentration in serum. The anti-IgE monoclonal antibody omalizumab improved the control of asthma, but its effect on airway hyperresponsiveness is controversial. Passive sensitization reproduced in vitro a bronchial hyperresponsiveness, an increase in IgE bearing cells, and a mast cell degranulation. This study was designed to examine the effect of omalizumab on passive sensitization-induced hyperresponsiveness, alterations in IgE positive inflammatory cells and mast cell degranulation within the bronchial wall. Methods:, Proximal (3,5 mm diameter) and distal (0.5,1.5 mm diameter) human bronchi dissected out from 10 lung specimens were incubated in normal or asthmatic serum containing various concentrations of omalizumab. Contractile responses to histamine or Dermatophagoides pteronyssinus (D. pter) were recorded using an organ bath system and expressed as percentage of maximal contractile response to acetylcholine (ACh). Immunohistochemistry was performed using monoclonal antibodies directed against IgE or tryptase. Mast cells were classified as fully granulated (type I), partly (type II) or largely degranulated (type III). Results:, The specific bronchial hyperresponsiveness to D. pter and the nonspecific bronchial hyperresponsiveness to histamine following passive sensitization were significantly inhibited by omalizumab in both distal and proximal airways. Passive sensitization-induced increase in IgE positive cells was also abolished by omalizumab in a concentration dependent manner. Mast cell degranulation which was inhibited by omalizumab was positively correlated with the contractile response to D. pter. Conclusions:, Omalizumab blocks specific and nonspecific bronchial hyperresponsiveness. Anti-IgE also decreases IgE bearing cell number and mast cell degranulation. [source]

Airway hyperresponsiveness and acute chest syndrome in children with sickle cell anemia

Airway function measurements and the long-term follow-up of survivors of preterm birth with and without chronic lung disease

PEDIATRIC PULMONOLOGY, Issue 6 2006
Indra Narang MRCPCH
Abstract This seventh paper in a review series on different aspects of chronic lung disease following preterm birth focuses on the current knowledge of respiratory symptoms, airway function, airway hyperresponsiveness, and exercise capacity from childhood to adulthood. This paper further considers the long-term implications of these studies for both future research and clinical practice. Pediatr Pulmonol. © 2006 Wiley-Liss, Inc. [source]

Outcome in adulthood of asymptomatic airway hyperresponsiveness in childhood: A longitudinal population study

PEDIATRIC PULMONOLOGY, Issue 3 2002
Finn Rasmussen MD
Abstract The clinical outcome of asymptomatic airway hyperresponsiveness (AHR) first detected in childhood is sparsely reported, with conflicting results. We used a birth cohort of 1,037 children followed to age 26 years to assess the clinical outcome of asymptomatic AHR to methacholine first documented in study members at age 9 years. Of 547 study members who denied wheezing symptoms ever at age 9 years, 41 (7.5%) showed AHR. Forty showed methacholine responsiveness, with a provocation concentration of methacholine that elicted a 20% drop in forced expired volume in 1 sec (PC20),,,8 mg/mL, and one had baseline airway obstruction with a bronchodilator response exceeding 10%. Of these 41 study members, 18 (44%), 11 (27%), and 4 (10%) maintained AHR in 1, 2, and 3 later assessments, respectively, while 23 (56%) manifested AHR only at age 9. Compared with asymptomatic study members without AHR, those with asymptomatic AHR at age 9 years were more likely to report asthma and wheeze at any subsequent assessment, were more likely to have high IgE levels and eosinophils at ages 11 and 21, and more often demonstrated positive responses to skin allergen testing at ages 13 and 21 years. Persistent AHR at later assessments increased these likelihoods further. In conclusion, asymptomatic children with AHR are more likely to develop asthma and atopy later in life compared with asymptomatic children without AHR. Persistent AHR, even though initially asymptomatic, was associated with an even greater increased risk of development of asthma. We suggest that rather than considering AHR as a marker of asthma, it should be regarded as a parallel pathological process that may lead to subsequent symptoms and clinical evidence of asthma. Pediatr Pulmonol. 2002; 34:164,171. © 2002 Wiley-Liss, Inc. [source]

Extrathoracic airway responsiveness in children with asthma-like symptoms, including chronic persistent cough

