Sample records for bronchoconstriction

  1. Asthma Bronchiale and Exercise-Induced Bronchoconstriction. (United States)

    Jayasinghe, Harshani; Kopsaftis, Zoe; Carson, Kristin


    Exercising regularly has a wide range of beneficial health effects; in particular, it has been well documented to help in the management of chronic illnesses including asthma. However, in some individuals, exertion can also trigger an exacerbation of asthmatic episodes and subsequent acute attacks of breathlessness, coughing, tightness of the chest and wheezing. This physiological process is called exercise-induced bronchoconstriction (EIB) whereby post-exercise forced expiratory volume in 1 s is reduced by 10-15% from baseline. While EIB is highly prevalent in asthmatics and presents with similar respiratory symptoms, asthma and EIB are not mutually exclusive. The aim of this review is to present a broad overview of both conditions in order to enhance the understanding of the similarities and differences distinguishing them as two separate entities. The pathophysiology and mechanisms underlying asthma are well described with research now focussing on defining phenotypes for targeted management strategies. Conversely, the mechanistic understanding of EIB remains largely under-described. Diagnostic pathways for both are established and similar, as are pharmacologic and non-pharmacologic treatments and management approaches, which have enhanced success with early detection. Given the potential for exacerbation of asthma, exercise avoidance is common but counterproductive as current evidence indicates that it is well tolerated and improves quality of life. Literature supporting the benefit of exercise for EIB sufferers is at present favourable, yet extremely limited; therefore, future research should be directed in this area as well as towards further developing the understanding of the pathophysiology and mechanisms underpinning both EIB and asthma.

  2. Benzalkonium Chloride Induced Bronchoconstriction in Patients with Stable Bronchial Asthma (United States)

    Lee, Byoung Hoon


    Background Although benzalkonium chloride (BAC)-induced bronchoconstriction occurs in patients with bronchial asthma, BAC-containing nebulizer solutions are still being used in daily practice in Korea. The aim of this study was to evaluate the effects of inhaled aqueous solutions containing BAC. Methods Thirty subjects with bronchial asthma and 10 normal controls inhaled up to three 600 µg nebulized doses of BAC using a jet nebulizer. FEV1 (forced expiratory volume at one second) was measured 15 minutes after each dose. Inhalations were repeated every 20 minutes until FEV1 decreased by 15% or more (defined as BAC-induced bronchoconstriction) or the 3 doses were administered. Results The percent fall in FEV1 in response to BAC inhalation was significantly higher in asthmatics than in normal subjects (p<0.05). BAC administration in subjects with asthma reached a plateau (maximal effect). BAC-induced bronchoconstriction was found in 6 asthmatics (20%), with two responders after the 2nd inhalation and after the 3rd inhalation. The percent fall in FEV1 in response to the 1st inhalation of BAC was significantly higher in asthmatics with higher bronchial hyperresponsiveness (BHR) than in those with lower BHR. Conclusions This study suggests that the available multi-dose nebulized solution is generally safe. However, significant bronchoconstriction can occur at a relatively low BAC dose in asthmatics with severe airway responsiveness. PMID:18309682

  3. Bronchoconstriction and airway biology : potential impact and therapeutic opportunities

    NARCIS (Netherlands)

    Gosens, Reinoud; Grainge, Chris


    Recent work has demonstrated that mechanical forces occurring in the airway as a consequence of bronchoconstriction are sufficient to not only induce symptoms but also influence airway biology. Animal and human in vitro and in vivo work demonstrates that the airways are structurally and functionally

  4. The inflammatory basis of exercise-induced bronchoconstriction. (United States)

    Brannan, John D; Turton, James A


    Exercise-induced bronchoconstriction (EIB) is common in individuals with asthma, and may be observed even in the absence of a clinical diagnosis of asthma. Exercise-induced bronchoconstriction can be diagnosed via standardized exercise protocols, and anti-inflammatory therapy with inhaled corticosteroids (ICS) is often warranted. Exercise-related symptoms are commonly reported in primary care; however, access to standardized exercise protocols to assess EIB are often restricted because of the need for specialized equipment, as well as time constraints. Symptoms and lung function remain the most accessible indicators of EIB, yet these are poor predictors of its presence and severity. Evidence suggests that exercise causes the airways to narrow as a result of the osmotic and thermal consequences of respiratory water loss. The increase in airway osmolarity leads to the release of bronchoconstricting mediators (eg, histamine, prostaglandins, leukotrienes) from inflammatory cells (eg, mast cells and eosinophils). The objective assessment of EIB suggests the presence of airway inflammation, which is sensitive to ICS in association with a responsive airway smooth muscle. Surrogate tests for EIB, such as eucapnic voluntary hyperpnea or the osmotic challenge tests, cause airway narrowing via a similar mechanism, and a response indicates likely benefit from ICS therapy. The complete inhibition of EIB with ICS therapy in individuals with asthma may be a useful marker of control of airway pathology. Furthermore, inhibition of EIB provides additional, useful information regarding the identification of clinical control based on symptoms and lung function. This article explores the inflammatory basis of EIB in asthma as well as the effect of ICS on the pathophysiology of EIB.

  5. Expression of CysLT2 receptors in asthma lung, and their possible role in bronchoconstriction

    Directory of Open Access Journals (Sweden)

    Tomohiko Sekioka


    Conclusions: CysLT2 receptors were expressed in lung specimens isolated from asthma subjects. Activation of CysLT2 receptors may contribute to antigen-induced bronchoconstriction in certain asthma population.

  6. The role of upper airways and of sensoric receptors on reflex bronchoconstriction. (United States)

    Zimmermann, I; Ulmer, W T; Weller, W


    The influence of bilateral transection of the nervi laryngici cranialis, laryngici caudalis and glossopharyngici on ACH and allergen-induced bronchoconstriction was tested in 15 dogs. In three dogs the free preparation of bilateral nervi laryngici cranialis was performed for control measurements. Partial transection of pulmonary left nervus vagus was performed in three dogs and compared to radical transection of the same nerve in three animals. Transection of the nervi laryngici cranialis as well as of the nervi glossopharyngici was followed by the inhibition of the allergen-induced bronchoconstriction. The bronchoconstriction following ACH challenge was not influenced by transection. Bronchoconstriction induced by allergen returned to the same values within three weeks after surgical intervention. Partial unilateral dissection of the vagus nerve on lung hilus shows a small decrease in bronchial constriction induced by allergen and by ACH. Complete unilateral dissection of the vagus nerve on the lung hilus reduced the bronchial constrictoric response to both substances significantly.

  7. Bronchoconstriction Induces TGF-β Release and Airway Remodelling in Guinea Pig Lung Slices.

    Directory of Open Access Journals (Sweden)

    Tjitske A Oenema

    Full Text Available Airway remodelling, including smooth muscle remodelling, is a primary cause of airflow limitation in asthma. Recent evidence links bronchoconstriction to airway remodelling in asthma. The mechanisms involved are poorly understood. A possible player is the multifunctional cytokine TGF-β, which plays an important role in airway remodelling. Guinea pig lung slices were used as an in vitro model to investigate mechanisms involved in bronchoconstriction-induced airway remodelling. To address this aim, mechanical effects of bronchoconstricting stimuli on contractile protein expression and TGF-β release were investigated. Lung slices were viable for at least 48 h. Both methacholine and TGF-β1 augmented the expression of contractile proteins (sm-α-actin, sm-myosin, calponin after 48 h. Confocal fluorescence microscopy showed that increased sm-myosin expression was enhanced in the peripheral airways and the central airways. Mechanistic studies demonstrated that methacholine-induced bronchoconstriction mediated the release of biologically active TGF-β, which caused the increased contractile protein expression, as inhibition of actin polymerization (latrunculin A or TGF-β receptor kinase (SB431542 prevented the methacholine effects, whereas other bronchoconstricting agents (histamine and KCl mimicked the effects of methacholine. Collectively, bronchoconstriction promotes the release of TGF-β, which induces airway smooth muscle remodelling. This study shows that lung slices are a useful in vitro model to study mechanisms involved in airway remodelling.

  8. Effects of lung inflation on airway heterogeneity during histaminergic bronchoconstriction. (United States)

    Kaczka, David W; Mitzner, Wayne; Brown, Robert H


    Lung inflation has been shown to dilate airways by altering the mechanical equilibrium between opposing airway and parenchymal forces. However, it is not known how heterogeneously such dilation occurs throughout the airway tree. In six anesthetized dogs, we measured the diameters of five to six central airway segments using high-resolution computed tomography, along with respiratory input impedance (Zrs) during generalized aerosol histamine challenge, and local histamine challenge in which the agonist was instilled directly onto the epithelia of the imaged central airways. Airway diameters and Zrs were measured at 12 and 25 cmH2O. The Zrs spectra were fitted with a model that incorporated continuous distributions of airway resistances. Airway heterogeneity was quantified using the coefficient of variation for predefined airway distribution functions. Significant reductions in average central airway diameter were observed at 12 cmH2O for both aerosolized and local challenges, along with significant increases upon inflation to 25 cmH2O. No significant differences were observed for the coefficient of variation of airway diameters under any condition. Significant increases in effective airway resistance as measured by Zrs were observed only for the aerosolized challenge at 12 cmH2O, which was completely reversed upon inflation. We conclude that the lung periphery may be the most dominant contributor to increases in airway resistance and tissue elastance during bronchoconstriction induced by aerosolized histamine. However, isolated constriction of only a few central airway segments may also affect tissue stiffness via interdependence with their surrounding parenchyma.

  9. Protective effect of oral terfenadine and not inhaled ipratropium on adenosine 5 '-monophosphate-induced bronchoconstriction in patients with COPD

    NARCIS (Netherlands)

    Rutgers, [No Value; Koeter, GH; Van der Mark, TW; Postma, DS


    Background Inhalation of adenosine 5'-monophosphate (AMP) causes bronchoconstriction in patients with asthma and in many patients with chronic obstructive pulmonary disease (COPD). In asthma, AMP-induced bronchoconstriction has been shown to be determined mainly by release of mast cell mediators, an

  10. Effect of verapamil and sodium cromoglycate on leukotriene D4 induced bronchoconstriction in patients with asthma. (United States)

    Roberts, J A; Rodger, I W; Thomson, N C


    Leukotriene D4 (LTD4) may be an important mediator in asthma. The effect of verapamil and sodium cromoglycate on LTD4 induced bronchoconstriction has been examined in seven patients with asthma. The bronchoconstrictor response to increasing concentrations of inhaled LTD4 (0.0032-50 micrograms/ml) was assessed by measuring changes in FEV1, specific airways conductance, and flow rate at 30% of vital capacity (V30(p)). Results were expressed as the provocation concentration (PC) producing a 10% fall in FEV1 (PC10FEV1), a 35% fall in specific airways conductance (PC35SGaw), and a 30% fall in flow at 30% of vital capacity (PC30 V30(p)). Neither verapamil nor cromoglycate inhibited LTD4 induced bronchoconstriction in asthmatic subjects. These results suggest that in asthmatic patients LTD4 induced bronchoconstriction is not mediated via verapamil or cromoglycate sensitive mechanisms. PMID:3097863

  11. Effects of Dietary Induced Weight Loss on Exercise-Induced Bronchoconstriction in Overweight and Obese Children

    NARCIS (Netherlands)

    van Leeuwen, Janneke C.; Hoogstrate, Mira; Duiverman, Eric J.; Thio, Boony J.


    RationalePrevious studies showed that obesity in asthmatic children is associated with more severe exercise-induced bronchoconstriction (EIB), compared with non-obese asthmatic children. This study investigates the effect of weight loss on EIB in overweight and obese asthmatic children. MethodsIn th

  12. Bradykinin-induced bronchoconstriction: inhibition by nedocromil sodium and sodium cromoglycate. (United States)

    Dixon, C M; Barnes, P J


    1. The effects of inhaled nedocromil sodium and sodium cromoglycate on bradykinin-induced bronchoconstriction have been studied in a double-blind, placebo controlled study, in eight mild asthmatic subjects. 2. The subjects attended on four occasions. Fifteen minutes after drug pre-treatment a bradykinin challenge was performed. Increasing concentrations were inhaled until a greater than 40% fall in expiratory flow at 30% of vital capacity from a partial flow volume manoeuvre (V p30) was demonstrated. 3. Inhaled bradykinin (0.06-8.0 mg ml-1) caused dose-related bronchoconstriction with the geometric mean cumulative dose causing a 40% fall in V p30 (PD40) of 0.035 (95% CI: 0.02-0.07) mumol, after placebo inhalation, which was similar to that measured before the trial (0.04: 0.02-0.09 mumol). 4. Both nedocromil sodium (4 mg) and sodium cromoglycate (10 mg) gave significant protection (P less than 0.05) against bradykinin-induced bronchoconstriction (PD40 0.37: 0.19-0.72 mumol after nedocromil sodium and 0.22: 0.11-0.49 after sodium cromoglycate). 5. Since bradykinin-induced bronchoconstriction is probably neurally mediated we conclude that both nedocromil sodium and sodium cromoglycate have an action on neural pathways which may be useful in the control of asthma symptoms. PMID:2547408

  13. Assessment of Exercise-Induced Bronchoconstriction in Adolescents and Young Children

    NARCIS (Netherlands)

    van Leeuwen, Janneke C.; Driessen, Jean M. M.; Kersten, Elin T. G.; Thio, Bernard J.


    Recent research shows important differences in exercise-induced bronchoconstriction (EIB) between children and adults, suggesting a different pathophysiology of EIB in children. Although exercise can trigger classic symptoms of asthma, in children symptoms can be subtle and nonspecific; parents, chi

  14. Acute relief of exercise-induced bronchoconstriction by inhaled formoterol in children with persistent asthma

    DEFF Research Database (Denmark)

    Hermansen, Mette Northman; Nielsen, Kim Gjerum; Buchvald, Frederik;


    -controlled, crossover study of the immediate effect of formoterol, 9 microg, vs terbutaline, 0.5 mg, and placebo administered as dry powder at different study days. Exercise challenge test was used as a model of acute bronchoconstriction. PATIENTS: Twenty-four 7- to 15-year-old children with persistent asthma...

  15. Sputum eosinophils and the response of exercise-induced bronchoconstriction to corticosteroid in asthma

    DEFF Research Database (Denmark)

    Duong, MyLinh; Subbarao, Padmaja; Adelroth, Ellinor;


    BACKGROUND: The relationship between eosinophilic airway inflammation and exercise-induced bronchoconstriction (EIB), and the response to inhaled corticosteroid (ICS) therapy was examined. METHODS: Twenty-six steroid-naïve asthmatic patients with EIB were randomized to two parallel, double-blind,...

