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Bronchoconstriction
Kinds of Bronchoconstriction Selected AbstractsCAN WE DIFFERENTIATE BETWEEN AIRWAY AND VASCULAR SMOOTH MUSCLE?CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 11 2004Darren J Fernandes SUMMARY 1.,Airway smooth muscle (ASM) has recently been termed the ,frustrated' cell of the lung given that contraction of ASM has no proven useful physiological function in adults and yet is indelibly associated with pathological conditions by virtue of its unwanted airflow-limiting actions in asthma. In contrast, pulmonary vascular smooth muscle contraction plays an essential role in the control of blood flow through the lung. 2.,Little is known of the differences in phenotype between human ASM and pulmonary vascular smooth muscle (VSM) tissues, but differences in contractile protein and transcription factor expression and regulation of contractile protein promoter activity have been documented. Similarly, the embryological signals in mice required for differentiation of ASM versus pulmonary VSM are distinct. 3.,Bronchoconstriction in asthma is currently treated with ,2 -adrenoceptor agonists, which relax contracted ASM cells. An additional approach may be to use gene therapy to render ASM unable to contract (via disruption of their contractile apparatus organization). 4.,Application of ASM-specific gene therapies would rely on minimal actions on other lung smooth muscle tissues, including pulmonary and bronchial vascular smooth muscle. The combination of mRNA analysis of laser-captured microdissected tissue with in situ immunohistochemical staining for protein should be very useful in terms of being able to characterize definitively the differences in mRNA and protein expression between the smooth muscle species of the lung. Any discovery of an ASM-selective target could provide a novel lead for ASM-directed anti-asthma therapy. [source] Spasmogenic action of endothelin-1 on isolated equine pulmonary artery and bronchusEQUINE VETERINARY JOURNAL, Issue 2 2003A. E. M. BENAMOU Summary Reasons for performing study: There is currently little published information about the effects of endothelin-1 (ET-1), a potent endogenous spasmogen of vascular and airway smooth muscle, on pulmonary vasculature and airways or which ET receptor subtypes mediate ET-1-induced vasoconstrictive and bronchoconstrictive action in the horse. Objectives: To investigate the effect of endothelin-1 (ET-1) on smooth muscle from isolated equine pulmonary artery and bronchus. In addition, the roles of ETA and ETB receptors in ET-1 mediated contraction in these tissues were assessed. Methods: The force generation of ring segments from pulmonary arteries or third-generation airways (obtained from horses subjected to euthanasia fororthopaedic reasons) were studied in an organ bath at 37°C in response to exogenous endothelin and selective endothelin A (BQ123) or B receptor (BQ788) antagonists. Results: ET-1 produced concentration-dependent contractions of the equine pulmonary artery and bronchus. The threshold for contraction was 10,10 and 10,9 mol/l ET-1 for pulmonary artery and bronchus, respectively. The maximal contraction induced by the highest ET-1 concentration (10,7 mol/l) was 173 and 194% of the contraction obtained with 100 mmol/l KCl in pulmonary artery and bronchus, respectively. ET-1 potency was 25 times greater in equine pulmonary artery than in equine bronchus (concentration of ET-1 producing 50% of maximal contraction [EC50] = 5.6 10,9 mol/l and 2.2 10,8 mol/l, respectively). In pulmonary artery, ET-1 induced contractions were significantly inhibited by the ETA receptor antagonist BQ123 (1 ,mol/l; dose-response curve to ET-1 was shifted to the right by 5.4-fold), but not by the ETB antagonist BQ788. In bronchus, dose-responses curves to ET-1 were shifted to the right by BQ123 (1 ,mol/l; 2.5-fold), but not by BQ788 (1 ,mol/l). In the presence of both antagonists, the dose-response curve to ET-1 was shifted to the right by 4.5-fold. Conclusions: These functional studies demonstrate that ET-1 is a potent spasmogen of equine third generation pulmonary artery and bronchus, and that contractions are mediated via ETA receptors in the former and both ETA and ETB receptors in the latter. Potential clinical relevance: Endothelin receptor antagonists may have potential for treating equine pulmonary hypertension or bronchoconstriction. [source] Adenosine receptors: promising targets for the development of novel therapeutics and diagnostics for asthmaFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2006Cristina Russo Abstract Interest in the role of adenosine in asthma has escalated considerably since the early observation of its powerful bronchoconstrictor effects in asthmatic but not normal airways. A growing body of evidence has emerged in support of a proinflammatory and immunomodulatory role for the purine nucleoside adenosine in the pathogenic mechanisms of chronic inflammatory disorders of the airways such as asthma. The fact that adenosine enhances mast cell allergen-dependent activation, that elevated levels of adenosine are present in chronically inflamed airways, and that adenosine given by inhalation cause dose-dependent bronchoconstriction in subjects with asthma emphasizes the importance of adenosine in the initiation, persistence and progression of these common inflammatory disorders of the airways. These distinctive features of adenosine have been recently exploited in the clinical and research setting to identify innovative diagnostic applications for asthma. In addition, because adenosine exerts its multiple biological activities by interacting with four adenosine receptor subtypes, selective activation or blockade of these receptors may lead to the development of novel therapies for asthma. [source] Toll-like receptor and tumour necrosis factor dependent endotoxin-induced acute lung injuryINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 6 2007Dieudonnée Togbe Summary Recent studies on endotoxin/lipopolysaccharide (LPS)-induced acute inflammatory response in the lung are reviewed. The acute airway inflammatory response to inhaled endotoxin is mediated through Toll-like receptor 4 (TLR4) and CD14 signalling as mice deficient for TLR4 or CD14 are unresponsive to endotoxin. Acute bronchoconstriction, tumour necrosis factor (TNF), interleukin (IL)-12 and keratinocyte-derived chemokine (KC) production, protein leak and neutrophil recruitment in the lung are abrogated in mice deficient for the adaptor molecules myeloid