Exercise-induced wheeze: Fraction of exhaled nitric oxide-directed management

RESPIROLOGY, Issue 4 2010
Douglas C. COWAN
ABSTRACT Background and objective: Exercise-induced wheeze (EIW) is common. Several treatment options exist. Patients with low fraction of exhaled nitric oxide (FENO) are unlikely to be steroid-responsive and might benefit from non-steroidal therapies. We assessed: the efficacy of cromoglycate, formoterol and montelukast in patients with EIW and low FENO (<35 ppb) in a randomized cross-over trial, and the efficacy of inhaled corticosteroid in a high FENO (>35 ppb) group. Methods: Patients had EIW and airway hyperresponsiveness (AHR) to mannitol and/or exercise. Those with low FENO (n = 19) received cromoglycate (20 mg inh. bd + before challenge tests), formoterol (12 µg inh. bd + before challenge tests) and montelukast (10 mg p.o. od), each for 2 weeks. Those with high FENO (n = 20) took inhaled fluticasone (500 µg) daily for 4 weeks. Primary end-points were: 50% reduction in maximum FEV1 %fall (clinical protection) and decrease in AHR to mannitol. Results: In patients with low FENO, cromoglycate, formoterol and montelukast significantly decreased AHR to mannitol in 63%, 61% and 47% of patients, respectively. In this group, the magnitude of exercise-induced bronchoconstriction (EIB) was significantly reduced with montelukast and formoterol; between-treatment differences were not significant. Of 6/19 with low FENO and EIB, protection occurred in 67% (cromoglycate), 83% (formoterol) and 50% (montelukast), respectively. In the high FENO group, AHR to mannitol and EIB decreased significantly with fluticasone (P < 0.001, P = 0.005, respectively), and protection occurred in 7/8 (88%) with EIB. Conclusions: In patients with EIW and low FENO, the number of ,responders' to cromoglycate, formoterol and montelukast was similar. In a high FENO population the response to inhaled corticosteroid was highly significant and comparable to previous studies. [source]

Effects of inhaled fluticasone propionate on CTLA-4-positive CD4+CD25+ cells in induced sputum in mild asthmatics

RESPIROLOGY, Issue 7 2008
Tomotaka KAWAYAMA
Background and objective: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) signalling of regulatory T cells regulates mucosal lymphocyte tolerance and differentiation, and may therefore have a beneficial effect in allergic diseases such as asthma. The aim of this study was to evaluate the effects of fluticasone propionate (FP) on CD4+CD25+ T cell co-expression of CTLA-4 in the sputum of mild asthmatic subjects. Methods: Eleven mild, stable asthmatic subjects completed a double-blind, randomized, cross-over, placebo-controlled study to compare the effects of 14 days 200 µg twice daily FP and placebo. Before and after treatment, airway hyperresponsiveness was measured, and sputum was induced for measurements of CTLA-4+CD4+CD25+ cells, eosinophils and levels of IL-10, IL-13 and transforming growth factor (TGF)-, Results: FP treatment increased co-expression of CTLA-4 on sputum CD4+CD25+ cells from a mean (SEM) of 7.9% (1.8) to 12.7% (3.3) after 14 days treatment (P < 0.05) compared with placebo. FP treatment also significantly increased IL-10 levels, reduced per cent sputum eosinophils, and reduced airway hyperresponsiveness (P < 0.05). There was a significant negative correlation between the change in airway hyperresponsiveness and per cent sputum eosinophils (P < 0.01), but no correlation with changes in CTLA-4+CD4+CD25+ cells (P > 0.05). There was no change in the levels of sputum IL-13 or TGF-, Conclusions: The percentage of airway CTLA-4+CD4+CD25+ cells increased after FP treatment, coincident with improvements in airway inflammation and hyperresponsiveness. Whether improved asthma assessments are related to the increase in CTLA-4+CD4+CD25+ cells and thus improved regulation of T-cell tolerance and differentiation will require a larger sample size to determine. The normalization of CTLA-4+CD4+CD25+ cells in asthma may contribute to the management of this disease. [source]

Respiratory morbidity and lung function in two Aboriginal communities in Western Australia

RESPIROLOGY, Issue 3 2002
Marieke W. VERHEIJDEN
Objective: To examine differences in the rates of respiratory symptoms, asthma and levels of lung function in two remote Aboriginal communities. Methodology: Respiratory symptoms, smoking history, skin prick test responses to common allergens, serum IgE, lung function, airway responsiveness to methacholine and white blood cell counts were compared in two Aboriginal communities, one from the central desert (n = 84) and another from the tropical north (n = 209) of Western Australia. Results: Compared with the tropical community, chest tightness and dyspnoea were more frequent and forced expiratory volume in 1 s and forced vital capacity were lower in the desert community, despite similar levels of wheeze, doctor-diagnosed asthma and skin prick test responses and lower levels of airway responsiveness and smoking. The total white cell and neutrophil counts were greater in the desert community. Serum IgE was very high and similar in both communities. Conclusions: Our findings show a low prevalence of asthma in children, a high prevalence of respiratory symptoms and low levels of lung function in remote Aboriginal communities. The greater prevalence of respiratory morbidity in the desert community was not explained by diagnosed asthma, airway hyperresponsiveness or cigarette smoking. The role of infection requires further investigation. The results suggest that the lower lung function observed in Aboriginal communities (compared with non-Aboriginal communities) results at least partly from environmental factors. [source]