  16. Muscarinic receptor-mediated bronchoconstriction is coupled to caveolae in murine airways


    Schlenz, Heike; Kummer, Wolfgang; Jositsch, Gitte; Wess, Jürgen; Krasteva, Gabriela


    Cholinergic bronchoconstriction is mediated by M2 and M3 muscarinic receptors (MR). In heart and urinary bladder, MR are linked to caveolin-1 or -3, the structural proteins of caveolae. Caveolae are cholesterol-rich, omega-shaped invaginations of the plasma membrane. They provide a scaffold for multiple G protein receptors and membrane-bound enzymes, thereby orchestrating signaling into the cell interior. Hence, we hypothesized that airway MR signaling pathways are coupled to caveolae as well...

  17. The role of vagus nerve on histamine- and acetylcholine-induced bronchoconstriction (experiments on cats). (United States)

    Zimmermann, I; Ulmer, W T


    During administration of highly concentrated acetyclcholine and histamine aerosol (20-40 min), different effects on tidal volume, respiratory rate, and bronchial tone could be demonstrated. Inhalation after vagotomy neither showed changes in respiratory rate nor in tidal volume. These results point out the importance of the nervus vagus in case of bronchoconstriction caused by mediators. It is discussed to which degree vagus activity is required for the direct effect of different mediators in living animals.

  18. Approach to the diagnosis and management of suspected exercise-induced bronchoconstriction by primary care physicians


    Hull, James; Hull, Peter; Parsons, Jonathan; Dickinson, John W.; Ansley, Les


    Abstract Background Exercise-related respiratory symptoms in the diagnosis of exercise-induced bronchoconstriction (EIB) have poor predictive value. The aim of this study was to evaluate how athletes presenting with these symptoms are diagnosed and managed in primary care. Methods An electronic survey was distributed to a random selection of family practitioners in England. The survey was designed to assess the frequency with which family practitioners encounter adults with exercise-related r...

  19. Approach to the diagnosis and management of suspected exercise-induced bronchoconstriction by primary care physicians


    Hull, James H.; Hull, Peter J; Parsons, Jonathan P.; Dickinson, John W.; Ansley, Les


    BACKGROUND:\\ud \\ud Exercise-related respiratory symptoms in the diagnosis of exercise-induced bronchoconstriction (EIB) have poor predictive value. The aim of this study was to evaluate how athletes presenting with these symptoms are diagnosed and managed in primary care.\\ud METHODS:\\ud \\ud An electronic survey was distributed to a random selection of family practitioners in England. The survey was designed to assess the frequency with which family practitioners encounter adults with exercise...

  20. The influence of ipratropium bromide and sodium cromoglycate on benzalkonium chloride-induced bronchoconstriction in asthma. (United States)

    Miszkiel, K A; Beasley, R; Holgate, S T


    1. Benzalkonium chloride, an antibacterial preservative that is added to nebuliser solutions, has been shown to cause bronchoconstriction when inhaled by asthmatic subjects. 2. To investigate the potential role of reflex and mast cell-dependent mechanisms in the pathogenesis of bronchoconstriction produced by benzalkonium chloride we examined the effects of ipratropium bromide and sodium cromoglycate on this response in both concentration-response and time-course studies in nine asthmatic subjects. 3. Pretreatment with inhaled ipratropium bromide (1 mg) and sodium cromoglycate (40 mg) displaced the benzalkonium chloride concentration-response curves to the right by a mean 2.2 fold and 3.1 fold respectively. 4. Ipratropium bromide and sodium cromoglycate markedly attenuated the airway response to benzalkonium chloride throughout the 45 min time course period, inhibiting the overall response by 56% and 78% respectively. 5. We conclude that benzalkonium chloride provokes bronchoconstriction in asthmatic subjects through a combination of mast cell activation and stimulation of peripheral and central neural pathways. PMID:2972308

  1. Nedocromil sodium versus sodium cromoglycate in treatment of exercise-induced bronchoconstriction: a systematic review. (United States)

    Kelly, K D; Spooner, C H; Rowe, B H


    The objective of this review was to compare the effects of prophylactic doses of nedocromil sodium (NCS) and sodium cromoglycate (SCG) on postexercise lung function, in persons diagnosed with exercise-induced bronchoconstriction. Randomized controlled trials were identified from the Cochrane Airways Review Group Asthma Register, plus hand searching for trials in journals, bibliographies of relevant studies and review articles. Randomized controlled trials comparing NCS to SCG in prophylactic treatment of exercise-induced bronchoconstriction were eligible. Studies were pooled using odds ratios (OR) for dichotomous outcomes or weighted mean differences (WMD) with 95% confidence intervals (95% CI) for continuous outcomes. No significant differences were noted between NCS and SCG with respect to the maximum per cent decrease in forced expiratory volume in one second (WMD=-0.88; 95% CI -4.50-2.74), complete protection (OR=0.95; 95% CI 0.50-1.81), clinical protection (OR=0.71; 95% CI 0.36-1.39), unpleasant taste (OR=6.85; 95% CI 0.77-60.73), or sore throat (OR=3.46; 95% CI 0.32-37.48). Subgroup analyses based on age, dosages of medications and timing of exercise postinhalation were consistent with the overall pooled analyses. No significant differences were evident between the effects of nedocromil sodium and sodium cromoglycate during the immediate postexercise period in adults and children with exercise-induced bronchoconstriction, with regards to maximum per cent decrease in forced expiratory volume in one second, complete protection, or clinical protection. Side-effect profiles were similar.

  2. The contribution of histamine release to bronchoconstriction provoked by inhaled benzalkonium chloride in asthma. (United States)

    Miszkiel, K A; Beasley, R; Rafferty, P; Holgate, S T


    1. To investigate the possibility that benzalkonium chloride-induced bronchoconstriction results from the endogenous release of histamine, we examined the effect of the selective histamine antagonists terfenadine and astemizole, on the airways response to inhaled benzalkonium chloride and histamine in 12 asthmatic subjects. 2. Double-blind concentration- and time-course studies were undertaken, 3 h after treatment with terfenadine or matched placebo. 3. Benzalkonium chloride and histamine caused concentration-related falls in FEV1 in all subjects with benzalkonium chloride being 7.4 times less potent as a bronchoconstrictor agonist than histamine. Terfenadine displaced to the right the benzalkonium chloride and histamine concentration-response curves by 3.7 and 111 fold respectively. Terfenadine attenuated the initial (5 min) bronchoconstrictor response to benzalkonium chloride by 40%. However, over the whole 45 min period, the response was reduced by only 13% compared with 86% inhibition of the response to histamine. 4. In an open study, eight of the 12 subjects undertook a time course study with inhaled benzalkonium chloride after pretreatment with the chemically unrelated histamine antagonist astemizole. Astemizole inhibited benzalkonium chloride-induced bronchoconstriction to an almost identical degree as that achieved with terfenadine. 5. We conclude that the initial bronchoconstrictor effect of benzalkonium chloride is due, in part, to histamine release. However, the majority of the adverse effect relates to other, as yet unrecognised effects of this bacteriocidal substance. PMID:2451929

  3. Role of acetylcholine and muscarinic receptors in serotonin-induced bronchoconstriction in the mouse. (United States)

    Kummer, Wolfgang; Wiegand, Silke; Akinci, Sibel; Schinkel, Alfred H; Wess, Jürgen; Koepsell, Hermann; Haberberger, Rainer Viktor; Lips, Katrin Susanne


    For the murine trachea, it has been reported that constriction evoked by serotonin (5-HT) is largely dependent on acetylcholine (ACh) released from the epithelium, owing to the sensitivity of the 5-HT response to epithelium removal, sensitivity to atropine, and insensitivity to tetrodotoxin (Moffatt et al., 2003). Consistent with this assumption, the respiratory epithelium contains ACh, its synthesizing enzyme, and the high-affinity choline transporter CHT1 (Reinheimer et al., 1996; Pfeil et al., 2003; Proskocil et al., 2004). Recently, we demonstrated that ACh can be released from non-neuronal cells by corticosteroid-sensitive polyspecific organic cation transporters (OCTs), which are also expressed by airway epithelial cells (Lips et al., 2005). Hence, we proposed that 5-HT evokes release of ACh from epithelial cells via OCTs and that this epithelial-derived ACh induces bronchoconstriction. We tested this hypothesis in a well-established model of videomorphometric analysis of bronchial diameter in precision-cut murine lung slices utilizing epithelium removal to assess the role of the epithelium, OCT mouse knockout (KO) strains to assess the role of OCT isoforms, and muscarinic receptor M2/M3 double-KO mice to assess the cholinergic component of 5-HT induced bronchoconstriction, as bronchi of this strain are entirely unresponsive to cholinergic stimulation(Struckmann et al., 2003).

  4. Inhaled sodium metabisulphite induced bronchoconstriction: inhibition by nedocromil sodium and sodium cromoglycate. (United States)

    Dixon, C M; Ind, P W


    1. The effects of nedocromil sodium and sodium cromoglycate on bronchoconstriction induced by inhaled sodium metabisulphite have been studied in eight atopic subjects, three of whom had mild asthma. 2. Nedocromil sodium (4 mg, 7.8 X 10(-6) M), sodium cromoglycate (10 mg, 24.1 X 10(-6) M) and matched placebo were administered by identical metered dose inhalers 30 min before a dose-response to sodium metabisulphite (5-100 mg ml-1) was performed. 3. Maximum fall in sGaw after placebo pre-treatment was -43.9 +/- 3.3% baseline (mean +/- s.e. mean). At the same metabisulphite concentration maximum fall in sGaw after sodium cromoglycate was -13.0 +/- 3.6% and after nedocromil sodium was +4.3 +/- 6.8%. Nedocromil sodium prevented any significant fall in sGaw even after higher concentrations of metabisulphite. 4. Both nedocromil sodium, 4 mg, and sodium cromoglycate, 10 mg, inhibited sodium metabisulphite induced bronchoconstriction but nedocromil sodium was significantly more effective. Relative in vivo potency of the two drugs is broadly in line with other in vivo and in vitro studies. PMID:2171616

  5. Sodium cromoglycate, verapamil and nicardipine antagonism to leukotriene D4 bronchoconstriction. (United States)

    Advenier, C.; Cerrina, J.; Duroux, P.; Floch, A.; Pradel, J.; Renier, A.


    1--The effects of nicardipine, verapamil and sodium cromoglycate (SCG) on the increase in pulmonary airway resistance(RAw) and decrease in pulmonary dynamic compliance (CDyn) induced by leukotriene D4 (LTD4) 0.5 micrograms kg-1 and acetylcholine (ACh) 3 micrograms kg-1 were investigated in anaesthetized guinea-pigs. The effects of these three agents on the contractile effects of LTD4 and ACh were tested on isolated tracheal preparations of the guinea-pig. 2--Nicardipine and verapamil (0.3 and 1 mg kg-1), as well as SCG (3 and 10 mg kg-1), partially but significantly inhibited the effects of LTD4 on RAw. Partial inhibition of the effect of LTD4 on CDyn was only observed with verapamil (0.3 and 1 mg kg-1). Nicardipine and verapamil had no effect on ACh-induced bronchoconstriction in vivo. 3--In concentrations higher than 10(-5) M, nicardipine and verapamil inhibited the contractile effects of LTD4 and ACh on guinea-pig isolated trachea. SCG had no effect on this preparation. 4--These results suggest that nicardipine, verapamil and SCG partially reduce the component of bronchoconstriction associated with stimulation of irritant receptors by LTD4. However, the site and mechanism of action of Ca2+-entry antagonists remain uncertain. PMID:6403095

  6. Attenuation of aspirin-induced bronchoconstriction by sodium cromoglycate and nedocromil sodium. (United States)

    Robuschi, M; Gambaro, G; Sestini, P; Pieroni, M G; Refini, R M; Vaghi, A; Bianco, S


    The protective activity of nedocromil sodium and of sodium cromoglycate against aspirin-induced asthma has never been investigated in controlled studies. Because it has been reported that aspirin-induced platelet-mediated cytotoxic activity in vitro is inhibited after treatment in vivo with nedocromil but not with cromoglycate, we investigated whether these compounds also exhibit a different protective activity against aspirin-induced bronchoconstriction. Ten patients with aspirin-induced asthma underwent three bronchial challenges with a single dose of lysine acetylsalicylate (LASA) that caused a decrease in FEV1 of 25% or more in a preliminary dose-response test 30 min after inhalation of 4 mg nedocromil sodium, 10 mg sodium cromoglycate, or placebo. FEV1 and SRaw were recorded at intervals for 195 min. After placebo, LASA caused a maximal decrease in FEV1 of 42 +/- 4% of baseline. After cromoglycate and nedocromil the maximal decrease in FEV1 was reduced to 20 +/- 3% and 18 +/- 4%, respectively (p sodium cromoglycate and nedocromil sodium are equally effective in attenuating aspirin-induced bronchoconstriction and that it is unlikely that platelet activation participates in the pathogenesis of aspirin-induced asthma.

  7. The effect of nedocromil sodium and sodium cromoglycate on antigen-induced bronchoconstriction in the Ascaris-sensitive monkey. (United States)

    Eady, R. P.; Greenwood, B.; Jackson, D. M.; Orr, T. S.; Wells, E.


    Nedocromil sodium inhibited the bronchoconstriction caused by antigen challenge in Ascaris-sensitive monkeys and in addition it prevented the release of histamine from mast cells lavaged from sensitive monkeys. Sodium cromoglycate was relatively inactive in both these systems. It is suggested that nedocromil sodium can stabilize both mucosal and connective tissue mast cells and may represent a new type of drug. PMID:2992657

  8. Lack of paradoxical bronchoconstriction after administration of tiotropium via Respimat® Soft Mist™ Inhaler in COPD

    Directory of Open Access Journals (Sweden)

    Hodder R


    Full Text Available Rick Hodder1, Demetri Pavia2, Angela Lee2, Eric Bateman31Divisions of Pulmonary and Critical Care, University of Ottawa, Ottawa, ON, Canada; 2Boehringer Ingelheim Limited, Bracknell, England, UK; 3Division of Pulmonology, Department of Medicine, University of Cape Town, Cape Town, South AfricaAbstract: Bronchoconstriction has been reported in asthma and chronic obstructive pulmonary disease (COPD patients after administration of some aqueous inhalation solutions. We investigated the incidence of this event during long-term clinical trials of tiotropium delivered via Respimat® Soft Mist™ Inhaler (SMI. We retrospectively analyzed pooled data from two identical Phase III clinical trials, in which 1990 patients with COPD received 48 weeks' treatment with once-daily tiotropium (5 or 10 µg or placebo inhaled via Respimat® SMI. We recorded the incidence of bronchospasm and of a range of respiratory events that could suggest bronchoconstriction during the first 30 minutes after inhalation of study treatment on each of the eight test days. No patients reported bronchospasm. Six patients (0.3% reported a combination of at least two events suggestive of bronchoconstriction, and 21 (1.1% reported either rescue medication use or a respiratory adverse event. Asymptomatic falls in forced expiratory volume in one second (FEV1 of ≥15% were recorded on all test days, with no change in incidence over time, and affected 8.2% of those in the tiotropium groups and 14.5% of those on placebo. In COPD patients receiving long-term treatment with tiotropium 5 or 10 µg via Respimat® SMI, no bronchospasm was recorded, and the number of events possibly indicative of paradoxical bronchoconstriction was very low.Keywords: inhalation device, bronchoconstriction, COPD, tiotropium

  9. Inhibition of methoxamine-induced bronchoconstriction by ipratropium bromide and disodium cromoglycate in asthmatic subjects. (United States)

    Black, J; Vincenc, K; Salome, C


    We compared the effects of pretreatment with saline, ipratropium bromide, and disodium cromoglycate (DSCG) on bronchoconstriction induced by methoxamine--an alpha-adrenoceptor agonist, in asthmatic subjects. All 12 patients bronchoconstricted in response to methoxamine after saline. The PD20 (the dose of methoxamine causing a 20% fall in forced expiratory volume in 1 s [FEV1]) ranged from 0.3-18 mumol. Ipratropium bromide (200 micrograms administered by aerosol) significantly inhibited (P less than 0.05) the response to methoxamine in all patients without producing significant changes in the mean baseline lung function. The mean PD20 for methoxamine after saline was 6.8 mumol and 95% confidence limits (CL) were 3.6, 12.7 mumol. The mean PD20 for methoxamine after ipratropium bromide was 35.4 (95% CL 28.8, 43.6) mumol. DSCG also produced significant (P less than 0.05) shifts to the right in the methoxamine dose response curves, but did not affect resting airway calibre as measured by the FEV1. The mean PD20 for methoxamine increased from 3.3 mumol (95% CL 1.1, 10.0 mumol) after saline to 25.1 mumol (95% CL 14.1, 44.6) after DSCG pretreatment. These findings suggest that alpha-adrenoceptors in the airways of asthmatic subjects may be located at sites other than smooth muscle--possibly on mast cells but more likely on nerve endings and/or parasympathetic ganglia. PMID:2992563

  10. Effects of oral cetirizine, a selective H1 antagonist, on allergen- and exercise-induced bronchoconstriction in subjects with asthma.