differentiation factor 88 (MyD88) and Toll/Interleukin-1 receptor (TIR)-domain-containing adaptor protein (TIRAP), but independent of TIR-domain-containing adaptor-inducing interferon-beta (TRIF). In particular, LPS-induced TNF is required for bronchoconstriction, but dispensable for inflammatory cell recruitment. Lipopolysaccharide induces activation of the p38 mitogen-activated protein kinase (MAPK). Inhibition of pulmonary MAPK activity abrogates LPS-induced TNF production, bronchoconstriction, neutrophil recruitment into the lungs and broncho-alveolar space. In conclusion, TLR4-mediated, bronchoconstriction and acute inflammatory lung pathology to inhaled endotoxin are dependent on TLR4/CD14/MD2 expression using the adapter proteins TIRAP and MyD88, while TRIF, IL-1R1 or IL-18R signalling pathways are dispensable. Further downstream in this axis of signalling, TNF blockade reduces only acute bronchoconstriction, while MAPK inhibition abrogates completely endotoxin-induced inflammation. [source] Chronic Obstructive Pulmonary Disease Diagnosis and Management in Older AdultsJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 6 2010Nalaka S. Gooneratne MD Chronic obstructive pulmonary disease (COPD) in older adults is a complex disorder with several unique age-related aspects. Underlying changes in pulmonary lung function and poor sensitivity to bronchoconstriction and hypoxia with advancing age can place older adults at greater risk of mortality or other complications from COPD. The establishment of the Global Initiative for Obstructive Lung Disease criteria, which can be effectively applied to older adults, has more rigorously defined the diagnosis and management of COPD. An important component of this approach is the use of spirometry for disease staging, a procedure that can be performed in most older adults. The management of COPD includes smoking cessation, influenza and pneumococcal vaccinations, and the use of short- and long-acting bronchodilators. Unlike with asthma, corticosteroid inhalers represent a third-line option for COPD. Combination therapy is frequently required. When using various inhaler designs, it is important to note that older adults, especially those with more-severe disease, may have inadequate inspiratory force for some dry-powder inhalers, although many older adults find the dry-powder inhalers easier to use than metered-dose inhalers. Other important treatment options include pulmonary rehabilitation, oxygen therapy, noninvasive positive airway pressure, and depression and osteopenia screening. Clinicians caring for older adults with an acute COPD exacerbation should also guard against prognostic pessimism. Although COPD is associated with significant disability, there is a growing range of treatment options to assist patients. [source] Standardized protocol to identify high-risk patients undergoing therapeutic apheresis proceduresJOURNAL OF CLINICAL APHERESIS, Issue 3 2008Qun Lu Abstract As the scope of therapeutic apheresis (TA) expands and more procedures are requested for critically ill patients, adverse reactions (AR) associated with TA become a major concern for physicians, nurses, patients and their families. To assess the risks for ARs associated with patients' underlying diseases, we developed a preprocedure assessment tool with a set of high-risk criteria which included: (1) unstable vital signs, (2) active nonphysiological bleeding, (3) evidence of severe bronchoconstriction, (4) severe anemia, (5) projected extracorporeal volume (ECV) >15% of total blood volume (TBV) in adults or >10% of TBV in pediatric patients, (6) pregnancy, and (7) conditions requiring continuous nursing support. A standard operating procedure with a "Request for Apheresis Procedure on High-Risk Patient" form and protocol were developed to identify patients as high-risk before initiation of a TA procedure. Here we report our experience in the 3-year period following the implementation of this protocol. During this period, a total of 3,254 TA procedures were performed, 44 of which were for patients identified as high-risk by the protocol. The incidence of overall ARs was 8% for all TA procedures and 45.5% for procedures performed for high-risk patients. The incidence of moderate-to-severe ARs was 3.7% for all TA procedures and 36.4% for procedures performed for high-risk patients. The protocol identified a group of patients with an increased risk for ARs, especially moderate-to-severe reactions during and/or immediately following TA. J. Clin. Apheresis, 2008. © 2008 Wiley-Liss, Inc. [source] Red wine polyphenolic compounds inhibit tracheal smooth muscle contraction during allergen-induced hyperreactivity of the airwaysJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 5 2007Sona Franova The aims of the study were to investigate the short and long-term effects of Provinol (red wine polyphenolic compounds) on tracheal smooth muscle reactivity using an in-vitro model of ovalbumin-induced airway inflammation in guinea-pig trachea, and to evaluate the role of nitric oxide (NO) in the bronchodilatory effect of Provinol. The amplitude of tracheal smooth muscle contraction in response to mediators of bronchoconstriction ,histamine (10 nM-1 mM), acetylcholine (10 nM-1 mM) and to allergen (ovalbumin 10,5 -10,3 g mL,1) was used as a parameter of tracheal smooth muscle reactivity. To test the short-term effects of Provinol, isolated tracheal strips were pre-treated for 30 min with Provinol (10,4mg mL,1) alone or in combination with N, -nitro-L-arginine methyl ester (L-NAME; 10,6mol L,1). To test the long-term effects of Provinol, isolated tracheal strips were prepared from guinea pigs that had been treated for 14 days with Provinol (20mg kg,1 per day) alone or in combination with L-NAME (40 mg kg,1 per day). Incubation of tracheal smooth muscle with Provinol decreased the amplitude of contraction in response to ovalbumin, histamine and acetylcholine. The non-selective NO synthase inhibitor L-NAME partially abolished the effect of Provinol on acetylcholine and ovalbumin-induced but not histamine-induced bronchoconstriction. A similar profile was observed after 14 days' oral administration of Provinol. In conclusion, Provinol inhibited the allergen- and spasmogen-induced contraction of tracheal smooth muscle in ovalbumin-sensitized guinea pigs via a mechanism that was mediated at least partially through the metabolism of NO. [source] Sensitization, asthma and allergic disease in young soccer playersALLERGY, Issue 4 2009M. T. Ventura Background:, The aim of this study was