Current and future use of the mannitol bronchial challenge in everyday clinical practice

THE CLINICAL RESPIRATORY JOURNAL, Issue 4 2009
Celeste Porsbjerg
Abstract Objectives:, Asthma is a disease associated with inflammation, airway hyperresponsiveness (AHR) and airflow limitation. Clinical diagnosis and management of asthma often relies on assessment of lung function and symptom control, but these factors do not always correlate well with underlying inflammation. Bronchial challenge tests (BCTs) assess AHR, and can be used to assist in the diagnosis and management of asthma. Data Source:, Data presented at the symposium ,Use of inhaled mannitol for assessing airways disease' organised by the Allied Respiratory Professionals Assembly (9) of the European Respiratory Society (ERS) at the ERS Congress, Berlin 2008. Results:, Indirect challenge tests such as exercise testing, hypertonic saline or adenosine 5,-monophosphate (AMP) are more specific though less sensitive than direct challenge tests (such as methacholine) for identifying patients with active asthma. Indirect BCTs may be used to diagnose exercise-induced bronchoconstriction or AHR consistent with active asthma, to evaluate AHR that will respond to treatment with anti-inflammatory drugs and to determine the effectiveness and optimal dosing of such therapy. An ideal indirect challenge test should be standardised and reproducible, and the test result should correlate with the degree of airway inflammation. The mannitol BCT provides a standardised and rapid point-of-need test to identify currently active asthma, and is clinically useful in the identification of patients with asthma who are likely to benefit from inhaled corticosteroid therapy. Conclusion:, In the future, mannitol BCT may be added to lung function and symptom assessment to aid in the everyday management of asthma. Please cite this paper as: Porsbjerg C, Backer V, Joos G, Kerstjens HAM and Rodriguez-Roisin R. Current and future use of the mannitol bronchial challenge in everyday clinical practice. The Clinical Respiratory Journal 2009; 3: 189,197. [source]

Monitoring asthma therapy using indirect bronchial provocation tests,

THE CLINICAL RESPIRATORY JOURNAL, Issue 1 2007
John D. Brannan
Abstract Objectives:, Bronchial provocation tests that assess airway hyperresponsiveness (AHR) are known to be useful in assisting the diagnosis of asthma and in monitoring inhaled corticosteroid therapy. We reviewed the use of bronchial provocation tests that use stimuli that act indirectly for monitoring the benefits of inhaled corticosteroids. Data Source:, Published clinical trials investigating the effect of inhaled corticosteroids on bronchial hyperresponsiveness in persons with asthma were used for this review. Study Selection:, Studies using indirect stimuli to provoke airway narrowing such as exercise, eucapnic voluntary hyperventilation, cold air hyperventilation, hypertonic saline, mannitol, or adenosine monophosphate (AMP) to assess the effect of inhaled corticosteroids were selected. Results:, Stimuli acting indirectly result in the release of a variety of bronchoconstricting mediators such as leukotrienes, prostaglandins, and histamine, from cells such as mast cells and eosinophils. A positive response to indirect stimuli is suggestive of active inflammation and AHR that is consistent with a diagnosis of asthma. Persons with a positive response to indirect stimuli benefit from daily treatment with inhaled corticosteroids. Symptoms and lung function are not useful to predict the long-term success of inhaled corticosteroid dose as they usually resolve rapidly, and well before inflammation and AHR has resolved. Following treatment, AHR to indirect stimuli is attenuated. Further, during long-term treatment, asthmatics can become as non-responsive as non-asthmatic healthy persons, suggesting that asthma is not active. Conclusions:, Non-responsiveness to indirect bronchial provocation tests following inhaled corticosteroids occurs weeks to months following the resolution of symptoms and lung function. Non-responsiveness to indirect stimuli may provide a goal for adequate therapy with inhaled corticosteroids. Please cite this paper as: Brannan JD, Koskela H and Anderson SD. Monitoring asthma therapy using indirect bronchial provocation tests. The Clinical Respiratory Journal 2007;1:3,15. [source]

Airway hyperresponsiveness: the usefulness of airway hyperresponsiveness testing in epidemiology, in diagnosing asthma and in the assessment of asthma severity