    LENUS (Irish Health Repository)

    Gong, H


    The protective efficacy of oral cetirizine, a selective and potent H1-receptor antagonist, against the immediate bronchoconstrictive response to allergen inhalation and exercise challenge was evaluated in 16 subjects with stable, predominantly mild asthma. The subjects underwent double-blind, crossover pretreatments in randomized order in two separate protocols with (1) three daily oral doses of 20 mg of cetirizine and placebo, followed by allergen inhalation, and (2) single oral doses of cetirizine (5, 10, and 20 mg), albuterol (4 mg), and placebo, followed by exercise with cold-air inhalation. Cetirizine failed to decrease bronchial sensitivity to inhaled allergen in eight of 10 subjects. Neither cetirizine nor albuterol uniformly inhibited exercise-induced bronchoconstriction. Serum concentrations of cetirizine were consistent with systemic H1-blocking activity. Modest bronchodilation occurred after administration of cetirizine and albuterol before exercise but not after the third dose of cetirizine in the allergen protocol. One subject developed moderate drowsiness during multiple dosing with cetirizine. Thus, cetirizine, in the doses studied, is not uniformly effective in preventing allergen- or exercise-induced bronchoconstriction. Histamine is one of many mediators participating in immediate asthmatic responses, and selective H1 antagonists do not completely block these airway events. However, cetirizine may still clinically benefit some patients with asthma, such as patients with allergic rhinitis or urticaria.

  11. Exercise-induced bronchoconstriction: The effects of montelukast, a leukotriene receptor antagonist

    Directory of Open Access Journals (Sweden)

    James P Kemp


    Full Text Available James P KempClinical Professor of Pediatrics, Division of Immunology and Allergy, University of California School of Medicine, San Diego, CA, USAAbstract: Exercise-induced bronchoconstriction (EIB is very common in both patients with asthma and those who are otherwise thought to be normal. The intensity of exercise as well as the type of exercise is important in producing symptoms. This may make some types of exercise such as swimming more suitable and extended running more difficult for patients with this condition. A better understanding of EIB will allow the physician to direct the patient towards a type of exercise and medications that can result in a more active lifestyle without the same concern for resulting symptoms. This is especially important for schoolchildren who are usually enrolled in physical education classes and elite athletes who may desire to participate in competitive sports. Fortunately several medications (short- and long-acting β2-agonists, cromolyn, nedocromil, inhaled corticosteroids, and more recently leukotriene modifiers have been shown to be effective in preventing or attenuating the effects of exercise in many patients. In addition, inhaled β2-agonists have been shown to quickly reverse the airway obstruction that develops in patients and continue to be the reliever medications of choice. Inhaled corticosteroids are increasingly being recommended as regular therapy now that the role of inflammation and airway injury has been identified in EIB. With the discovery that there is a release of mediators such as histamine and leukotrienes from cells in the airway following exercise with resulting airway obstruction in susceptible individuals, interest has turned to attenuating their effects with mediator antagonists especially those that block the effects of leukotrienes. Studies with an oral leukotriene antagonist, montelukast, have shown beneficial effects in adults and children aged as young as 6 years with EIB


    Institute of Scientific and Technical Information of China (English)

    陶梦非; 梁永杰


    Objective To evaluate effect of Neurokinin receptor antagonist on the prevention from hyperpnea-induced bronchoconstriction using a dual Neurokinin receptor antagonist FK224. Methods 12 pathogenfree Hartley guinea pigs were divided into two groups randomly: Dimethyl sulfoxide (DMSO) control group (n =6)and FK224 group (n =6). Guinea pigs were anesthetized with pentobarbital sodium. A cervical tracheostomy was performed and a polyethylene tube was inserted into the trachea. After measuring baseline value of the lung resistance (RL) and dynamic compliance of respiratory system (Cdyn) , DMSO (0. 3ml/kg) and FK224 ( 1mg/kg) were administered by injection through jugular vein respectively. A rodent respirator with dry 5% CO2-95% O2 mixture at room temperature provided mechanical ventilation ( VT 8ml/animal, 100breaths/min ) for 5min. RL and Cdyn of 2groups were measured after isocapnic hyperpnea challenge. Results In DMSO control group, isocapnic hyperpnea of dry gas elicited a marked increase in RL and decrease in Cdyn. RL and Cdyn of FK224 group did not change significantly. Conclusion FK224 can inhibit the increase in RL and decrease in Cdyn caused by isocapnic hyperpnea in guinea pigs. And antagonists of tachykinins receptors might have effect on prophylaxis and treatment in exercise-induced asthma.

  13. A computed tomographic scan assessment of endotracheal suctioning-induced bronchoconstriction in ventilated sheep. (United States)

    Lu, Q; Capderou, A; Cluzel, P; Mourgeon, E; Abdennour, L; Law-Koune, J D; Straus, C; Grenier, P; Zelter, M; Rouby, J J


    This study was directed at assessing changes in bronchial cross-sectional surface areas (BCSA) and in respiratory resistance induced by endotracheal suctioning in nine anesthetized sheep. Cardiorespiratory parameters (Swan-Ganz catheter), respiratory resistance (inspiratory occlusion technique), BCSA, and lung aeration (computed tomography) were studied at baseline, during endotracheal suctioning, and after 20 consecutive hyperinflations. Measurements performed initially at an inspired oxygen fraction (FI(O(2))) of 0.3 were repeated at an FI(O(2)) of 1.0. At an FI(O(2)) of 0.3, endotracheal suctioning resulted in atelectasis, a reduction in BCSA of 29 +/- 23% (mean +/- SD), a decrease in arterial oxygen saturation from 95 +/- 3% to 87 +/- 12% (p = 0.02), an increase in venous admixture from 19 +/- 10% to 31 +/- 19% (p = 0. 006), and an increase in lung tissue resistance (DR(rs)) (p = 0. 0003). At an FI(O(2)) of 1.0, despite an extension of atelectasis and an increase in pulmonary shunt from 19 +/- 5% to 36 +/- 2% (p sheep, the endotracheal suctioning-induced reduction of BCSA was entirely prevented. These data suggest that the endotracheal suctioning-induced decrease in BCSA is related to atelectasis and bronchoconstriction. Both effects can be reversed by hyperoxygenation maneuver before suctioning in combination with recruitment maneuver after suctioning.

  14. Improving screening and diagnosis of exercise-induced bronchoconstriction: a call to action. (United States)

    Weiler, John M; Hallstrand, Teal S; Parsons, Jonathan P; Randolph, Christopher; Silvers, William S; Storms, William W; Bronstone, Amy


    This article summarizes the findings of an expert panel of nationally recognized allergists and pulmonologists who met to discuss how to improve detection and diagnosis of exercise-induced bronchoconstriction (EIB), a transient airway narrowing that occurs during and most often after exercise in people with and without underlying asthma. EIB is both commonly underdiagnosed and overdiagnosed. EIB underdiagnosis may result in habitual avoidance of sports and physical activity, chronic deconditioning, weight gain, poor asthma control, low self-esteem, and reduced quality of life. Routine use of a reliable and valid self-administered EIB screening questionnaire by professionals best positioned to screen large numbers of people could substantially improve the detection of EIB. The authors conducted a systematic review of the literature that evaluated the accuracy of EIB screening questionnaires that might be adopted for widespread EIB screening in the general population. Results of this review indicated that no existing EIB screening questionnaire had adequate sensitivity and specificity for this purpose. The authors present a call to action to develop a new EIB screening questionnaire, and discuss the rigorous qualitative and quantitative research necessary to develop and validate such an instrument, including key methodological pitfalls that must be avoided.

  15. High incidence of exercise‐induced bronchoconstriction in triathletes of the Swiss national team (United States)

    Knöpfli, Bruno H; Luke‐Zeitoun, Mona; von Duvillard, Serge P; Burki, Adrian; Bachlechner, Christian; Keller, Heidi


    Aim To assess the progression of bronchial reactivity (BR) and incidence of bronchial hyperreactivity (BH), exercise‐induced bronchoconstriction (EIB) and asthma in triathletes over 2 years. Methods Subjects were seven athletes from the Swiss national triathlon team (mean (SD) age 24.3 (4.8) years), who initially were not asthmatic, not treated with antiasthmatic medication, and who had performed at international level for more than 3 consecutive years (2001–2003). To assess BR, BH and EIB, subjects ran on a 400 m track for 8 min at intensities equal to the anaerobic threshold. Tests were conducted in ambient temperatures of 4.4 (2.8)°C, –8.8 (2.4)°C and 3.6 (1.5)°C, and humidity of 52 (16)%, 83 (13)% and 93 (2)%. Forced expiratory volume in 1 s (FEV1) was measured before and at 2, 5, 10 and 15 min after EIB, and 5 min after inhalation of a β2 agonist. Two methods were used to calculate the incidence: (1) the standard assessment; (2) extrapolation of the decrease in FEV1 to the BH limit. Results BR increased significantly in the seven athletes (FEV1: year, p = 0.04; year × EIB, p = 0.002; EIB p<0.001). Within 2 years, BR had increased significantly and even reached BH in some athletes. Three athletes exhibited BH. After extrapolation of the decrease in FEV1 in all seven athletes, the limit of 10% by definition for BH was determined to occur within 1.77–4.81 years, resulting in 21–57% of athletes with newly developed BH per year. Conclusion Athletes develop EIB quickly, a rate of increase 195–286 times that of the normal rate for development of asthma. PMID:17237120

  16. The role of inspiratory muscle training in the management of asthma and exercise-induced bronchoconstriction. (United States)

    Shei, Ren-Jay; Paris, Hunter L R; Wilhite, Daniel P; Chapman, Robert F; Mickleborough, Timothy D


    Asthma is a pathological condition comprising of a variety of symptoms which affect the ability to function in daily life. Due to the high prevalence of asthma and associated healthcare costs, it is important to identify low-cost alternatives to traditional pharmacotherapy. One of these low cost alternatives is the use of inspiratory muscle training (IMT), which is a technique aimed at increasing the strength and endurance of the diaphragm and accessory muscles of respiration. IMT typically consists of taking voluntary inspirations against a resistive load across the entire range of vital capacity while at rest. In healthy individuals, the most notable benefits of IMT are an increase in diaphragm thickness and strength, a decrease in exertional dyspnea, and a decrease in the oxygen cost of breathing. Due to the presence of expiratory flow limitation in asthma and exercise-induced bronchoconstriction, dynamic lung hyperinflation is common. As a result of varying operational lung volumes, due in part to hyperinflation, the respiratory muscles may operate far from the optimal portion of the length-tension curve, and thus may be forced to operate against a low pulmonary compliance. Therefore, the ability of these muscles to generate tension is reduced, and for any given level of ventilation, the work of breathing is increased as compared to non-asthmatics. Evidence that IMT is an effective treatment for asthma is inconclusive, due to limited data and a wide variation in study methodologies. However, IMT has been shown to decrease dyspnea, increase inspiratory muscle strength, and improve exercise capacity in asthmatic individuals. In order to develop more concrete recommendations regarding IMT as an effective low-cost adjunct in addition to traditional asthma treatments, we recommend that a standard treatment protocol be developed and tested in a placebo-controlled clinical trial with a large representative sample.

  17. Approach to the diagnosis and management of suspected exercise-induced bronchoconstriction by primary care physicians

    Directory of Open Access Journals (Sweden)

    Hull James H


    Full Text Available Abstract Background Exercise-related respiratory symptoms in the diagnosis of exercise-induced bronchoconstriction (EIB have poor predictive value. The aim of this study was to evaluate how athletes presenting with these symptoms are diagnosed and managed in primary care. Methods An electronic survey was distributed to a random selection of family practitioners in England. The survey was designed to assess the frequency with which family practitioners encounter adults with exercise-related respiratory symptoms and how they would approach diagnostic work-up and management. The survey also evaluated awareness of and access to diagnostic tests in this setting and general knowledge of prescribing asthma treatments to competitive athletes. Results 257 family practitioners completed the online survey. One-third of respondents indicated they encountered individuals with this problem at a frequency of more than one case per month. Over two-thirds of family practitioners chose investigation as an initial management strategy, while one-quarter would initiate treatment based on clinical information alone. PEFR pre- and post-exercise was the most commonly selected test for investigation (44%, followed by resting spirometry pre- and post-bronchodilator (35%. Short-acting β2-agonists were the most frequently selected choice of treatment indicated by respondents (90%. Conclusion Family practitioners encounter individuals with exercise-related respiratory symptoms commonly and although objective testing is often employed in diagnostic work-up, the tests most frequently utilised are not the most accurate for diagnosis of EIB. This diagnostic approach may be dictated by the reported lack of access to more precise testing methods, or may reflect a lack of dissemination or awareness of current evidence. Overall the findings have implications both for the management and hence welfare of athletes presenting with this problem to family practitioners and also for the

  18. Inhibition of histamine-induced bronchoconstriction in Guinea pig and Swine by pulsed electrical vagus nerve stimulation. (United States)

    Hoffmann, Thomas J; Mendez, Steven; Staats, Peter; Emala, Charles W; Guo, Puyun


    Objective. Smooth muscle help regulate the diameter of the airways and their constriction can contribute to the pathology of acute asthma attacks. This study sought to determine if applying a specific electrical signal to the vagus nerve (VN) could minimize histamine-induced bronchoconstriction. Methods. Sixteen guinea pigs and three swine were anesthetized and had bipolar electrodes positioned on the cervical VNs. After the animals stabilized, i.v. histamine was titrated to elicit a moderate 2-4 cm H(2) O increase in pulmonary inflation pressure (Ppi). Histamine was then dosed with or without concurrent low voltage VN stimulation. Results. The peak change in Ppi following a histamine challenge was reduced in the guinea pig by VN stimulation (3.4 ± 0.4 vs. 2.1 ± 0.2 cm H(2) O, p < 0.001). The results were confirmed in a limited study in swine and indicate VN treatment is applicable to larger animals. Conclusion. This study suggests that VN stimulation can reduce bronchoconstriction and may prove useful as a rescue therapy in the treatment of acute asthma.