to identify the prevalence of allergic disease in young soccer players compared to age-matched students and to evaluate if this prevalence changes as the intensity of training increases. Methods:, A modified ECRHS questionnaire was administered to 194 soccer players divided by age as Beginners (8,11 years), Juniors (12,16 years) and Under 21 (17,20 years) to evaluate the prevalence of allergic diseases and symptoms as well as drug consumption. Subjects with a positive personal history of allergic diseases underwent skin prick and/or patch tests. Age-matched students (n = 136) were used as a control group. Results:, The prevalence of allergic diseases was 34.5% in soccer players and 31.6% in control subjects (n.s.). Skin sensitization to inhalant allergens was detected in 14.4% of symptomatic soccer players and in 19.2% of control students (n.s.). Patch tests were positive in 35.7% of soccer players and 23.0% of controls with allergic dermatitis (n.s.). The prevalence of allergic diseases did not significantly change in relation to the intensity of training. Although the relative prevalence of sensitization to perennial allergens and asthma was less frequent in soccer players than in controls, and the occurrence of exercise-induced bronchoconstriction was similar in the two groups, soccer players used twice as many anti-allergic and anti-asthmatic drugs as control students. Conclusions:, An increasingly intensive training programme is not associated with greater risk of allergic disease in soccer players. Therapy regimens of allergic athletes and exercisers should be monitored more closely to guarantee adequate treatment yet avoid inappropriate drug use and doping practices. [source] Exercise-induced hypersensitivity syndromes in recreational and competitive athletes: a PRACTALL consensus report (what the general practitioner should know about sports and allergy)ALLERGY, Issue 8 2008L. B. Schwartz Exercise-induced (EI) hypersensitivity disorders are significant problems for both recreational and competitive athletes. These include EI-asthma, EI-bronchoconstriction, EI-rhinitis, EI-anaphylaxis and EI,urticaria. A group of experts from the European Academy of Allergology and Clinical Immunology and the American Academy of Allergy Asthma and Immunology met to discuss the pathogenesis of these disorders and how to diagnose and treat them, and then to develop a consensus report. Key words (exercise with asthma, bronchoconstriction, rhinitis, urticaria or anaphylaxis) were used to search Medline, the Cochrane database and related websites through February 2008 to obtain pertinent information which, along with personal reference databases and institutional experience with these disorders, were used to develop this report. The goal is to provide physicians with guidance in the diagnosis, understanding and management of EI-hypersensitivity disorders to enable their patients to safely return to exercise-related activities. [source] Influence of total IgE levels on the severity of sting reactions in Hymenoptera venom allergyALLERGY, Issue 8 2007G. J. Sturm Background:, Detection of specific IgE for Hymenoptera venoms and skin tests are well established diagnostic tools for the diagnosis of insect venom hypersensitivity. The aim of our study was to analyze the effect of total IgE levels on the outcome of generalized anaphylactic reactions after a Hymenoptera sting. Methods:, Two hundred and twenty patients allergic to bee, wasp, or European hornet venom were included in the study. Their specific and total IgE levels, serum tryptase levels, skin tests, and sting history were analyzed. Results:, In patients with mild reactions (grade I, generalized skin symptoms) we observed higher total IgE levels (248.0 kU/l) compared to patients with moderate reactions (grade II, moderate pulmonary, cardiovascular, or gastrointestinal symptoms; 75.2 kU/l) and severe reactions (grade III, bronchoconstriction, emesis, anaphylactic shock, or loss of consciousness; 56.5 kU/l; P < 0.001). Accordingly, 25% of the patients with low levels of total IgE (<50 kU/l), but no individual with total IgE levels >250 kU/l, developed loss of consciousness (P = 0.001). Additionally, specific IgE levels were related to total IgE levels: Specific IgE levels increased from 1.6 to 7.1 kU/l in patients with low (<50 kU/l) and high (>250 kU/l) total IgE levels, respectively (P < 0.001). Specific IgE levels correlated inversely to the clinical reaction grades, however, this trend was not statistically significant (P = 0.083). Conclusion:, Patients with Hymenoptera venom allergy and high levels (>250 kU/l) of total IgE, predominantly develop grade I and grade II reactions and appear to be protected from grade III reactions. However, this hypothesis should be confirmed by extended studies with sting challenges. [source] Release of prostaglandin D2 and leukotriene C4 in response to hyperosmolar stimulation of mast cellsALLERGY, Issue 12 2006M. Gulliksson Background:, Mannitol-induced bronchoconstriction in subjects with exercise-induced asthma is associated with increased urinary excretion of 9,, 11, -PGF2, a metabolite of prostaglandin D2 (PGD2) serving as a mast cell marker. It has however been questioned whether or not human mast cells release PGD2 and leukotriene C4 (LTC4) after osmotic challenge with mannitol in vitro. Methods:, Cord blood-derived human mast cells were stimulated osmotically, immunologically or with a combination of both. Supernatants were analysed for PGD2, LTC4 and histamine contents with enzyme immunoassays. Results:, Significant release of de novo synthesized eicosanoids, predominantly PGD2 [12 (8.8, 14) pmol/106cells; median (25th, 75th percentile) but also LTC4 (0.1 (0.08, 0.15) pmol/106 cells] were found in mast cells in vitro in response to 0.7 M mannitol stimulation. A massive release of histamine [70 (5.3)% of total; mean (SEM)] was also found. There were no correlations between the levels of released mediators after mannitol stimulation. In contrast, there was a correlation between release of PGD2 and LTC4, following immunological stimulation. Conclusion:, The findings support that hyperosmolar challenge activates mast cells, but different than antigen stimulation. [source] Exhaled nitric oxide and exercise-induced bronchoconstriction in young wheezy children , interactions with atopyPEDIATRIC ALLERGY AND IMMUNOLOGY, Issue 7 2009L. Pekka Malmberg The association between exercise-induced bronchoconstriction (EIB) and exhaled nitric oxide (FENO) has not been investigated in young children with