REVIEW ARTICLE: Maternal Transmission of Asthma Risk

AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 1 2009
Robert H. Lim
Maternal asthma significantly increases the risk of asthma in offspring, but the mechanisms remain poorly defined. We review animal models used to study the maternal effect, focusing on a murine model developed in our laboratory. Mother mice rendered allergic to ovalbumin produce offspring that are more susceptible to allergic sensitization, seen as airway hyperresponsiveness and allergic airway inflammation after a sensitization protocol, which has minimal effects on newborns from normal mothers. Mechanistic analyses identify a role for interleukin-4 (based on pre-mating injection of neutralizing antibodies), dendritic cells and allergen-specific T cells (based on adoptive transfer experiments). Other maternal exposures (e.g. pollutant exposure and non-pulmonary allergy) can increase asthma susceptibility in offspring. This observation implies that the maternal transmission of asthma represents a final common pathway to various types of inflammatory stimuli. Identification of the shared molecular mechanisms in these models may allow better prevention and therapy. Current knowledge, gaps in knowledge and future directions are discussed. [source]

Role of 5-HT2A, 5-HT4 and 5-HT7 receptors in the antigen-induced airway hyperresponsiveness in guinea-pigs

CLINICAL & EXPERIMENTAL ALLERGY, Issue 2 2010
P. Segura
Summary Background A possible role of 5-hydroxytryptamine (5-HT) in the origin of antigen-induced airway hyperresponsiveness (AI-AHR) has been scarcely investigated. Objective To explore the participation of different 5-HT receptors in the development of AI-AHR in guinea-pigs. Methods Lung resistance was measured in anaesthetized guinea-pigs sensitized to ovalbumin (OVA). Dose,response curves to intravenous (i.v.) acetylcholine (ACh) were performed before and 1 h after antigenic challenge and expressed as the 200% provocative dose (PD200). Organ bath experiments, confocal microscopy and RT-PCR were additionally used. The 5-HT content in lung homogenates was measured by HPLC. Results Antigenic challenge significantly decreased PD200, indicating the development of AI-AHR. This hyperresponsiveness was abolished by a combination of methiothepin (5-HT1/5-HT2/5-HT5/5-HT6/5-HT7 receptors antagonist) and tropisetron (5-HT3/5-HT4 antagonist). Other 5-HT receptor antagonists showed three different patterns of response. Firstly, WAY100135 (5-HT1A antagonist) and ondansetron (5-HT3 antagonist) did not modify the AI-AHR. Secondly, SB269970 (5-HT7 antagonist), GR113808 (5-HT4 antagonist), tropisetron or methiothepin abolished the AI-AHR. Thirdly, ketanserin (5-HT2A antagonist) produced airway hyporresponsiveness. Animals with bilateral vagotomy did not develop AI-AHR. Experiments in tracheal rings showed that pre-incubation with LP44 or cisapride (agonists of 5-HT7 and 5-HT4 receptors, respectively) induced a significant increase of the cholinergic contractile response to the electrical field stimulation. In sensitized lung parenchyma strips, ketanserin diminished the contractile responses to ACh. Sensitization was associated with a ninefold increase in the 5-HT content of lung homogenates. Confocal microscopy showed that sensitization enhanced the immunolabelling and co-localization of nicotinic receptor and 5-HT in airway epithelium, probably located in pulmonary neuroendocrine cells (PNECs). RT-PCR demonstrated that neither sensitization nor antigen challenge modified the 5-HT2A receptor mRNA levels. Conclusions Our results suggested that 5-HT was involved in the development of AI-AHR to ACh in guinea-pigs. Specifically, 5-HT2A, 5-HT4 and 5-HT7 receptors seem to be particularly involved in this phenomenon. Participation of 5-HT might probably be favoured by the enhancement of the PNECs 5-HT content observed after sensitization. Cite this as: P. Segura, M. H. Vargas, G. Córdoba-Rodríguez, J. Chávez, J. L. Arreola, P. Campos-Bedolla, V. Ruiz, L. M. García-Hernández, C. Méndez and L. M. Montaño, Clinical & Experimental Allergy, 2010 (40) 327, 338. [source]