  19. Effect of ipratropium bromide and/or sodium cromoglycate pretreatment on water-induced bronchoconstriction in asthma. (United States)

    Tranfa, C M; Vatrella, A; Parrella, R; Bariffi, F


    The mechanisms underlying water-induced bronchoconstriction are still not fully understood. Cholinergic reflexes and mast cell mediator release are currently believed to play an important pathogenetic role. In order to evaluate the relative contribution of each of these mechanisms, we studied the effect of ipratropium bromide (80 micrograms), a muscarinic antagonist, and sodium cromoglycate (20 mg), an inhibitor of mast cell mediator release, administered alone and in combination, in the prevention of bronchospasm induced by ultrasonic mist of distilled water (UMDW). Fifteen patients with documented atopic asthma and hyperresponsiveness to distilled water were selected for this randomized, placebo-controlled, double-blind study. Airway responses to pharmachological agents and bronchial challenge were measured by change in specific airways conductance (sGaw). Sodium cromoglycate had no effect on bronchial calibre, whilst ipratropium bromide and the combination of the two drugs produced a significant bronchodilation 30, 60 and 90 min after treatments. The maximal increase in sGaw (mean % +/- SD) was observed at 90 min: 63 +/- 28% and 58 +/- 22% after ipratropium bromide and the combined drugs respectively. UMDW (2, 4, 8, 16 ml water) caused a -36 +/- 19%, -42 +/- 19%, -49 +/- 18%, -56 +/- 15% mean % +/- SD fall in sGaw after placebo. Pretreatment with sodium cromoglycate abolished the bronchoconstriction to 2 ml (fall sGaw -5 +/- 23% NS) and significantly reduced the effect of 4 (-15 +/- 22%), 8 (-21 +/- 20%) and 16 ml (-24 +/- 18%) water.(ABSTRACT TRUNCATED AT 250 WORDS)

  20. Exertional-induced bronchoconstriction: Comparison between cardiopulmonary exercise test and methacholine challenging test

    Directory of Open Access Journals (Sweden)

    Mostafa Ghanei


    Full Text Available Introduction: Exertional-induced bronchoconstriction is a condition in which the physical activity causes constriction of airways in patients with airway hyper- responsiveness. In this study, we tried to study and evaluate any relationship between the findings of cardiopulmonary exercise testing (CPET and the response to methacholine challenge test (MCT in patients with dyspnea after activity. Materials and Methods: Thirty patients with complaints of dyspnea following activity referred to "Lung Clinic" of Baqiyatallah Hospital but not suffering from asthma were entered into the study. The subjects were excluded from the study if: Suffering from any other pulmonary diseases, smoking more than 1 cigarette a week in the last year, having a history of smoking more than 10 packets of cigarettes/year, having respiratory infection in the past 4 weeks, having abnormal chest X-ray or electrocardiogram, and cannot discontinue the use of medicines interfering with bronchial provocation. Baseline spirometry was performed for all the patients, and the values of forced expiratory volume in 1 second (FEV1, forced vital capacity (FVC, and FEV/FVC were recorded. The MCT and then the CPET were performed on all patients. Results: The mean VO 2 (volume oxygen in patients with positive methacholine test (20.45 mL/kg/min was significantly lower than patients with negative MCT (28.69 mL/kg/min (P = 0.000. Respiratory rates per minute (RR and minute ventilation in the group with positive MCT (38.85 and 1.636 L were significantly lower than the group with negative methacholine test (46.78 and 2.114 L (P < 0.05. Also, the O 2 pulse rate in the group with negative methacholine test (116.27 mL/beat was significantly higher than the group with positive methacholine test (84.26 mL/beat (P < 0.001. Conclusion: Pulmonary response to exercise in patients with positive methacholine test is insufficient. The dead space ventilation in these patients has increased. Also, dynamic

  1. Pre-Exercise Hyperpnea Attenuates Exercise-Induced Bronchoconstriction Without Affecting Performance (United States)

    Eichenberger, Philipp A.; Scherer, Thomas A.; Spengler, Christina M.


    Whole-body warm-up exercises were shown to attenuate exercise-induced bronchoconstriction (EIB). Whether intense pre-exercise hyperpnea offers similar protection and whether this might negatively affect exercise performance is unknown. Nine subjects with EIB (25±5 yrs; forced expiratory volume in 1s [FEV1], 104±15% predicted) performed an exercise challenge (ECh) followed—after 30min—by a constant-load cycling test to exhaustion. The ECh was preceded by one of four conditions: by i) control warm-up (CON) or by 10min of normocapnic hyperpnea with partial rebreathing at either ii) 50% (WU50) or iii) variable intensity (8x 30s-80%/45s-30%; WU80/30), or at iv) 70% (WU70) of maximal voluntary ventilation. FEV1 was measured at baseline and in 5-min intervals until 15min after CON/warm-up and 30min after ECh. None of the warm-up conditions induced EIB. The maximal post-ECh decrease in FEV1 was -13.8±3.1% after CON, −9.3±5.0% after WU50 (p = 0.081 vs. CON), −8.6±7.5% after WU80/30 (p = 0.081 vs. CON) and −7.2±5.0% after WU70 (p = 0.006 vs. CON), and perception of respiratory exertion was significantly attenuated (all p≤0.048), with no difference between warm-up conditions. Only after CON, FEV1 remained significantly reduced up to the start of the cycling endurance test (−8.0±4.3%, p = 0.004). Cycling performance did not differ significantly between test days (CON: 13±7min; WU50: 14±9min; WU80/30: 13±9min; WU70: 14±7min; p = 0.582). These data indicate that intense hyperpnea warm-up is effective in attenuating EIB severity and accelerating lung function recovery while none of the warm-up condition do compromise cycling performance. PMID:27898744

  2. A critical role of acute bronchoconstriction in the mortality associated with high-dose sarin inhalation: Effects of epinephrine and oxygen therapies

    Energy Technology Data Exchange (ETDEWEB)

    Gundavarapu, Sravanthi; Zhuang, Jianguo; Barrett, Edward G.; Xu, Fadi; Russell, Robert G.; Sopori, Mohan L., E-mail:


    Sarin is an organophosphate nerve agent that is among the most lethal chemical toxins known to mankind. Because of its vaporization properties and ease and low cost of production, sarin is the nerve agent with a strong potential for use by terrorists and rouge nations. The primary route of sarin exposure is through inhalation and, depending on the dose, sarin leads to acute respiratory failure and death. The mechanism(s) of sarin-induced respiratory failure is poorly understood. Sarin irreversibly inhibits acetylcholine esterase, leading to excessive synaptic levels of acetylcholine and, we have previously shown that sarin causes marked ventilatory changes including weakened response to hypoxia. We now show that LD{sub 50} sarin inhalation causes severe bronchoconstriction in rats, leading to airway resistance, increased hypoxia-induced factor-1α, and severe lung epithelium injury. Transferring animals into 60% oxygen chambers after sarin exposure improved the survival from about 50% to 75% at 24 h; however, many animals died within hours after removal from the oxygen chambers. On the other hand, if LD{sub 50} sarin-exposed animals were administered the bronchodilator epinephrine, > 90% of the animals survived. Moreover, while both epinephrine and oxygen treatments moderated cardiorespiratory parameters, the proinflammatory cytokine surge, and elevated expression of hypoxia-induced factor-1α, only epinephrine consistently reduced the sarin-induced bronchoconstriction. These data suggest that severe bronchoconstriction is a critical factor in the mortality induced by LD{sub 50} sarin inhalation, and epinephrine may limit the ventilatory, inflammatory, and lethal effects of sarin. - Highlights: • Inhalation exposure of rats to LD{sub 50} sarin causes death through respiratory failure. • Severe bronchoconstriction is the major cause of sarin-induced respiratory failure. • Transfer of sarin exposed rats to 60% oxygen improves the mortality temporarily.

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

    Simpson, A J; Bood, J R; Anderson, S D; Romer, L M; Dahlén, B; Dahlén, S-E; Kippelen, P


    Release of bronchoactive mediators from mast cells during exercise hyperpnea is a key factor in the pathophysiology of exercise-induced bronchoconstriction (EIB). Our aim was to investigate the effect of a standard, single dose of an inhaled β2-adrenoceptor agonist on mast cell activation in response to dry air hyperpnea in athletes with EIB. Twenty-seven athletes with EIB completed a randomized, double-blind, placebo-controlled, crossover study. Terbutaline (0.5 mg) or placebo was inhaled 15 min prior to 8 min of eucapnic voluntary hyperpnea (EVH) with dry air. Pre- and postbronchial challenge, urine samples were analyzed by enzyme immunoassay for 11β-prostaglandin F2α (11β-PGF2α). The maximum fall in forced expiratory volume in 1 s of 14 (12-20)% (median and interquartile range) following placebo was attenuated to 7 (5-9)% with the administration of terbutaline (P < 0.001). EVH caused a significant increase in 11β-PGF2α from 41 (27-57) ng/mmol creatinine at baseline to 58 (43-72) ng/mmol creatinine at its peak post-EVH following placebo (P = 0.002). The rise in 11β-PGF2α was inhibited with administration of terbutaline: 39 (28-44) ng/mmol creatinine at baseline vs. 40 (33-58) ng/mmol creatinine at its peak post-EVH (P = 0.118). These data provide novel in vivo evidence of mast cell stabilization following inhalation of a standard dose of terbutaline prior to bronchial provocation with EVH in athletes with EIB.

  4. Inhibition by sodium cromoglycate of bronchoconstriction stimulated by respiratory heat loss: comparison of pressurised aerosol and powder. (United States)

    Latimer, K M; Roberts, R; Morris, M M; Hargreave, F E


    The protective effect was examined of three doses (2, 10, and 20 mg) of sodium cromoglycate inhaled from a pressurised metered dose inhaler on the response to isocapnic hyperventilation of cold dry air in 10 asthmatic subjects. This was compared with the effect of cromoglycate powder (20 mg) inhaled from a Spincap and with placebo given on two occasions. The medications were inhaled on separate days, in random order and with the use of a double blind double dummy technique, 20 minutes before isocapnic hyperventilation of two fold increasing volumes of air (-15 degrees C, 0% humidity) to produce a 20% fall in the post-treatment FEV1. The response was expressed as the provocative dose of respiratory heat loss required to cause a fall in FEV1 of 15% (PD15, kcal/min). The mean baseline spirometric indices exceeded 85% of predicted normal values on each test day; both placebo treatments reduced the baseline FEV1 by comparison with all active treatments (p less than 0.0001). Comparison of the PD15 on the two placebo days confirmed excellent reproducibility. All doses of cromoglycate shifted the respiratory heat loss dose-response curve to the right of the placebo curve; PD15 after all active treatments exceeded PD15 after placebo (p less than 0.0001). There was no cromoglycate dose-response relationship between the three doses of aerosol (p greater than 0.05), or between any dose of aerosol and powder (p greater than 0.05). It is concluded that cromoglycate aerosol inhaled from a pressurised inhaler in a dose of 2 mg gives the same magnitude of protection against bronchoconstriction stimulated by airway cooling as 20 mg of pressurised aerosol or powder from a Spincap. PMID:6426073

  5. Comparison of mannitol and methacholine to predict exercise-induced bronchoconstriction and a clinical diagnosis of asthma

    Directory of Open Access Journals (Sweden)

    Spector Sheldon L


    Full Text Available Abstract Background Asthma can be difficult to diagnose, but bronchial provocation with methacholine, exercise or mannitol is helpful when used to identify bronchial hyperresponsiveness (BHR, a key feature of the disease. The utility of these tests in subjects with signs and symptoms of asthma but without a clear diagnosis has not been investigated. We investigated the sensitivity and specificity of mannitol to identify exercise-induced bronchoconstriction (EIB as a manifestation of BHR; compared this with methacholine; and compared the sensitivity and specificity of mannitol and methacholine for a clinician diagnosis of asthma. Methods 509 people (6–50 yr were enrolled, 78% were atopic, median FEV1 92.5% predicted, and a low NAEPPII asthma score of 1.2. Subjects with symptoms of seasonal allergy were excluded. BHR to exercise was defined as a ≥ 10% fall in FEV1 on at least one of two tests, to methacholine a PC20 ≤ 16 mg/ml and to mannitol a 15% fall in FEV1 at ≤ 635 mg or a 10% fall between doses. The clinician diagnosis of asthma was made on examination, history, skin tests, questionnaire and response to exercise but they were blind to the mannitol and methacholine results. Results Mannitol and methacholine were therapeutically equivalent to identify EIB, a clinician diagnosis of asthma, and prevalence of BHR. The sensitivity/specificity of mannitol to identify EIB was 59%/65% and for methacholine it was 56%/69%. The BHR was mild. Mean EIB % fall in FEV1 in subjects positive to exercise was 19%, (SD 9.2, mannitol PD15 158 (CI:129,193 mg, and methacholine PC20 2.1(CI:1.7, 2.6mg/ml. The prevalence of BHR was the same: for exercise (43.5%, mannitol (44.8%, and methacholine (41.6% with a test agreement between 62 & 69%. The sensitivity and specificity for a clinician diagnosis of asthma was 56%/73% for mannitol and 51%/75% for methacholine. The sensitivity increased to 73% and 72% for mannitol and methacholine when two exercise tests were

  6. The effect of nebulized salbutamol or isotonic saline on exercise-induced bronchoconstriction in elite skaters following a 1,500-meter race : study protocol for a randomized controlled trial

    NARCIS (Netherlands)

    Driessen, Jean M. M.; Gerritsma, Margryt; Westbroek, Jaap; ten Hacken, Nick H. T.; de Jongh, Frans H. C.