atopic or non-atopic wheeze, two different phenotypes of asthma in the early childhood. Steroid naļve 3- to 7-yr-old children with recent wheeze (n = 84) and age-matched control subjects without respiratory symptoms (n = 71) underwent exercise challenge test, measurement of FENO and skin prick testing (SPT). EIB was assessed by using impulse oscillometry, and FENO by standard online technique. Although FENO levels were highest in atopic patients with EIB, both atopic and non-atopic wheezy children with EIB showed higher FENO than atopic and non-atopic control subjects, respectively. In atopic wheezy children, a significant relationship between FENO and the severity of EIB was found (r = 0.44, p = 0.0004), and FENO was significantly predictive of EIB. No clear association between FENO and EIB or predictive value was found in non-atopic wheezy children. Both atopic and non-atopic young wheezy children with EIB show increased FENO levels. However, the association between the severity of EIB and FENO is present and FENO significantly predictive of EIB only in atopic subjects, suggesting different interaction between bronchial responsiveness and airway inflammation in non-atopic wheeze. [source] Pilot study: The effect of reducing treatment on exercise induced bronchoconstriction,PEDIATRIC PULMONOLOGY, Issue 9 2010E.T.G. Kersten MD Abstract Rationale Asthma therapy should be stepped up or stepped down in response to changes in asthma control. However, there is little evidence available on the optimal timing, sequence, and degree of medication reductions. In this study we analyzed clinically stable asthmatic children who underwent a medication reduction from a combination preparation consisting of an inhaled corticosteroid (ICS) and long acting beta2-agonist (LABA) to monotherapy with the same dose of the ICS. We hypothesized that the extent of exercise-induced bronchoconstriction (EIB) would not increase after the cessation of the LABA. Methods Nineteen children, aged 8,16 years, with clinically stable asthma, receiving LABA/ICS combination therapy, were analyzed in this open-label pilot study. Children performed an exercise challenge at baseline and 3 weeks after the medication reduction. Best values of spirometric measurements of the forced expiratory volume in 1,sec (FEV1) were used for statistical calculations. Results Maximum percent fall in FEV1 was significantly lower after 3 weeks of ICS monotherapy (P,=,0.03). Eight of 19 children had a ,15% fall in FEV1 after exercise at the initial exercise challenge. In this subgroup, maximum percent fall in FEV1 after the medication reduction was significantly lower (P,<,0.01), and in six children it decreased to <15%, indicating they no longer had EIB. Conclusion In clinically stable asthmatic children on LABA/ICS combination therapy, the cessation of the LABA can reduce and in most cases abolish EIB. Pediatr. Pulmonol. 2010; 45:927,933. © 2010 Wiley-Liss, Inc. [source] Safety and use of sputum induction in children with cystic fibrosis,PEDIATRIC PULMONOLOGY, Issue 4 2003Ranjan Suri MRCPCH Abstract We assessed the safety and use of induced sputum (IS) in children with cystic fibrosis (CF). Forty-eight children (19 males) with CF, mean age 12.6 (range, 7.3,17.0) years and median forced expired volume in 1 sec (FEV1) 48% (range, 14,77%) predicted were recruited. Patients spontaneously expectorated sputum and then performed sputum induction by inhalation of nebulized 7% hypertonic saline. Samples were sent for bacteriological culture, and for measurement of the following inflammatory mediators: interleukin-8, myeloperoxidase, eosinophil cationic protein, and neutrophil elastase activity. FEV1 was performed before and after inhalation of hypertonic saline. There was no increase in mediator levels in IS compared to expectorated sputum (ES) samples. Only 3 patients demonstrated significant bronchoconstriction following inhalation of hypertonic saline, by the method used. From the ES samples, Pseudomonas aeruginosa was isolated in 13 patients, Staphylococcus aureus in 7 patients, Stenotrophomonas maltophilia in 1 patient, and both Pseudomonas aeruginosa and Staphylococcus aureus in 5 patients. All these organisms were found in the IS samples. However, in 2 patients whose ES grew no organisms, one patient's IS grew Pseudomonas aeruginosa, and the other patient's IS grew Staphylococcus aureus. In our study, sputum induction was safe, with no proinflammatory effect. Pediatr Pulmonol. 2003; 35:309,313. © 2003 Wiley-Liss, Inc. [source] Respiratory impedance response to a deep inhalation in children with history of cough or asthmaPEDIATRIC PULMONOLOGY, Issue 6 2002Franēois Marchal MD Abstract The aim of this study was to describe the change in respiratory impedance induced by a deep inhalation (DI) in children who developed a positive response to inhalation of methacholine (Mch). Eighteen children aged 4.5,12.5 years, presenting with chronic cough or doctor-diagnosed asthma, were studied at baseline after inhalation of Mch and after inhalation of a bronchodilator. Respiratory resistance (Rrs) and reactance (Xrs) were measured by the forced oscillation technique, varying transrespiratory pressure at 12 Hz around the head. The tidal flow (V,) and volume (V) dependence of Rrs before and after the DI was characterized according to the equation Rrs,=,K1,+,K2,·,|V,|,+,K3,·,V. DI induced no significant change at baseline or after inhalation of a bonchodilator. During Mch challenge, Rrs and K1 were significantly lower, and K3 and Xrs significantly less negative after DI than before, during both inspiration and expiration; there was no change in K2. We conclude that DI results in a decrease in Rrs in children with induced bronchoconstriction. The associated changes in Xrs, K1, and K3, and lack of decrease in K2, suggest that dilatation of airways occurs at the bronchial level, with little contribution of the upper airways or of a change in breathing patterns. Pediatr Pulmonol. 