Regulatory T cells and asthma

CLINICAL & EXPERIMENTAL ALLERGY, Issue 9 2009
D. S. Robinson
Airway inflammation in asthma is characterized by activation of T helper type-2 (Th2) T cells, IgE production and eosinophilia. In many cases, this process is related to an inappropriate T cell response to environmental allergens, and other T cell-dependent pathways may also be involved (such as Th17). Regulatory T cells (Tregs) are T cells that suppress potentially harmful immune responses. Two major subsets of Treg are CD25hi, Foxp3+Tregs and IL-10-producing Tregs. There is evidence that the numbers or function of both subsets may be deficient in patients with atopic allergic disease. Recent work has extended these findings into the airway in asthma where Foxp3 expression was reduced and CD25hi Treg-suppressive function was deficient. In animal models of allergic airways disease, Tregs can suppress established airway inflammation and airway hyperresponsiveness, and protocols to enhance the development, recruitment and function of Tregs have been described. Together with studies of patients and in vitro studies of human T cells, these investigations are defining potential interventions to enhance Treg function in the airway in asthma. Existing therapies including corticosteroids and allergen immunotherapy act on Tregs, in part to increase IL-10 production, while vitamin D3 and long-acting ,-agonists enhance IL-10 Treg function. Other possibilities may be enhancement of Treg function via histamine or prostanoid receptors, or by blocking pro-inflammatory pathways that prevent suppression by Tregs (activation of Toll-like receptors, or production of cytokines such as IL-6 and TNF-,). As Tregs can also suppress the potentially beneficial immune response important for controlling infections and cancer, a therapeutic intervention should target allergen- or site-specific regulation. [source]

Plasminogen activator inhibitor-1 and asthma: role in the pathogenesis and molecular regulation

CLINICAL & EXPERIMENTAL ALLERGY, Issue 8 2009
Z. Ma
Summary Plasminogen activator inhibitor (PAI)-1 is a major inhibitor of the fibrinolytic system. PAI-1 levels are markedly increased in asthmatic airways, and mast cells (MCs), a pivotal cell type in the pathogenesis of asthma, are one of the main sources of PAI-1 production. Recent studies suggest that PAI-1 may promote the development of asthma by regulating airway remodelling, airway hyperresponsiveness (AHR), and allergic inflammation. The single guanosine nucleotide deletion/insertion polymorphism (4G/5G) at ,675 bp of the PAI-1 gene is the major genetic determinant of PAI-1 expression. Plasma PAI-1 level is higher in people with the 4G/4G genotype than in those with the 5G/5G genotype. A strong association between the 4G/5G polymorphism and the risk and the severity of asthma has been suggested. Levels of plasma IgE and PAI-1 and severity of AHR are greater in asthmatic patients with the 4G/4G genotype than in those with the 5G/5G genotype. The PAI-1 promoter with the 4G allele renders higher transcription activity than the PAI-1 promoter with the 5G allele in stimulated MCs. The molecular mechanism for the 4G allele-mediated higher PAI-1 expression is associated with greater binding of upstream stimulatory factor-1 to the E-box adjacent to the 4G site (E-4G) than to the E-5G. In summary, PAI-1 may play an important role in the pathogenesis of asthma. Further studies evaluating the mechanisms of PAI-1 action and regulation may lead to the development of a novel prognostic factor and therapeutic target for the treatment and prevention of asthma and other PAI-1-associated diseases. [source]

Toll-like receptor 2 agonist Pam3CSK4 enhances the induction of antigen-specific tolerance via the sublingual route

CLINICAL & EXPERIMENTAL ALLERGY, Issue 11 2008
V. Lombardi
Summary Background Sublingual immunotherapy (SLIT) has been established in humans as a safe and efficacious treatment for type I respiratory allergies. Objective In this study, we compared three Toll-like receptor (TLR) 2 ligands (Pam3CSK4, Porphyromonas gingivalis lipopolysaccharide and lipoteichoic acid) as potential adjuvants for sublingual allergy vaccines. Methods These molecules were tested in co-cultures of adjuvant-pre-treated dendritic cells (DCs) with murine naïve CD4+ T lymphocytes. Patterns of cytokine production, phenotype, proliferation and gene expression were analysed by ELISA, cytofluorometry and quantitative PCR, respectively. TLR2 ligands were subsequently tested in a model of SLIT in BALB/c mice sensitized with ovalbumin (OVA). Results Among the three TLR2 ligands tested, the synthetic lipopeptide Pam3CSK4 is the most potent inducer of IL-12p35 and IL-10 gene expression in murine bone marrow-derived DCs, as well as in purified oral myeloid DCs. Only Pam3CSK4-treated DCs induce IFN-, and IL-10 secretion by naïve CD4+ T cells. Sublingual administration of Pam3CSK4 together with the antigen in BALB/c mice sensitized to OVA decreases airway hyperresponsiveness as well as OVA-specific T-helper type 2 (Th2) responses in cervical lymph nodes dramatically. Conclusion Pam3CSK4 induces Th1/regulatory T cell responses, and as such, is a valid candidate adjuvant for sublingual allergy vaccines. [source]