    Background: Prevalence of exercise-induced bronchoconstriction (EIB) is high in elite athletes, especially after many years training in cold and dry air conditions. The primary treatment of EIB is inhaling a short-acting beta-2-agonist such as salbutamol. However, professional speed skaters also inh

  7. Exercise-Induced Bronchoconstriction (United States)

    ... Education Center Fellows-in-Training Grants & Awards Program Directors Practice Resources ASTHMA IQ Consultation and Referral Guidelines Practice Financial Survey Practice Tools Running a Practice Statements and Practice Parameters About AAAAI Advocacy Allergist / Immunologists: ...

  8. Exercise-Induced Bronchoconstriction Quiz (United States)

    ... Education Center Fellows-in-Training Grants & Awards Program Directors Practice Resources ASTHMA IQ Consultation and Referral Guidelines Practice Financial Survey Practice Tools Running a Practice Statements and Practice Parameters About AAAAI Advocacy Allergist / Immunologists: ...

  9. Efeito do salbutamol liberado através de inalador de pó seco sobre o broncoespasmo induzido por metacolina Effects of salbutamol delivered by dry-powder inhaler on methacholine-induced bronchoconstriction

    Directory of Open Access Journals (Sweden)

    Adalberto Sperb Rubin


    (MDIs are the drugs usually used for the reversal of methacholine-induced bronchoconstriction. The b2 agonists that are delivered by dry-powder inhaler (DPI can be an efficacious option. OBJECTIVE: To evaluate the effectiveness and speed of action of salbutamol delivered by DPI (Pulvinal; Butovent®, in comparison to salbutamol delivered by MDI, in reversing methacholine-induced bronchoconstriction. METHOD: Sixty successive methacholine-induced bronchoconstriction patients who presented a decrease of at least 20% in forced expiratory volume (FEV1 were evaluated prospectively. Of these 60 patients, we randomized 30 (first group to receive 200 mcg of salbutamol by MDI and 30 (second group to receive 200 mcg of salbutamol by DPI (Pulvinal. Both drugs were administered with the objective of reversing bronchoconstriction during the final phase of a bronchoprovocation test. The FEV1 values obtained at 1 and 5 minutes after bronchodilator administration were evaluated. RESULTS: The groups were comparable in gender distribution, age, weight, dose level provoking a 20% drop in FEV1 (first group: 1.3 mg; second group: 1.19 mg; p = 0.79 and post-methacholine FEV1 (first group: 2.03 l; second group: 1.99 l; p = 0.87, with no statistically significant differences between the two groups. In the first group (MDI, the mean increase in FEV1 was 16.2% (at 1 minute and 22.2% (at 5 minutes, and in the second group (DPI it was 17% (at 1 minute and 23.6% (at 5 minutes. There was no statistically significant difference between the groups (p = 0.8. CONCLUSION: The beta2-agonists delivered by DPI (Pulvinal present the same bronchodilator efficacy and speed of action as do those delivered by the more traditional MDI method.

  10. Treatment of exercise-induced bronchoconstriction

    DEFF Research Database (Denmark)

    Backer, Vibeke; Sverrild, Asger; Porsbjerg, Celeste


    impairment of performance to severe bronchospasm and a large reduction in FEV1. Treatment of EIB varies from daily to less frequent therapy, depending on the level of activity. In this article, the authors evaluate the treatment possibilities before, during, and after exercise. They also review medications...

  11. Exercise-induced bronchoconstriction : clinical studies in childhood asthma

    NARCIS (Netherlands)

    W.B. Hofstra (Winfried)


    textabstractAt present, astluna is regarded as a chronic inflammatory disorder of the airways, In susceptible individuals, asthma causes symptoms, that are usually associated with variable, but often reversible airflow obstmction. Astlulla is the most conunon lung disease in childhood, with a sympto

  12. Air quality and exercise-induced bronchoconstriction in elite athletes. (United States)

    Rundell, Kenneth W; Sue-Chu, Malcolm


    A higher prevalence of airway hyperresponsiveness, airway remodeling, and asthma has been identified among athletes who compete and train in environmental conditions of cold dry air and/or high air pollution. Repeated long-duration exposure to cold/dry air at high minute ventilation rates can cause airway damage. Competition or training at venues close to busy roadways, or in indoor ice arenas or chlorinated swimming pools, harbors a risk for acute and chronic airway disorders from high pollutant exposure. This article discusses the effects of these harsh environments on the airways, and summarizes potential mechanisms and prevalence of airway disorders in elite athletes.

  13. The impact of exercise-induced bronchoconstriction on athletic performance

    DEFF Research Database (Denmark)

    Price, Oliver J; Hull, James H; Backer, Vibeke


    of this review is to provide a systematic appraisal of the current status of knowledge regarding EIB and exercise performance and to highlight potential mechanisms by which performance may be compromised by EIB. DATA SOURCES AND STUDY SELECTION: PubMed/Medline and EBSCO databases were searched up to May 2014...

  14. Relief of dyspnoea by beta(2)-agonists after methacholine-induced bronchoconstriction

    NARCIS (Netherlands)

    van der Woude, HJ; Postma, DS; Politiek, MJ; Winter, TH; Aalbers, R


    Virtually all asthma patients use bronchodilators. Formoterol and salbutamol have a rapid onset of bronchodilating effect, whereas salmeterol acts slower. We studied the onset of improvement of dyspnoea sensation after inhalation with these bronchodilators and placebo to reverse a methacholine-induc

  15. Exhaled nitric oxide predicts exercise-induced bronchoconstriction in asthmatic school children

    DEFF Research Database (Denmark)

    Buchvald, Frederik; Hermansen, Mette N; Nielsen, Kim G;


    used in routine monitoring of pediatric asthma control. The fractional concentration of exhaled nitric oxide (FeNO) also reflects uncontrolled asthma. We hypothesized that FeNO may be used for prescreening of asthmatic children to exclude those with good asthma control unlikely to have EIB, thereby...

  16. Aspirin, salicylate, sulfite and tartrazine induced bronchoconstriction. Safe doses and case definition in epidemiological studies. (United States)

    Corder, E H; Buckley, C E


    Allergic-like reactions to chemical components of foods and medicines may be common. The prevalence of idiosyncratic reactions to aspirin, salicylate, metabisulfite and tartrazine is not known. We used a tertiary referral clinic population to estimate safe exposure doses for epidemiological studies. A 15% decrease in the amount of air expired in one second was defined a positive response. The median effective molar doses of the agents were remarkably similar: metabisulfite 0.19 mM, 34.4 mg [95% confidence interval (CI) 0.14, 0.27 mM]; tartrazine 0.10 M, 55.0 mg (95% CI 0.05, 0.21 mM); aspirin 0.09 mM, 16.5 mg (95% CI 0.04, 0.19 mM); and salicylate 0.11 mM, 15.3 mg (95% CI 0.05, 0.27 mM). Doses to which the most sensitive (5%) and practically all (95%) susceptible persons might respectively respond are: metabisulfite 4.6 mg, 255.8 mg; tartrazine 3.4 mg, 885.6 mg; aspirin 0.8 mg, 332.3 mg; and salicylate 2.6 mg, 89.9 mg. Doses within these ranges can be used in epidemiological studies.

  17. Exercise-induced bronchoconstriction and non-specific airway hyperreactivity in patients suffering from bronchial asthma

    Directory of Open Access Journals (Sweden)

    Novković Dobrivoje


    Full Text Available Background/Aim. Physical activity is a common stimulus of asthmatic symptoms manifestation. Airway hyperreactivity is a predisposing cause of exercise induced bronchial obstruction, diagnosed by histamine inhalation. The aim of this study was to determine the relation between the amounts of histamine needed to induce non-specific airway hyperreactivity and exercise-induced bronchial obstruction. Methods. This randomized cross-over study included 160 male patients (age 19-27 years suffering from bronchial asthma who showed positive results as the reaction after the histamine bronchial provocation test. Histamine concentrations were in a range of 0.03 to 4 mg/mL. Each patient participated in the exercise stress test conducted on a conveyor belt. The results of the exercise stress test were considered positive if the FEV1 level dropped by at least 15% from its initial value, 5-10 minutes after the test. Results. All the patients showed positive results as the reaction after the histamine bronchial provocation test, while 50 of them showed positive results after the exercise-induced stress test. There was a statistically highly significant difference in administrated histamine concentrations between the group of patients that had positive results on exercise stress test and those who did not (1mg/mL vs 0.5mg/mL; U = 1678; p < 0.01. Also, there was a statistically significant difference concerning the frequency of the positive results regarding histamine concentration after induced stress test (χ2 = 10.885; p = 0.001. Among the patients with positive results, there was a statistically highly significant number of patients with bronchial obstruction induced by less than 2 mg/mL of histamine (p < 0.01. A statistically significant relation between the amount of histamine needed to induce bronchial obstruction and the results of the exercise stress test (p < 0.01 was also observed after the testing. Conclusion. In the group of patients with positive results after the exercise-induced stress test, there were significantly more patients with positive results to non-specific bronchial provocation test with lower histamine concentrations. Histamine concentrations needed to induce non-specific hyperreactivity of asthmatic airway were shown to be related to the reactivity to physical effort.

  18. Exhaled breath temperature and exercise-induced bronchoconstriction in asthmatic children. (United States)

    Peroni, Diego G; Chinellato, Iolanda; Piazza, Michele; Zardini, Federica; Bodini, Alessandro; Olivieri, Francesca; Boner, Attilio L; Piacentini, Giorgio L


    It has been hypothesized that exhaled breath temperature (EBT) is related to the degree of airway inflammation/remodeling in asthma. The purpose of this study was to evaluate the relationship between the level of airway response to exercise and EBT in a group of controlled or partly controlled asthmatic children. Fifty asthmatic children underwent measurements of EBT before and after a standardized exercise test. EBT was 32.92 ± 1.13 and 33.35 ± 0.95°C before and after exercise, respectively (P < 0.001). The % decrease in FEV(1) was significantly correlated with the increase in EBT (r = 0.44, P = 0.0013), being r = 0.49 (P < 0.005) in the children who were not receiving regular inhaled corticosteroids (ICS) and 0.37 (n.s.) in those who were. This study further supports the hypothesis that EBT can be considered a potential composite tool for monitoring asthma.

  19. Dysfunctional muscarinic M(2) autoreceptors in vagally induced bronchoconstriction of conscious guinea pigs after the early allergic reaction

    NARCIS (Netherlands)

    TenBerge, REJ; Krikke, M; Teisman, ACH; Roffel, AF; Zaagsma, J


    We studied the function of autoinhibitory muscarinic M(2) receptors on vagal nerve endings in the airways of conscious, unrestrained, ovalbumin-sensitized guinea pigs after the early and late allergic reaction. For this purpose, the effects of the selective muscarinic M(2) receptor antagonist gallam

  20. Protective effect of a PAR2-activating peptide on histamine-induced bronchoconstriction in guinea-pig


    Cicala, C; Spina, D.; Keir, S D; Severino, B.; Meli, R; Page, C. P.; Cirino, G.


    Protease activated receptor-2 (PAR2) is a seven transmembrane domain G protein coupled receptor proteolytically activated. PAR2, together with other PARs, can be also activated by peptides mimicking the sequence of the receptor tethered ligand. We have evaluated the effect of systemic administration of a peptide activating PAR2 (PAR2-AP, SLIGRL) on histamine-induced increase in lung resistances in the guinea-pig.Intravenous administration of PAR2-AP (1 mg kg−1) significantly inhibited histami...

  1. Dose-responses over time to inhaled fluticasone propionate treatment of exercise- and methacholine-induced bronchoconstriction in children with asthma

    NARCIS (Netherlands)

    Hofstra, WB; Neijens, HJ; Duiverman, EJ; Kouwenberg, JM; Mulder, PGH; Kuethe, MC; Sterk, PJ


    When treating bronchial hyperresponsiveness to so-called direct and indirect stimuli, distinct pathophysiological mechanisms might require differences in dose and duration of inhaled corticosteroid therapy. To test this hypothesis in children with asthma, we investigated the time- and dose-dependent

  2. Comparing the effects of two inhaled glucocorticoids on allergen-induced bronchoconstriction and markers of systemic effects, a randomised cross-over double-blind study

    Directory of Open Access Journals (Sweden)

    Lötvall Jan


    Full Text Available Abstract Background Inhaled glucocorticoids are efficient in protecting against asthma exacerbations, but methods to compare their efficacy vs systemic effects have only been attempted in larger multi-centre studies. The aim of the current study was therefore to directly compare the effects of two separate inhaled glucocorticoids, mometasone and budesonide, to compare the effects on the early and late asthmatic responses to inhaled allergen in patients with mild allergic asthma, and sputum eosinophils, and to relate the clinical positive effects to any systemic effects observed. Methods Twelve patients with documented early and late asthmatic responses (EAR and LAR to inhaled allergen at a screening visit were randomized in a double-blind fashion to treatment with mometasone (200 μg × 2 or 400 μg × 2, budesonide (400 μg × 2 or placebo in a double-blind crossover fashion for a period of seven days. Challenge with the total allergen dose causing both an EAR and LAR was given on the last day of treatment taken in the morning. Lung function was assessed using FEV1, and systemic glucocorticoid activity was quantified using 24 h urinary cortisol. Results Mometasone and budesonide attenuate both EAR and LAR to allergen to a similar degree. No significant dose-related effects on the lung function parameters were observed. Both treatments reduced the relative amount of sputum eosinophils (% after allergen. At the dose of 800 μg daily, mometasone reduced 24 h urinary cortisol by approximately 35%. Both drugs were well tolerated. Conclusions Mometasone and budesonide are equieffective in reducing early and late asthmatic responses induced by inhaled allergen challenge. Mometasone 800 μg given for seven days partially affects the HPA axis.

  3. Exercise-Induced Asthma (United States)

    ... management of exercise-induced bronchoconstriction: A practice parameter. Annals of Allergy, Asthma & Immunology. 2010;105:S1. Krafczyk ... up exercise on exercise-induced bronchoconstriction. Medicine and Science in Sports and Exercise. 2012;44:383. Asthma ...

  4. Optimizing inhalation therapy in childhood asthma

    NARCIS (Netherlands)

    Visser, Reina


    Childhood asthma is a common chronic disease, featured by inflammation of the airways and episodic bronchoconstriction. Exercise is an important trigger for bronchoconstriction in asthmatic children. They experience this symptom, limiting participation in play and sports, as the most bothersome aspe

  5. Effects of IL-4 and IL-13 on adenosine receptor expression and responsiveness of the human mast cell line 1

    NARCIS (Netherlands)

    Versluis, Mieke; Postma, Dirkje S.; Timens, Wim; Hylkema, Machteld N.