2002; 33:411,418. © 2002 Wiley-Liss, Inc. [source] Exercise-induced wheeze: Fraction of exhaled nitric oxide-directed managementRESPIROLOGY, Issue 4 2010Douglas 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] Changes in the highest frequency of breath sounds without wheezing during methacholine inhalation challenge in childrenRESPIROLOGY, Issue 3 2010Chizu HABUKAWA ABSTRACT A breath sound analyser was used to detect bronchoconstriction without wheezing during methacholine inhalation challenge in children. The highest frequency of inspiratory breath sounds increased significantly during bronchoconstriction and decreased after inhalation of a bronchodilator. The highest frequency of inspiratory breaths sounds was correlated with bronchial reactivity. Background and objective: It is difficult for clinicians to identify changes in breath sounds caused by bronchoconstriction when wheezing is not audible. A breath sound analyser can identify changes in the frequency of breath sounds caused by bronchoconstriction. The present study aimed to identify the changes in the frequency of breath sounds during bronchoconstriction and bronchodilatation using a breath sound analyser. Methods: Thirty-six children (8.2 ± 3.7 years; males : females, 22 : 14) underwent spirometry, methacholine inhalation challenge and breath sound analysis. Methacholine inhalation challenge was performed and baseline respiratory resistance, minimum dose of methacholine (bronchial sensitivity) and speed of bronchoconstriction in response to methacholine (Sm: bronchial reactivity) were calculated. The highest frequency of inspiratory breath sounds (HFI), the highest frequency of expiratory breath sounds (HFE) and the percentage change in HFI and HFE were determined. The HFI and HFE were compared before methacholine inhalation (pre-HFI and pre-HFE), when respiratory resistance reached double the baseline value (max HFI and max HFE), and after bronchodilator inhalation (post-HFI and post-HFE). Results: Breath sounds increased during methacholine-induced bronchoconstriction. Max HFI was significantly greater than pre-HFI (P < 0.001), and decreased to the basal level after bronchodilator inhalation. Post-HFI was significantly lower than max HFI (P < 0.001). HFI and HFE were also significantly changed (P < 0.001). The percentage change in HFI showed a significant correlation with the speed of bronchoconstriction in response to methacholine (P = 0.007). Conclusions: Methacholine-induced bronchoconstriction significantly increased HFI, and the increase in HFI was correlated with bronchial reactivity. [source] Assessment of inhaled corticosteroid treatment response in asthma using hypertonic histamine challenge-induced coughTHE CLINICAL RESPIRATORY JOURNAL, Issue 2 2010Minna Purokivi Abstract Background and Aims:, Bronchial provocation tests may be utilised to monitor the efficacy of the corticosteroid treatment. Unfortunately, these measurements necessitate good patient cooperation during the spirometry. Coughing during such tests is related to the degree of the bronchoconstriction and occurs involuntarily, i.e. independent of patient cooperation. This study aimed to evaluate the utility of a hypertonic histamine challenge-induced cough in assessing the efficacy of inhaled corticosteroid treatment. Methods:, A total of 16 steroid-naļve asthmatics and 10 non-asthmatic, symptomatic controls received 800-µg beclomethasone (Beclomet Easyhaler®, Orion Ltd., Orion Pharma, Helsinki, Finland) via powder inhaler per day for 8 weeks. Videoed inhalation challenge with hypertonic histamine solution was performed before and after the treatment. Symptom questionnaire was completed before both challenges. The airway responsiveness to hypertonic histamine was expressed as the cumulative number of coughs divided by the final histamine concentration administered [coughs/concentration ratio (CCR)] and as the provocative concentration of histamine to induce a 20% fall in FEV1(PC20). Results:, CCR [geometric mean; 95% confidence interval (CI)] of the asthmatic subjects decreased from 494 (209,1168) to 73.6 (29.8,182) coughs per mg/mL (P = 0.002). Their PC20 levels were 1.31 (1.07,1.60) and 1.91 (1.33,2.74) mg/mL over the treatment period (P = 0.01). The symptom frequency also decreased significantly in the asthmatics (P = 0.039). There were no significant changes in PC20 level, in CCR level or in symptom frequency in non-asthmatic subjects during the treatment. Conclusions:, Hypertonic histamine challenge-induced cough and PC20 are sensitive measures in assessing the treatment effect in asthma. The cough response may be especially useful in subjects who cannot perform spirometry reliably. Please cite this paper as: Purokivi M, Koskela H, Koistinen T, Peuhkurinen K and Kontra KM. Assessment of inhaled corticosteroid treatment response in asthma using hypertonic histamine challenge-induced cough. The Clinical Respiratory Journal 2010; 4: 67,73. [source] Current and future use of the mannitol bronchial challenge in everyday clinical practiceTHE CLINICAL RESPIRATORY JOURNAL, Issue 4 2009Celeste 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] Suppression of histamine-induced tachypnoea in the rhesus monkey by sibenadet: no role for dopamine D2 receptorsAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 1 2004J. R. Fozard Summary 1 Sibenadet (Viozan®), a dual dopamine D2/,2 -adrenoceptor agonist, suppresses histamine-induced tachypnoea in the dog by activating dopamine D2 receptors. We here compare the effects of sibenadet and formoterol, a selective ,2 -adrenoceptor agonist, on histamine-induced tachypnoea in the rhesus monkey. 2 Anaesthetized, spontaneously breathing, rhesus monkeys were set up for measuring airways resistance, respiratory rate, blood pressure and heart rate. 3 Both sibenadet and formoterol administered by aerosol, induced inhibition of the bronchoconstrictor response to aerosolized methacholine accompanied by tachycardia. Sibenadet, but not formoterol, also reduced blood pressure. 4 Administration of histamine by inhalation induced tachypnoea which was accompanied by bronchoconstriction. Tachypnoea to histamine was suppressed by both sibenadet and formoterol at doses which manifest anti-bronchoconstrictor activity. These effects and the accompanying tachycardia but not the hypotension induced by sibenadet were abolished by pretreatment with propranolol. 5 The dopamine D2 receptor agonist, quinagolide, did not suppress tachypnoea to histamine despite inducing a fall in blood pressure indicating activation of dopamine D2 receptors. 6 Thus, both sibenadet and formoterol suppress histamine-evoked tachypnoea in the rhesus monkey. The effect arises exclusively through activation of ,2 -adrenoceptors and probably reflects the anti-bronchoconstrictor effects of these agents. The results reveal a fundamental difference in the role of dopamine receptors in the airways of dog and rhesus monkey. [source] Species differences in bradykinin receptor-mediated responses of the airwaysAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 1 2002K. M. Ellis Summary1 Bradykinin (BK) is a nine amino acid peptide (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) formed from the plasma precursor kininogen during inflammation and tissue injury. The actions of BK are mediated by G protein-coupled cell surface receptors, designated B1 and B2. 