    Background: Inhalation of adenosine-5'-monophosphate (AMP) causes bronchoconstriction in asthma but not in healthy subjects. Bronchoconstriction upon AMP inhalation is thought to occur by histamine release and subsequent binding to receptors on airway smooth muscle cells. Methods: To explain enhance

  6. Dicty_cDB: SHE502 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available on, kit and method for treating respiratory tract disorder related to bronchoconstriction, pneumonia, allerg... 71 unordered pieces. 40 0.009 2 BD323302 |BD323302.1 Low-adenosine antisense oligonucleotide, its compositi

  7. Dicty_cDB: FC-IC0700 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available ating respiratory tract disorder related to bronchoconstriction, pneumonia, allergy...09 5 BD322951 |BD322951.1 Low-adenosine antisense oligonucleotide, its composition, kit and method for tre

  8. Cholinergic regulation of airway inflammation and remodelling

    NARCIS (Netherlands)

    Kolahian, Saeed; Gosens, Reinoud


    Acetylcholine is the predominant parasympathetic neurotransmitter in the airways that regulates bronchoconstriction and mucus secretion. Recent findings suggest that acetylcholine regulates additional functions in the airways, including inflammation and remodelling during inflammatory airway disease

  9. Prostaglandin E2 Prevents Hyperosmolar-Induced Human Mast Cell Activation through Prostanoid Receptors EP2 and EP4


    Ivonne Torres-Atencio; Erola Ainsua-Enrich; Fernando de Mora; César Picado; Margarita Martín


    BACKGROUND: Mast cells play a critical role in allergic and inflammatory diseases, including exercise-induced bronchoconstriction (EIB) in asthma. The mechanism underlying EIB is probably related to increased airway fluid osmolarity that activates mast cells to the release inflammatory mediators. These mediators then act on bronchial smooth muscle to cause bronchoconstriction. In parallel, protective substances such as prostaglandin E2 (PGE2) are probably also released and could explain the r...

  10. Anticholinergic treatment in airways diseases.

    LENUS (Irish Health Repository)

    Flynn, Robert A


    The prevalence of chronic airways diseases such as chronic obstructive pulmonary disease and asthma is increasing. They lead to symptoms such as a cough and shortness of breath, partially through bronchoconstriction. Inhaled anticholinergics are one of a number of treatments designed to treat bronchoconstriction in airways disease. Both short-acting and long-acting agents are now available and this review highlights their efficacy and adverse event profile in chronic airways diseases.

  11. Toll-like receptor and tumour necrosis factor dependent endotoxin-induced acute lung injury (United States)

    Togbe, Dieudonnée; Schnyder-Candrian, Silvia; Schnyder, Bruno; Doz, Emilie; Noulin, Nicolas; Janot, Laure; Secher, Thomas; Gasse, Pamela; Lima, Carla; Coelho, Fernando Rodrigues; Vasseur, Virginie; Erard, François; Ryffel, Bernhard; Couillin, Isabelle; Moser, Rene


    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. PMID:18039275

  12. β2-Agonist induced cAMP is decreased in asthmatic airway smooth muscle due to increased PDE4D

    NARCIS (Netherlands)

    Trian, Thomas; Burgess, Janette K; Niimi, Kyoko; Moir, Lyn M; Ge, Qi; Berger, Patrick; Liggett, Stephen B; Black, Judith L; Oliver, Brian G


    BACKGROUND AND OBJECTIVE: Asthma is associated with airway narrowing in response to bronchoconstricting stimuli and increased airway smooth muscle (ASM) mass. In addition, some studies have suggested impaired β-agonist induced ASM relaxation in asthmatics, but the mechanism is not known. OBJECTIVE:

  13. Asthma control during the year after bronchial thermoplasty

    DEFF Research Database (Denmark)

    Cox, Gerard; Thomson, Neil C.; Rubin, Adalberto S.


    BACKGROUND: Bronchial thermoplasty is a bronchoscopic procedure to reduce the mass of airway smooth muscle and attenuate bronchoconstriction. We examined the effect of bronchial thermoplasty on the control of moderate or severe persistent asthma. METHODS: We randomly assigned 112 subjects who had...

  14. Chest physical therapy in acute viral bronchiolitis: an updated review. (United States)

    Postiaux, Guy; Zwaenepoel, Bruno; Louis, Jacques


    We describe the various therapies for infant acute viral bronchiolitis and the contradictory results obtained with chest physical therapy. The treatment target is bronchial obstruction, which is a multifactorial phenomenon that includes edema, bronchoconstriction, and increased mucus production, with a clinical grading defined as severe, moderate, or mild. Chest physical therapy is revisited in its various modalities, according to preliminary scoring of the disease.

  15. Early Detection Of Breast Cancer using Post-Translationally Modified Biomarkers (United States)


    Pounds, and R.C. Zangar Smoking and COPD have Opposite Effects on 3-Nitrotyrosine in Plasma Proteins Environmental Health Perspectives, 2011, 119...halotyrosine levels correlated (r2 ~ 0.5) with exercise -induced bronchoconstriction measures of asthma, but the eosinophil counts did not. CONCLUSIONS: We

  16. Salbutamol pMDI gives less protection to methacholine induced airway obstruction than salbutamol via spacer or DPI.

    NARCIS (Netherlands)

    Broeders, M.E.A.C.; Molema, J.; Hop, W.C.J.; Folgering, H.T.M.


    BACKGROUND: Inhalation device and inhalation technique influence the deposition of drug in the lung. This study evaluated the efficacy of salbutamol as a bronchoprotective agent administered via Diskus, Turbuhaler, pMDI or pMDI + Volumatic against methacholine-induced bronchoconstriction. METHODS: T

  17. Nitrogen Dioxide Exposure and Airway Responsiveness in Individuals with Asthma (United States)

    Controlled human exposure studies evaluating the effect of inhaled NO2 on the inherent responsiveness of the airways to challenge by bronchoconstricting agents have had mixed results. In general, existing meta-analyses show statistically significant effects of NO2 on the airway r...

  18. Levodropropizine (LD) activity in allergic asthmatic patients, challenged with ultrasonically nebulized distilled water, metacholine and allergen-induced bronchospasm. (United States)

    Bossi, R; Banfi, P; Filipazzi, V; Castelli, C; Braga, P C


    The antitussive compound Levodropropizine (LD) is active in animal bronchoconstriction induced by histamine and capsaicin and in man protects from bronchoconstriction induced by capsaicin. The primary objective of this study was to evaluate the mechanism of action of LD given at 60 mg t.i.d. as oral drops, for 8 days by means of specific bronchial challenges (allergens) and of aspecific challenges acting via different receptors and fibers (i.e. metacholine via cholinergic receptors and ultrasonically nebulized distilled water (UNDW) via histamine and neuropeptide release). The study design is randomized, double-blind, cross-over versus placebo in 30 allergic asthmatic patients. Baseline bronchial tone and bronchoconstrictor response to metacholine (MCh) were not modified by active treatment nor by placebo. On the contrary, in airway responsiveness to UNDW, the active treatment showed an antagonist effect against induced bronchoconstriction of 59% [activity ratio (AR) as antilog = 0.41; 95% confidence interval 0.35-0.54; p cough, LD is also partially effective in inhibiting bronchial hyperreactive response against specific allergen and UNDW bronchoconstriction. Hence, LD might act by partly inhibiting histamine and neuropeptide release.

  19. A new perspective on muscarinic receptor antagonism in obstructive airways diseases

    NARCIS (Netherlands)

    Meurs, Herman; Oenema, Tjitske A.; Kistemaker, Loes E. M.; Gosens, Reinoud


    Acetylcholine has traditionally only been regarded as a neurotransmitter of the parasympathetic nervous system, causing bronchoconstriction and mucus secretion in asthma and COPD by muscarinic receptor activation on airway smooth muscle and mucus-producing cells. Recent studies in experimental model

  20. Relationship between airway narrowing, patchy ventilation and lung mechanics in asthmatics. (United States)

    Tgavalekos, N T; Musch, G; Harris, R S; Vidal Melo, M F; Winkler, T; Schroeder, T; Callahan, R; Lutchen, K R; Venegas, J G


    Bronchoconstriction in asthma results in patchy ventilation forming ventilation defects (VDefs). Patchy ventilation is clinically important because it affects obstructive symptoms and impairs both gas exchange and the distribution of inhaled medications. The current study combined functional imaging, oscillatory mechanics and theoretical modelling to test whether the degrees of constriction of airways feeding those units outside VDefs were related to the extent of VDefs in bronchoconstricted asthmatic subjects. Positron emission tomography was used to quantify the regional distribution of ventilation and oscillatory mechanics were measured in asthmatic subjects before and after bronchoconstriction. For each subject, ventilation data was mapped into an anatomically based lung model that was used to evaluate whether airway constriction patterns, consistent with the imaging data, were capable of matching the measured changes in airflow obstruction. The degree and heterogeneity of constriction of the airways feeding alveolar units outside VDefs was similar among the subjects studied despite large inter-subject variability in airflow obstruction and the extent of the ventilation defects. Analysis of the data amongst the subjects showed an inverse relationship between the reduction in mean airway conductance, measured in the breathing frequency range during bronchoconstriction, and the fraction of lung involved in ventilation defects. The current data supports the concept that patchy ventilation is an expression of the integrated system and not just the sum of independent responses of individual airways.

  1. Rho-kinase as a drug target for the treatment of airway hyperresponsiveness in asthma

    NARCIS (Netherlands)

    Gosens, R; Schaafsma, D; Nelemans, SA; Halayko, AJ


    In asthma, inflammatory and structural cells contribute to increased bronchoconstriction acutely and more chronically to airway remodelling. Current asthma therapy doesn't inhibit these features satisfactorily. This review discusses Rho-kinase as a potential drug target, since increasing evidence su

  2. Wheezing in school children is not always asthma

    NARCIS (Netherlands)

    Nystad, W; Stensrud, T; Rijcken, B; Magnus, P; Carlsen, KH


    Our objective was to study whether children with reported asthma differed from children with wheeze but without asthma, and from children with neither asthma nor wheeze, regarding lung function, bronchial hyper-responsiveness (BHR) using methacholine inhalation, exercise-induced bronchoconstriction

  3. Metabolic effects of beta2-agonists in relation to exercise performance

    DEFF Research Database (Denmark)

    Kalsen, Anders


    Beta2-agonists are frequently used in the treatment of asthma and exercise-induced bronchoconstriction in elite athletes. However, aside from a bronchodilatory effect, beta2-agonists have also been shown to improve exercise performance, which makes these substances subjected to misuse by elite...

  4. Terbutaline: level the playing field for inhaled β2-agonists by introducing a dosing and urine threshold

    DEFF Research Database (Denmark)

    Jacobson, Glenn A; Hostrup, Morten


    Terbutaline, a short-acting β2-agonist similar to salbutamol, is widely used in Europe in the treatment of asthma and exercise-induced bronchoconstriction. Unlike salbutamol, terbutaline requires therapeutic use exemption (TUE) for therapeutic inhaled use in competitive sport. There is now...

  5. Effect of unilateral vagus blockade on allergen-induced airway obstruction: results of short- and long-term experiments. (United States)

    Zimmermann, I; Ulmer, W T


    Unilateral application of ascaris extract on segment bronchus as the influence of contralateral vagus blockade on reflex bronchoconstriction was studied on four boxer dogs in a first group (A) of experiments: ascaris extract was applied in liquid form directly through a catheter into the right segment bronchus. This application was repeated after contralateral vagus blockade and once more after its lavage. All the animals showed an increase of airway resistance under local application of ascaris extract which could not be avoided by contralateral central vagus blockade. In the second group (B) isolation of unilateral vagus for reproducible performance of blockade as a long-term model was investigated in three boxer dogs for 7 weeks and the influence of this method of unilateral vagus blockade on exposure to allergen aerosol was studied. The unilateral blockade of the nerve vagus was again always successful in decreasing the reflex bronchoconstriction following allergen inhalation. The effect of unilateral section of nervus vagus 3 weeks after this vagotomy was tested on two boxer dogs. Reflex bronchoconstriction following ascaris extract inhalation can be avoided by unilateral section of the nervus vagus the first time after section. Three weeks after this unilateral vagotomy, the reflex bronchoconstriction becomes managed by the remaining vagus trunk to the same degree as observed by bilateral intact vagi.

  6. Regulation of actin dynamics by wnt-5a : Implications for human airway smooth muscle contraction

    NARCIS (Netherlands)

    Koopmans, Tim; Kumawat, Kuldeep; Menzen, Mark; Halayko, Andrew; Gosens, Reinoud


    An important pathophysiological feature of asthma is airway hyperresponsiveness (AHR), characterized by exaggerated bronchoconstriction in which the airway smooth muscle (ASM) is fundamentally involved. How the ASM in asthmatics differs from that in non-asthmatics is a current focus for research. We

  7. Chemical Terrorism for the Intensivist (United States)


    lary muscles and upper respiratory glands producing miosis, rhinorrhea, and salivation. Inhalation of the nerve vapor leads to bronchoconstriction and...bronchorrhea. Circulating agent next affects the gastrointestinal tract causing cramping , abdom- inal pain, and defecation. The effect on the...acetylcholinesterase will result in twitching, fascicu- lations, and weakness. The muscle twitching is often confused with seizures. As the syndrome

  8. Utilization of pressure-volume curves in the pediatric patient. (United States)

    Bone, R C; Jantzen, D; Heithold, R


    Seven patients treated with continuous mechanical ventialtion were monitored with static and dynamic pressure-volume curves. Three patients developed no pulmonary complications, and mechanical ventilation was discontinued within 96 hr. In four patients, pressure-volume curves were used as a diagnostic aid in the detection of the physiologic defect resulting from bronchoconstriction, atelectasis, loculated pleural fluid, pulmonary edema, and mucous plugging. These measurements were also utilized to evaluate the effectivess of therapeutic modalities such as treatment of bronchoconstriction with bronchodilators, mucous plugging with adequate suctioning, and drainage of loculated pleural effusion. Pressure-v-lume measurements are simple, noninvasive, and require the smae equipment used in continuous mechanical ventilation. Pressure-volume monitoring of pediatric patients with curves warrants further investigation to evaluate its value.

  9. [Bronchomotoric in antigen induced airway obstruction (author's transl)]. (United States)

    Zimmermann, I; Ulmer, W T


    Ascaris suum extract inhalation causes bronchoconstriction in dogs. Following this reaction, the bronchi stay oversensitive against acetylcholine for at least 7 h. Electrical stimulation of the peripheral end of a nervus vagus after cutting supports the meaning that the bronchoconstriction will be caused mainly by challenge of sensory receptors. The reflex way runs through the nervus vagus. Sensitization of the bronchial tree means sensitization of the sensory receptors. Results of the arterial blood gases correspond to earlier results which showed two parts of the bronchial tree: the vagus-controlled part is mainly respnsible for the airway resistance, the vagus-noncontrolled part is mainly responsible for the regulation of the ventilation/perfusion relationships.

  10. Precipitating factors of asthma. (United States)

    Lee, T H


    Asthma is characterised by bronchial hyperresponsiveness. This feature of the asthmatic diathesis predisposes patients to wheezing in response to a number of different factors. These precipitating factors include specific allergen acting via sensitised mediator cells through an IgE-dependent mechanism. There are irritants which may work through a non-specific manner, or stimuli such as exercise and hyperventilation, which probably also act through mediator release via a non-IgE-dependent manner. The mechanism whereby physical stimuli such as exercise induce bronchoconstriction is of interest, because it increases the context in which the mast cell may participate in acute asthmatic bronchoconstriction. Respiratory infections also commonly provoke asthma, especially in infants and may, indeed, precipitate the asthmatic state itself. Finally, drugs can often trigger asthma attacks and the mechanisms of asthma precipitated by non-steroidal anti-inflammatory drugs such as aspirin have been the subject of recent research.

  11. Asthma in elite athletes: pathogenesis, diagnosis, differential diagnoses, and treatment

    DEFF Research Database (Denmark)

    Pedersen, Lars; Elers, Jimmi; Backer, Vibeke


    Elite athletes have a high prevalence of asthma and exercise-induced bronchoconstriction. Although respiratory symptoms can be suggestive of asthma, the diagnosis of asthma in elite athletes cannot be based solely on the presence or absence of symptoms; diagnosis should be based on objective...... measurements, such as the eucapnic voluntary hyperpnea test or exercise test. When considering that not all respiratory symptoms are due to asthma, other diagnoses should be considered. Certain regulations apply to elite athletes who require asthma medication for asthma. Knowledge of these regulations...... is essential when treating elite athletes. This article is aimed at physicians who diagnose and treat athletes with respiratory symptoms. It focuses on the pathogenesis of asthma and exercise-induced bronchoconstriction in elite athletes and how the diagnosis can be made. Furthermore, treatment of elite...

  12. Nebulised sodium cromoglycate in infancy: airway protection after deterioration.


    O'Callaghan, C.; Milner, A. D.; Swarbrick, A.


    Over a two year period 100 infants with histories of wheeze were challenged with nebulised water. They were sedated and lung function measured by total body plethysmography. Thirteen of the 53 infants who developed bronchoconstriction after challenge with nebulised water were given nebulised sodium cromoglycate and rechallenged with nebulised water. All infants were initially challenged with normal saline, after which there was no significant change in lung function. After challenge with nebu...

  13. Effects of inhaled acid aerosols on lung mechanics: an analysis of human exposure studies.


    Utell, M J


    There exist significant gaps in our understanding of human health effects from inhalation of pollutants associated with acid precipitation. Controlled clinical studies examine effects of criteria pollutants almost exclusively by assessing changes in lung mechanics. One constituent of acid precipitation, sulfuric acid aerosols, has been shown to induce bronchoconstriction in exercising extrinsic asthmatics at near ambient levels. These asthmatics may be an order of magnitude more sensitive to ...

  14. Virus- and interferon-induced loss of inhibitory M2 muscarinic receptor function and gene expression in cultured airway parasympathetic neurons.


    Jacoby, D B; Xiao, H Q; Lee, N. H.; Chan-Li, Y; Fryer, A. D.


    Viral infections increase vagally mediated reflex bronchoconstriction. Decreased function of inhibitory M2 muscarinic receptors on the parasympathetic nerve endings is likely to contribute to increased acetylcholine release. In this study, we used cultured airway parasympathetic neurons to determine the effects of parainfluenza virus and of interferon (IFN)-gamma on acetylcholine release, inhibitory M2 receptor function, and M2 receptor gene expression. In control cultures, electrically stimu...

  15. Retinoic acid prevents virus-induced airway hyperreactivity and M2 receptor dysfunction via anti-inflammatory and antiviral effects


    Moreno-Vinasco, Liliana; Verbout, Norah G.; Fryer, Allison D.; Jacoby, David B.


    Inhibitory M2 muscarinic receptors on airway parasympathetic nerves normally limit acetylcholine release. Viral infections decrease M2 receptor function, increasing vagally mediated bronchoconstriction. Since retinoic acid deficiency causes M2 receptor dysfunction, we tested whether retinoic acid would prevent virus-induced airway hyperreactivity and prevent M2 receptor dysfunction. Guinea pigs infected with parainfluenza virus were hyperreactive to electrical stimulation of the vagus nerves,...

  16. Sodium cromoglycate in nocturnal asthma.



    To investigate whether mast cell degranulation was important in producing nocturnal asthma, the effect of a single high dose of nebulised sodium cromoglycate on overnight bronchoconstriction, oxygen saturation, and breathing patterns in eight patients with nocturnal wheeze was examined. The study took the form of a double blind placebo controlled crossover comparison. Treatment with cromoglycate did not reduce the overnight fall in FEV1 or FVC, although it was associated with improved nocturn...

  17. House dust mite major allergens Der p 1 promote the production of IL-8 and MUC5AC in human airway-derived epithelial cells by NF-kB mechanism

    Institute of Scientific and Technical Information of China (English)

    Renping Liu; Qi Hou; and Aiming Meng


    Backgroud: House dust mite allergens (HDM) is the most commonly encountered patho- gen of humans, predominantly causing bronchoconstriction in asthma patients and inducing an inflammatory response in the lungs dune to the release of cytokines, chemokines and other medi- ators. During the clinical course of treatment, dexamethasone has a limited effect on asthma pa- tients, especially for refractory asthma, because it is infective to block a large number of theneutrophils to invade the lung tissue.

  18. Neurally mediated airway constriction in human and other species: a comparative study using precision-cut lung slices (PCLS.

    Directory of Open Access Journals (Sweden)

    Marco Schlepütz

    Full Text Available The peripheral airway innervation of the lower respiratory tract of mammals is not completely functionally characterized. Recently, we have shown in rats that precision-cut lung slices (PCLS respond to electric field stimulation (EFS and provide a useful model to study neural airway responses in distal airways. Since airway responses are known to exhibit considerable species differences, here we examined the neural responses of PCLS prepared from mice, rats, guinea pigs, sheep, marmosets and humans. Peripheral neurons were activated either by EFS or by capsaicin. Bronchoconstriction in response to identical EFS conditions varied between species in magnitude. Frequency response curves did reveal further species-dependent differences of nerve activation in PCLS. Atropine antagonized the EFS-induced bronchoconstriction in human, guinea pig, sheep, rat and marmoset PCLS, showing cholinergic responses. Capsaicin (10 µM caused bronchoconstriction in human (4 from 7 and guinea pig lungs only, indicating excitatory non-adrenergic non-cholinergic responses (eNANC. However, this effect was notably smaller in human responder (30 ± 7.1% than in guinea pig (79 ± 5.1% PCLS. The transient receptor potential (TRP channel blockers SKF96365 and ruthenium red antagonized airway contractions after exposure to EFS or capsaicin in guinea pigs. In conclusion, the different species show distinct patterns of nerve-mediated bronchoconstriction. In the most common experimental animals, i.e. in mice and rats, these responses differ considerably from those in humans. On the other hand, guinea pig and marmoset monkey mimic human responses well and may thus serve as clinically relevant models to study neural airway responses.

  19. A novel model of IgE-mediated passive pulmonary anaphylaxis in rats. (United States)

    Wex, Eva; Thaler, Eva; Blum, Sylvia; Lamb, David


    Mast cells are central effector cells in allergic asthma and are augmented in the airways of asthma patients. Attenuating mast cell degranulation and with it the early asthmatic response is an important intervention point to inhibit bronchoconstriction, plasma exudation and tissue oedema formation. To validate the efficacy of novel pharmacological interventions, appropriate and practicable in vivo models reflecting mast cell-dependent mechanisms in the lung, are missing. Thus, we developed a novel model of passive pulmonary anaphylaxis in rats. Rats were passively sensitized by concurrent intratracheal and intradermal (ear) application of an anti-DNP IgE antibody. Intravenous application of the antigen, DNP-BSA in combination with Evans blue dye, led to mast cell degranulation in both tissues. Quantification of mast cell degranulation in the lung was determined by (1) mediator release into bronchoalveolar lavage, (2) extravasation of Evans blue dye into tracheal and bronchial lung tissue and (3) invasive measurement of antigen-induced bronchoconstriction. Quantification of mast cell degranulation in the ear was determined by extravasation of Evans blue dye into ear tissue. We pharmacologically validated our model using the SYK inhibitor Fostamatinib, the H1-receptor antagonist Desloratadine, the mast cell stabilizer disodium cromoglycate (DSCG) and the β2-adrenergic receptor agonist Formoterol. Fostamatinib was equally efficacious in lung and ear. Desloratadine effectively inhibited bronchoconstriction and ear vascular leakage, but was less effective against pulmonary vascular leakage, perhaps reflecting the differing roles for histamine receptor sub-types. DSCG attenuated both vascular leakage in the lung and bronchoconstriction, but with a very short duration of action. As an inhaled approach, Formoterol was more effective in the lung than in the ear. This model of passive pulmonary anaphylaxis provides a tissue relevant readout of early mast cell activity and

  20. A novel model of IgE-mediated passive pulmonary anaphylaxis in rats.

    Directory of Open Access Journals (Sweden)

    Eva Wex

    Full Text Available Mast cells are central effector cells in allergic asthma and are augmented in the airways of asthma patients. Attenuating mast cell degranulation and with it the early asthmatic response is an important intervention point to inhibit bronchoconstriction, plasma exudation and tissue oedema formation. To validate the efficacy of novel pharmacological interventions, appropriate and practicable in vivo models reflecting mast cell-dependent mechanisms in the lung, are missing. Thus, we developed a novel model of passive pulmonary anaphylaxis in rats. Rats were passively sensitized by concurrent intratracheal and intradermal (ear application of an anti-DNP IgE antibody. Intravenous application of the antigen, DNP-BSA in combination with Evans blue dye, led to mast cell degranulation in both tissues. Quantification of mast cell degranulation in the lung was determined by (1 mediator release into bronchoalveolar lavage, (2 extravasation of Evans blue dye into tracheal and bronchial lung tissue and (3 invasive measurement of antigen-induced bronchoconstriction. Quantification of mast cell degranulation in the ear was determined by extravasation of Evans blue dye into ear tissue. We pharmacologically validated our model using the SYK inhibitor Fostamatinib, the H1-receptor antagonist Desloratadine, the mast cell stabilizer disodium cromoglycate (DSCG and the β2-adrenergic receptor agonist Formoterol. Fostamatinib was equally efficacious in lung and ear. Desloratadine effectively inhibited bronchoconstriction and ear vascular leakage, but was less effective against pulmonary vascular leakage, perhaps reflecting the differing roles for histamine receptor sub-types. DSCG attenuated both vascular leakage in the lung and bronchoconstriction, but with a very short duration of action. As an inhaled approach, Formoterol was more effective in the lung than in the ear. This model of passive pulmonary anaphylaxis provides a tissue relevant readout of early mast cell

  1. Antiasthmatic activity of a novel thromboxane A2 antagonist, S-1452, in guinea pigs. (United States)

    Arimura, A; Asanuma, F; Kurosawa, A; Harada, M


    We examined the effect of a potent thromboxane (Tx) A2 receptor antagonist, calcium (1R, 2S, 3S, 4S)-(5Z)-7-(((phenylsulfonyl)amino)bicyclo[2.2.1] hept-2-yl)-5-heptenoate dihydrate (S-1452), on antigen- and various allergic-spasmogen-induced contractions of guinea pig lung parenchymal strips and on the increase in insufflation pressure, an index of bronchoconstriction, in anesthetized guinea pigs. In isolated guinea pig lung parenchymal strips, S-1452 showed competitive antagonism of the contractile activity of U-46619, a TxA2 mimetic, with a pA2 value of 8.9. The compound also inhibited the contraction induced by prostaglandin (PG) D2 and PGF2 alpha, but a TxA2 synthetase inhibitor, OKY-046, did not. In contrast, both drugs inhibited not only leukotriene (LT) D4-induced contraction but also antigen-induced contraction in the presence of a histamine antagonist. In anesthetized guinea pigs, oral administration of S-1452 markedly inhibited the bronchoconstrictions induced by intravenous injection of U-46619, PGD2, PGF2 alpha, LTD4 and platelet-activating factor (PAF) with ED50 values of 0.006, 0.031, 0.112, 0.033 and 0.115 mg/kg, respectively, but OKY-046 inhibited only that by LTD4 and PAF. Additionally, bronchoconstriction following intravenous injection of antigen was almost completely suppressed by S-1452 (0.1 mg/kg) and partially by OKY-046 (300 mg/kg) in passively sensitized guinea pigs which were treated with diphenydramine and propranolol. The inhibitory effect of S-1452 against U-46619-induced broncho-constriction persisted up to 7 h after oral administration.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. Structure Activity Relationship of Brevenal Hydrazide Derivatives

    Directory of Open Access Journals (Sweden)

    Allan Goodman


    Full Text Available Brevenal is a ladder frame polyether produced by the dinoflagellate Karenia brevis. This organism is also responsible for the production of the neurotoxic compounds known as brevetoxins. Ingestion or inhalation of the brevetoxins leads to adverse effects such as gastrointestinal maladies and bronchoconstriction. Brevenal shows antagonistic behavior to the brevetoxins and shows beneficial attributes when administered alone. For example, in an asthmatic sheep model, brevenal has been shown to increase tracheal mucosal velocity, an attribute which has led to its development as a potential treatment for Cystic Fibrosis. The mechanism of action of brevenal is poorly understood and the exact binding site has not been elucidated. In an attempt to further understand the mechanism of action of brevenal and potentially develop a second generation drug candidate, a series of brevenal derivatives were prepared through modification of the aldehyde moiety. These derivatives include aliphatic, aromatic and heteroaromatic hydrazide derivatives. The brevenal derivatives were tested using in vitro synaptosome binding assays to determine the ability of the compounds to displace brevetoxin and brevenal from their native receptors. A sheep inhalation model was used to determine if instillation of the brevenal derivatives resulted in bronchoconstriction. Only small modifications were tolerated, with larger moieties leading to loss of affinity for the brevenal receptor and bronchoconstriction in the sheep model.

  3. Paradoxical bronchospasm from benzalkonium chloride (BAC) preservative in albuterol nebulizer solution in a patient with acute severe asthma. A case report and literature review of airway effects of BAC. (United States)

    George, Mathew; Joshi, Saumya Vinod; Concepcion, Emily; Lee, Haesoon


    Nebulized bronchodilator solutions are available in the United States as both nonsterile and sterile-filled products. Sulfites, benzalkonium chloride (BAC), or chlorobutanol are added to nonsterile products to prevent bacterial growth. Bronchoconstriction from inhaled BAC is cumulative, prolonged, and correlates directly with basal airway responsiveness. The multi-dose dropper bottle of albuterol sulfate solution contains 50 μg BAC per/2.5 mg of albuterol, which may be below or at the lower limit of the threshold dose for bronchoconstriction. However, with repeated albuterol nebulization, the effect can be additive and cumulative, often exceeding the bronchoconstriction threshold. We report a case of a 17 years old patient, who received 32 mg of BAC via nebulization over a period of 3.5 days that probably caused persistent bronchospasm evidenced by failure to improve clinically and to increase peak expiratory flow rate (PEFR) from 125 L/min (27% of predicted value) to 300 L/min (68% of predicted value) within 2 hours of withdrawing BAC. The patient's respiratory status and PEFR improved dramatically once the nebulization solution was switched to BAC free lev-albuterol solution. The pediatric providers, particularly the emergency department physicians, intensivists and pulmonologists need to be aware of this rare albeit possible toxicity to the respiratory system caused by BAC used as a preservative in albuterol nebulizer solution.