2 BK has a plethora of effects in the airways including bronchoconstriction, bronchodilation, stimulation of cholinergic and sensory nerves, mucus secretion, cough and oedema resulting from promotion of microvascular leakage. These airway effects are mediated in the main by the B2 receptor subtype. 3 BK acts mainly indirectly, primarily through airway nerve activation, but also by the release of prostanoids, thromboxanes and nitric oxide (NO). 4 Airway responses to BK have been studied in detail in guinea-pigs, mice, sheep and rats. This review describes the effects of BK in these species and draws comparison with its effects in normal humans and patients with respiratory diseases. 5 Despite its many and varied effects in the airways of animals and man, the exact contribution of BK to airways disease remains unclear. [source] Sensory neuropeptides are not involved in acetaldehyde-induced bronchoconstriction in guinea-pigsAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 3 2001S. Myou 1,Alcohol-induced asthma is characterized by worsening of asthmatic symptoms after alcohol ingestion. Acetaldehyde, a metabolite of ethanol, is thought to be a main factor of alcohol-induced asthma. Although airway sensory nerves are known to be activated in asthma, there have been no studies investigating the role of tachykinins in the airway response to acetaldehyde. The purpose of the present study was to evaluate the involvement of tachykinins on acetaldehyde-induced bronchoconstriction in guinea-pigs. 2,After capsaicin desensitization or intravenous administration of 10 mg kg,1 FK224, a NK1 and NK2 dual antagonist, airway responses to ascending doses (2.5,20 mg ml,1) of inhaled acetaldehyde was examined using a modified Konzett,Rössler method in guinea-pigs. 3,Inhalation of acetaldehyde induced bronchoconstriction in a dose-dependent manner. The FK224 failed to reduce the acetaldehyde-induced bronchoconstriction. Pretreatment with capsaicin did not alter the bronchoconstriction induced by acetaldehyde at a dose of 2.5,10 mg ml,1. Pretreatment with capsaicin slightly, but significantly, inhibited bronchoconstriction induced by 20 mg ml,1 of acetaldehyde. 4,The present results suggest that tachykinins are not involved in acetaldehyde-induced bronchoconstriction in guinea-pigs. [source] Influence of alpha-adrenoceptor blockade on antigen- and propranolol-induced bronchoconstriction in guinea-pigs in vivoAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 1 2000Y. Ishiura 1 Beta-adrenoceptor antagonists, such as propranolol, can provoke severe bronchoconstriction only in asthmatic subjects. Recently, we developed a guinea-pig model of propranolol-induced bronchoconstriction (PIB) and the purpose of this study was to investigate the role of alpha-adrenergic nerve pathways in this reaction. 2 Phentolamine administered after an antigen challenge did not inhibit PIB; however, its administration before the antigen challenge significantly inhibited the antigen-induced bronchoconstriction and also bronchoconstriction induced by methacholine inhalation. 3 We conclude that the alpha-adrenergic nerve system is not involved in the development of PIB following allergic reaction in our guinea-pig model. [source] Plasma concentrations of fluticasone propionate and budesonide following inhalation: effect of induced bronchoconstrictionBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 4 2007Kevin J. Mortimer What is already known about this subject ,,All inhaled corticosteroids are absorbed into the systemic circulation and hence have the potential to cause adverse systemic effects. ,,Plasma drug concentrations following inhalation of 1000 µg fluticasone are considerably lower in people with airflow obstruction than in healthy volunteers but this is not the case for budesonide. What this study adds ,,This is the first study to determine whether changes in airflow obstruction within an individual affect the systemic absorption of inhaled fluticasone and budesonide; ,,Plasma concentrations of fluticasone and, to a lesser extent, those of budesonide were lower when the drugs were inhaled following induced bronchoconstriction; ,,The lower plasma concentrations of corticosteroids seen when the drugs were inhaled following induced bronchoconstriction is likely to reflect variations that will occur with fluctuations in airway caliber in asthma. Aims To determine whether and to what extent bronchoconstriction affects plasma concentrations of fluticasone and budesonide following inhalation. Methods Twenty people with mild asthma inhaled 1000 µg fluticasone (Accuhaler®) plus 800 µg budesonide (Turbohaler®) on two visits. On one occasion, prior to drug inhalation, FEV1 was decreased by at least 25% using inhaled methacholine. Plasma drug concentrations were measured for each drug over 5 h and area under the plasma concentration-time curve (AUC(0,5 h)) compared between visits. Results The mean difference in FEV1 prior to drug inhalation on the 2 days was 33%. AUC(0,5 h) values for fluticasone and budesonide were lower by a median of 60% (IQR 36,75) and 29% (IQR 2,44), respectively, when administered following bronchoconstriction; the reduction was greater for fluticasone than for budesonide, P = 0.007. Conclusions The lower plasma concentrations of fluticasone and, to a lesser extent, budesonide seen when the drugs were inhaled following induced bronchoconstriction, is likely to reflect variations that will occur with fluctuations in airway caliber in asthma. [source] RSD931, a novel anti-tussive agent acting on airway sensory nervesBRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2003J J Adcock The anti-tussive effects, of the local anaesthetic, lidocaine and carcainium chloride (RSD931) have been investigated in guinea-pigs and rabbits. Pre-treatment of guinea-pigs with aerosols of lidocaine or RSD931 at 0.1, 1.0 and 10 mg ml,1 reduced the number of citric acid-induced coughs by 9.3, 32.6 and 40.9% (P>0.05) for lidocaine and by 25.3% (P>0.05), 40.4% (P>0.05) and 97.6% (P<0.01) for RSD931, respectively and increased the latency to onset of cough at 10.0 mg ml,1 only. In addition, RSD931 at 10 mg ml,1 reduced citric acid-evoked cough responses in rabbits (with prior exposure to ozone at 3 p.p.m. for 1 h) from 22.1±5.1 to 2.7±0.9 coughs (P<0.01). Acute pre-treatment of guinea-pigs with aerosols of lidocaine or RSD931 at 10.0 and 30.0 mg ml,1 reduced the number of capsaicin-evoked coughs by 42.2 and 10.3% (P>0.05) (lidocaine) and by 25% (P>0.05) and 76.9% (P<0.01) (RSD931), respectively. Lidocaine had little effect on the latency of cough onset at either 10.0 or 30.0 mg ml,1, however, RSD at 30.0 mg ml,1 significantly (P<0.05) prolonged the latency of cough onset. RSD931 (10.0 mg ml,1) significantly (P<0.05,<0.01) reduced the spontaneous and histamine-evoked discharges in A,-fibres originating from airway, rapidly adapting stretch receptors (RARs) without affecting histamine-evoked bronchoconstriction. Lidocaine at 10.0 mg ml,1 also significantly (P<0.05) inhibited the spontaneous and histamine-induced discharges of RARs without affecting histamine-evoked bronchoconstriction. Aerosols of RSD931 (10.0 mg ml,1) caused a transient, but significant (P<0.05), activation of pulmonary C-fibre endings 2.5 min after administration started. RSD931 had no significant (P>0.05) effects on discharges in bronchial C-fibres originating from bronchial C-fibre endings, capsaicin-evoked discharges of either pulmonary or bronchial C-fibre endings or on capsaicin-evoked bronchoconstriction. In contrast, lidocaine (10.0 mg ml,1) significantly (P<0.05) inhibited spontaneous and capsaicin-induced discharges in both pulmonary and bronchial C-fibres respectively. Lidocaine also significantly (P<0.05) reduced capsaicin-evoked bronchoconstriction. These studies suggest that the anti-tussive actions of RSD931 are mediated via inhibition of discharges in A,-fibres originating from airway RARs. The mechanism of action of RSD931 is distinct from that of the local anaesthetic lidocaine and RSD931 may represent a novel class of anti-tussive agent. British Journal of Pharmacology (2003) 138, 407,416. doi:10.1038/sj.bjp.0705056 [source] Nociceptin/orphanin FQ inhibits capsaicin-induced guinea-pig airway contraction through an inward-rectifier potassium channelBRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2002Yanlin Jia Nociceptin/orphanin FQ (N/OFQ), an endogenous opioid-like orphan receptor (NOP receptor, previously termed ORL1 receptor) agonist, has been found to inhibit capsaicin-induced bronchoconstriction in isolated guinea-pig lungs and in vivo. The underlying mechanisms are not clear. In the present studies, we tested the effect of N/OFQ on VR1 channel function in isolated guinea-pig nodose ganglia cells. Capsaicin increased intracellular Ca2+ concentration in these cells through activation of vanilloid receptors. Capsaicin-induced Ca2+ responses were attenuated by pretreatment of nodose neurons with N/OFQ (1 ,M). N/OFQ inhibitory effect on the Ca2+ response in nodose ganglia cells was antagonized by tertiapin (0.5 ,M), an inhibitor of inward-rectifier K+ channels, but not by verapamil, a voltage gated Ca2+ channel blocker, indicating that an inward-rectifier K+ channel is involved in N/OFQ inhibitory effect. In isolated guinea-pig bronchus, N/OFQ (1 ,M) inhibited capsaicin-induced airway contraction. Tertiapin (0.5 ,M) abolished the N/OFQ inhibition of capsaicin-induced bronchial contraction. Capsaicin (10 ,g) increased pulmonary inflation pressure in the isolated perfused guinea-pig lungs. This response was significantly attenuated by pretreatment with N/OFQ (1 ,M). Tertiapin also abolished the N/OFQ inhibitory effect on capsaicin-induced bronchoconstriction in perfused lungs. Capsaicin increased the release of substance P and neurokinin A from isolated lungs. N/OFQ (1 ,M) blocked the capsaicin-induced tachykinin release. These results indicate that N/OFQ-induced hyperpolarization of tachykinin containing airway sensory nerves, through an inward-rectifier K+ channel activation, accounts for the inhibition of capsaicin-evoked broncoconstriction. British Journal of Pharmacology (2002) 135, 764,770; doi:10.1038/sj.bjp.0704515 [source] Nitric oxide (NO) modulation of PAF-induced cardiopulmonary action: interaction between NO synthase and cyclo-oxygenase-2 pathwaysBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2001Fulvia Fabi To further investigate into the mechanisms of PAF-induced cardiopulmonary actions, we examined the effects of the nitric oxide synthase (NOS) inhibitor L -N, -nitro- L -arginine (L -NNA), of the specific cyclooxygenase-2 (COX-2) inhibitor NS 398, and of the combined presence of both COX and NOS inhibitors on the PAF responses in the heart lung preparation of guinea-pig (HLP). In HLPs perfused with homologous blood, dose-response curves for the haemodynamic and bronchial effects of PAF (1 , 32 ng) were carried out in the absence or presence of L -NNA (200 ,M). L -NNA caused an increase in the resting pulmonary arterial pressure (PAP) without affecting the other basal values, and strongly potentiated the bronchoconstriction and pulmonary hypertension elicited by PAF. An enhancement of the PAF-induced actions on right atrial pressure (RAP) and cardiac output (CO) was also observed. All the effects of L -NNA were antagonized by L -arginine (2 mM). The presence of L -NNA in the perfusing blood of HLPs failed to affect the pulmonary hypertensive and bronchoconstrictor responses induced by the thromboxane A2 mimetic U46619 (0.05 , 1.6 ,g), 5-hydroxytryptamine (0.1 , 1.6 ,g), and histamine (0.1 , 1.6 ,g), thus suggesting that these PAF secondary mediators are not responsible for the hyper-responsiveness to PAF induced by L -NNA. Blocking COX-2 pathway with NS 398 (15 , 30 ,M) did not alter the cardiopulmonary resting variables. However, a reduction of the PAF-mediated pulmonary hypertension, but not of bronchoconstriction, was observed. When L -NNA was added to the perfusing medium of HLPs pre-treated with NS 398 or with indomethacin (15 ,M), the basal PAP values were enhanced. However, in the combined presence of COX and NOS inhibitors, only a slight increase in the hypertensive responses to the highest doses of PAF was observed, whereas the PAF mediated actions at bronchial and cardiac level were unaffected. This study indicates that (i) the cardiopulmonary actions induced by PAF are specifically modulated by endogenous NO through the NOS pathway, and (ii) COX-2 isoform is involved in the pulmonary hypertensive, but not bronchoconstrictor, effects of PAF. Furthermore, an interaction between PAF stimulated COX, particularly COX-2, and NOS pathways appears to take a functional role at both bronchial and cardiovascular level. British Journal of Pharmacology (2001) 134, 777,788; doi:10.1038/sj.bjp.0704311 [source] Disconnect between standardized field-based testing and mannitol challenge in Scottish elite swimmersCLINICAL & EXPERIMENTAL ALLERGY, Issue 5 2010K. L. Clearie Summary Background Elite swimmers have high rates of rhinoconjunctivitis and exercise-induced bronchoconstriction. Moreover, exposure to chlorine and chlorine metabolites is known to induce bronchial hyper-reactivity. Objective To assess the early and late effects of chlorine and exercise on the unified airway of elite swimmers, and to compare the response to mannitol and field-based exercise challenge. Methods The Scottish national squad underwent exhaled tidal (FENO) and nasal (NNO) nitric oxide measurement, peak nasal inspiratory flow (PNIF), and forced expiratory volume in 1 s before, immediately after, and 4,6 h post-swimming. A sport-specific exercise test was carried out during an intensive lactate set (8 min at 80% maximum hear rate). All swimmers underwent mannitol challenge, and completed a health questionnaire. Results N=61 swimmers were assessed: 8/59 (14%) of swimmers had a positive mannitol challenge. Nine out of 57 (16%) of swimmers had a positive exercise test. Only one swimmer was positive to both. Swimmers with a positive mannitol had a significantly higher baseline FENO (37.3 vs. 18.0 p.p.b., P=0.03) than those with a positive exercise challenge. A significant decrease in FENO was observed pre vs. immediate and delayed post-chlorine exposure: mean (95% CI) 18.7 (15.9,22.0) p.p.b. vs. 15.9 (13.3,19.1) p.p.b. (P<0.01), and 13.9 (11.5,16.7) p.p.b. (P<0.01), respectively. There were no significant differences in NNO. Mean PNIF increased from 142.4 L/min (5.8) at baseline to 162.6 L/min (6.3) immediately post-exposure (P<0.01). Delayed post-exposure PNIF was not significantly different from pre-exposure. Conclusions No association was found between mannitol and standardized field-based testing in elite swimmers. Mannitol was associated with a high baseline FENO; however, exercise/chlorine challenge was not. Thus, mannitol may identify swimmers with a ,traditional' inflammatory asthmatic phenotype, while field-based exercise/chorine challenge may identify a swimmer-specific bronchoconstrictor response. A sustained fall in FENO following chlorine exposure suggests that a non-cellular, perhaps neurogenic, response may be involved in this group of athletes. Cite this as: K. L. Clearie, P. A. Williamson, S. Vaidyanathan, P. Short, A. Goudie, P. Burns, P. Hopkinson, K. Meldrum, L. Howaniec and B. J. Lipworth, Clinical & Experimental Allergy, 2010 (40) 731,737. [source] Association of angiotensin I-converting enzyme gene polymorphisms with aspirin intolerance in asthmaticsCLINICAL & EXPERIMENTAL ALLERGY, Issue 11 2008T-H. Kim Summary Background Aspirin-intolerant asthma (AIA) refers to the development of bronchoconstriction in asthmatic individuals following the ingestion of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs). Angiotensin I-converting enzyme (ACE), a membrane-bound peptidase present in the lung, plays a pivotal role in the metabolism of the endogenous peptides involved in the pathogenesis of asthma. Methods We screened a Korean asthma cohort (581 asthmatics including 81 aspirin-intolerant asthmatics and 231 aspirin-tolerant asthmatics, and 181 normal controls) for four single nucleotide polymorphisms (SNPs; ,262 A>T and ,115 T>C in the 5,-flanking region and +5467 T>C [Pro450Pro] and+11860 A>G [Thr776Thr] in the coding region) and one ins/del (+21288 CT) in the ACE gene. Results None of the SNPs or haplotypes showed any association with the development of asthma, but they were significantly associated with the risk of AIA. Logistic regression indicated that the frequency of the rare alleles of ,262 A>T and ,115 T>C was higher in subjects with AIA than in subjects with aspirin-tolerant asthma (ATA) (P=0.003,0.01, P corr=0.015,0.05). Subjects homozygous for the rare alleles of ,262 A>T and ,115 T>C showed a greater decline in forced expiratory volume in 1 s (FEV1) after aspirin provocation than those homozygous for the common alleles (P<0.05). A luciferase reporter assay indicated that ACE promoters containing the rare ,262 A>T allele possessed lower activity than did those containing the common allele (P=0.009). In addition, ACE promoters bearing the rare ,115 T>C allele had no luciferase activity. DNA,protein binding assays revealed a band containing the ACE promoter region (including ,262 A) and a protein complex. Conclusion The ,262 A>T polymorphism in the promoter of the ACE gene is associated with AIA, and the rare allele of ,262 A>T may confer aspirin hypersensitivity via the down-regulation of ACE expression. [source] Potentiation of allergic bronchoconstriction by repeated exposure to formaldehyde in guinea-pigs in vivoCLINICAL & EXPERIMENTAL ALLERGY, Issue 12 2003T. Kita Summary Background Indoor formaldehyde (FA) might worsen allergies and be an underlying factor for the increasing incidence and severity of asthma; the exact mechanism, however, remains unclear. Objective The present study examined the effects of repeated exposure to FA on methacholine- and antigen-induced bronchoconstriction in guinea-pigs in vivo. Methods First, non-sensitized guinea-pigs were transnasally treated with 0.1 or 1.0% FA or saline three times a week for 6 weeks, and increasing concentrations of methacholine (50, 100, and 200 ,g/mL) were inhaled at 5-min intervals. Second, guinea-pigs pre-treated with transnasal administration of FA or saline using the same protocol were passively sensitized with anti-ovalbumin (OA) serum 7 days before antigen challenge. Third, guinea-pigs were actively sensitized with OA and pre-treated with transnasal administration of FA or saline using the same protocol. The lateral pressure of the tracheal tube (Pao) was measured under anesthesia and artificial ventilation. Results The antigen-induced increase in Pao in actively sensitized guinea-pigs was significantly potentiated by FA exposure in a dose-dependent manner. The dose,response curve of the methacholine-induced increase in Pao in non-sensitized guinea-pigs or of the antigen-induced increase in Pao in passively sensitized guinea-pigs was not altered by FA exposure. Transnasal administration of FA significantly increased the serum anti-OA homocytotropic antibody titre (IgG) as measured by the passive cutaneous anaphylaxis reaction in actively sensitized guinea-pigs. Conclusion The results suggest that repeated exposure to FA worsens allergic bronchoconstriction through enhancing antigen sensitization. [source] | ||||||||||||||||||||||||||||