  4. The ventilatory effect of external oscillation. (United States)

    Isabey, D; Piquet, J


    High frequency ventilation (HFV) may be achieved by external oscillation (external HFV) applied around the chest wall (HFCWO) in large animals and humans, or over the entire body (HFBSO) in small animals, instead of being applied via the trachea (internal HFV). We present a synthesis of the results obtained with external HFV in both normal and bronchoconstricted subjects. Whereas external and internal HFV were found to be equivalent in terms of gas exchange in normal rats, external HFV was found to have a beneficial effect in bronchoconstricted rabbits, but internal HFV did not. From the frequency-oscillatory tidal volume relationship determined in normocapnic rabbits, HFBSO at 5 Hz was found to be the optimal frequency at which to ventilate with tidal volumes close to the dead space volume, and which was also shown to be the optimal volume to obtain normocapnia. Moreover, 5 Hz oscillations (HFCWO) at 20 ml and 40 ml superimposed on tidal breathing accelerated nitrogen washout, i.e., gas exchange in normal humans. Unfortunately, only oscillations with much smaller volumes (5-10 ml) were obtainable in COPD patients. Nevertheless, they produced a clear change in breathing pattern associated with a slight improvement in gas exchange and a potentially positive effect on inspiratory muscle fatigue. These results support the concept that non-invasive external HFV technique may be of use in assisting ventilation in bronchoconstricted subjects and may possibly replace conventional controlled ventilation, at least in subjects with high lung compliance, such as babies, neonates and normal adults.

  5. Effect of acupuncture on bronchial asthma. (United States)

    Yu, D Y; Lee, S P


    1. Needle acupuncture was performed at three sites in twenty patients in a clinical attack of bronchial asthma. 2. In all patients the symptoms of bronchoconstriction improved during the attacks when the correct site was stimulated, and in five patients wheezing was abolished. 3. Stimulation at the correct site produced a significant increase in the mean FEV1-0 (58%) and FVC (29%) but not in maximal mid-expiratory flow rate (MMFR; 76%), when compared with the findings before acupuncture, along with a significant fall in the Pa,CO2 and an insignificant fall in Pa,O2. A mild tachycardia was also observed. 4. After acupuncture a greater improvement in FEV1-0, FVC and MMFR was produced by inhalation of isoprenaline. 5. No significant changes in FEV1-0, FVC, MMFR, pulse rate or arterial blood gas tensions occurred after acupuncture at control sites. 6. In four of the patients during clinical remission acupuncture was performed before and after histamine aerosol challenge, but there was no effect on either the severity or the duration of the histamine-induced bronchoconstriction. 7. It is concluded that acupunture probably reduced the reflex component of the bronchoconstriction, but failed to influence direct smooth muscle constriction caused by histamine.

  6. Asthma and the elite athlete: summary of the International Olympic Committee's consensus conference, Lausanne, Switzerland, January 22-24, 2008. (United States)

    Fitch, Kenneth D; Sue-Chu, Malcolm; Anderson, Sandra D; Boulet, Louis-Philippe; Hancox, Robert J; McKenzie, Donald C; Backer, Vibeke; Rundell, Kenneth W; Alonso, Juan M; Kippelen, Pascale; Cummiskey, Joseph M; Garnier, Alain; Ljungqvist, Arne


    Respiratory symptoms cannot be relied on to make a diagnosis of asthma and/or airways hyperresponsiveness (AHR) in elite athletes. For this reason, the diagnosis should be confirmed with bronchial provocation tests. Asthma management in elite athletes should follow established treatment guidelines (eg, Global Initiative for Asthma) and should include education, an individually tailored treatment plan, minimization of aggravating environmental factors, and appropriate drug therapy that must meet the requirements of the World Anti-Doping Agency. Asthma control can usually be achieved with inhaled corticosteroids and inhaled beta(2)-agonists to minimize exercise-induced bronchoconstriction and to treat intermittent symptoms. The rapid development of tachyphylaxis to beta(2)-agonists after regular daily use poses a dilemma for athletes. Long-term intense endurance training, particularly in unfavorable environmental conditions, appears to be associated with an increased risk of developing asthma and AHR in elite athletes. Globally, the prevalence of asthma, exercise-induced bronchoconstriction, and AHR in Olympic athletes reflects the known prevalence of asthma symptoms in each country. The policy of requiring Olympic athletes to demonstrate the presence of asthma, exercise-induced bronchoconstriction, or AHR to be approved to inhale beta(2)-agonists will continue.

  7. Gender and perception of dyspnea: The role of the variation in the forced expiratory volume in one second

    Directory of Open Access Journals (Sweden)

    Carlos A. Nigro


    Full Text Available During bronchoconstriction women perceive more breathlessness than men. The aims of study were 1 to evaluate if quality of dyspnea in bronchoconstriction was different in women and men 2 to assess if gender difference in the perception of dyspnea could be related to the level of bronchoconstriction. 457 subjects (257 women inhaled methacholine to a 20% decrease in FEV1, or 32 mg/ml. Dyspnea was evaluated using the modified Borg scale and a list of expressions of dyspnea. Borg scores were recorded immediately before the challenge test baseline and at the maximum FEV1 decrease. The prevalence of descriptors of dyspnea reported by women and men was similar. Dyspnea was related to the level of FEV1 (ΔFEV1: OR 1.05, 95%CI 1.01-1.09, p 0.0095, females (OR 2.90, 95%CI 1.33-6.33, p 0.0072, younger subjects (OR 0.93, 95%CI 0.89- 0.97, p 0.0013 and body mass index (BMI (OR 1.11, 95%CI 1.01-1.23, p 0.023. As the FEV1 fell less than 20% from baseline, only the ΔFEV1 was significantly associated with dyspnea (ΔFEV1:OR 1.15, 95%CI 1.07- 1.24, p 0.0002. Instead, if the FEV1 fell higher ≥ 20%, the presence of dyspnea was related to the degree of bronchoconstriction (ΔFEV1: OR 1.04, 95%CI 1.01-1.09, p 0.0187, females (OR 3.02, 95%CI 1.36-6.72, p 0.0067, younger subjects (OR 0.92, 95%CI 0.88-0.96, p 0.0007 and BMI (OR 1.12, 95%CI 1.01-1.23, p 0.023. The quality of dyspnea during the bronchoconstriction was similar in women and men; women showed a higher perception of dyspnea than men only when the FEV1 fell more than 20% from baseline.

  8. TPI 1020, a novel anti-inflammatory, nitric oxide donating compound, potentiates the bronchodilator effects of salbutamol in conscious guinea-pigs. (United States)

    Turner, Dawn L; Ferrari, Nicolay; Ford, William R; Kidd, Emma J; Paquet, Luc; Renzi, Paulo; Broadley, Kenneth J


    Inhaled corticosteroids are regularly co-administered with beta(2)-adrenoceptor agonists. This study evaluates in conscious guinea-pigs the bronchodilator effect, alone or combined with salbutamol, of TPI 1020, a novel anti-inflammatory corticosteroid and nitric oxide (NO) donor derived from budesonide. Guinea-pigs received inhaled histamine (3 mM) and specific airway conductance (sG(aw)) measured. Responses to histamine were measured before and on the next day 15 min after a 15 min inhalation of vehicle, salbutamol, TPI 1020, budesonide, the NO-donor, S-nitroso-N-acetylpenicillamine (SNAP), or combinations of these drugs. Salbutamol and TPI 1020 caused concentration-dependent bronchodilatation measured as inhibition of histamine-induced bronchoconstriction. TPI 1020-induced bronchodilatation was blocked by the guanylyl cyclise inhibitor, ODQ, indicating cGMP-dependence through released NO. While salbutamol at 80 microM did not exert significant bronchodilatation, significant inhibitions were observed when co-administered with TPI 1020, 0.11 and 0.33 mM. The combined effects of TPI 1020 and salbutamol lasted significantly longer than either drug alone. Inhaled budesonide was a weak bronchodilator and when co-administered with salbutamol there was enhanced bronchodilatation. Addition of the NO-donor, SNAP (0.1 mM), to the budesonide/salbutamol combination, also improved the inhibition of histamine-induced bronchoconstriction. This study has shown that TPI 1020 potentiates the bronchodilator activity of salbutamol, and their combination lasted longer than either drug administered individually. Both the corticosteroid and NO-releasing activities of TPI 1020 appear to be required for the potentiation of salbutamol. Combination of TPI 1020 with a beta(2)-adrenoceptor agonist may therefore be useful against acute bronchoconstriction episodes in asthma, and may offer an opportunity for reducing doses of inhaled beta(2)-adrenoceptor agonists.

  9. Vital capacities in acute and chronic airway obstruction: dependence on flow and volume histories. (United States)

    Brusasco, V; Pellegrino, R; Rodarte, J R


    The aim of this study was to investigate whether measurements of vital capacity (VC) are affected by the direction of the manoeuvre (inspiratory vs expiratory) and by the rate of expiratory flow. The study was performed on 25 individuals with chronic airway obstruction (CAO) and a forced expiratory volume in one second (FEV1) (expressed in standardized residuals (SR)) of -2.0+/-1.4 SD (CAO group), and 10 asthmatic subjects with methacholine (MCh)-induced bronchoconstriction (FEV1 -23+/-1.02 SR) (MCh group). VCs were measured during fast inspiration following both slow (FIVCse) and forced (FIVCfe) expiration from end-tidal inspiration to residual volume (RV), and during slow (EVC) or forced (FVC) expiration from total lung capacity (TLC). In the CAO group, FVC was the smallest volume (3.75+/-1.03 L) and significantly different from the other three estimates of VC; FIVCse (4.03+/-0.91 L) was the largest volume and significantly different from FVC and FIVCfe (3.83+/-0.98 L). In the MCh group, FVC (4.16+/-0.94 L) and EVC (4.19+/-0.89 L) were the largest volumes, although only the difference between FVC and FIVCfe (3.76+/-0.81 L) reached statistical significance. These data suggest that both flow and volume histories contribute to decreased vital capacities during bronchoconstriction. However, whereas increasing expiratory flow always tends to decrease vital capacity, the volume history of full inflation has different effects in chronic and acute bronchoconstriction, probably due to different effects on airway calibre. These results stress the importance of using standardized manoeuvres in order to obtain comparable values of vital capacity.

  10. Nonsteroidal Anti-Inflammatory Agents in the Treatment of Asthma in Children

    Directory of Open Access Journals (Sweden)

    Pierre Gaudreault


    Full Text Available The increasing scientific information clearly demonstrates the important role of inflammation in asthma. This evidence has led physicians to focus their treatment on the elimination of inflammation instead of working solely against bronchoconstriction. Steroids and nonsteroidal agents are currently used to prevent this inflammatory component. This paper focuses only on nonstcroidal anti-inflammatory agents such as sodium cromoglycate, nedocromil sodium and ketotifen and their use in pediatric asthma. The discussion on each medication addresses its mechanism of action, the evidence concerning its efficacy in pediatrics (ie, clinical pharmacology, acute bronchial challenge, late asthmatic response, bronchial hyperrcactivity, clinical efficacy and the pediatric dose.

  11. Effects of inhaled acid aerosols on lung mechanics: an analysis of human exposure studies. (United States)

    Utell, M J


    There exist significant gaps in our understanding of human health effects from inhalation of pollutants associated with acid precipitation. Controlled clinical studies examine effects of criteria pollutants almost exclusively by assessing changes in lung mechanics. One constituent of acid precipitation, sulfuric acid aerosols, has been shown to induce bronchoconstriction in exercising extrinsic asthmatics at near ambient levels. These asthmatics may be an order of magnitude more sensitive to sulfuric acid aerosols than normal adults. More recently, a second component nitrogen dioxide has been observed to provoke changes in lung mechanics at progressively lower concentrations. To date, virtually no data exist from clinical exposures to acidic aerosols for subjects with chronic obstructive pulmonary disease.

  12. Asthma pharmacotherapy. (United States)

    Schofield, Minka L


    Asthma is a chronic inflammatory disease of the airway that leads to airway obstruction via bronchoconstriction, edema, and mucus hypersecretion. The National Asthma Education and Prevention Program has outlined evidence-based guidelines to standardize asthma therapy and improve outcomes. The initial recommendation of choice for persistent asthmatic patients is an inhaled corticosteroid (ICS). Long-acting beta-2 agonists in combination with ICS, oral corticosteroids, leukotriene modifiers, and anti-IgE therapeutic options can be considered for patients with persistent or worsening symptoms. Many novel therapies are being developed, with an emphasis on anti-inflammatory mechanisms, gene expression, and cytokine modification.

  13. Sodium cromoglycate in nocturnal asthma. (United States)

    Morgan, A D; Connaughton, J J; Catterall, J R; Shapiro, C M; Douglas, N J; Flenley, D C


    To investigate whether mast cell degranulation was important in producing nocturnal asthma, the effect of a single high dose of nebulised sodium cromoglycate on overnight bronchoconstriction, oxygen saturation, and breathing patterns in eight patients with nocturnal wheeze was examined. The study took the form of a double blind placebo controlled crossover comparison. Treatment with cromoglycate did not reduce the overnight fall in FEV1 or FVC, although it was associated with improved nocturnal oxygenation. This study suggests that mast cell degranulation may not be important in the pathogenesis of nocturnal asthma. PMID:3085257

  14. Can resistive breathing injure the lung? Implications for COPD exacerbations

    Directory of Open Access Journals (Sweden)

    Vassilakopoulos T


    Full Text Available Theodoros Vassilakopoulos, Dimitrios Toumpanakis Pulmonary and Critical Care Medicine, Medical School, National and Kapodistrian University of Athens, Greece Abstract: In obstructive lung diseases, airway inflammation leads to bronchospasm and thus resistive breathing, especially during exacerbations. This commentary discusses experimental evidence that resistive breathing per se (the mechanical stimulus in the absence of underlying airway inflammation leads to lung injury and inflammation (mechanotransduction. The potential implications of resistive breathing-induced mechanotrasduction in COPD exacerbations are presented along with the available clinical evidence. Keywords: resistive breathing, COPD, mechanotransduction, bronchoconstriction, inflammation

  15. Cholinergic Regulation of Airway Inflammation and Remodelling

    Directory of Open Access Journals (Sweden)

    Saeed Kolahian


    Full Text Available Acetylcholine is the predominant parasympathetic neurotransmitter in the airways that regulates bronchoconstriction and mucus secretion. Recent findings suggest that acetylcholine regulates additional functions in the airways, including inflammation and remodelling during inflammatory airway diseases. Moreover, it has become apparent that acetylcholine is synthesized by nonneuronal cells and tissues, including inflammatory cells and structural cells. In this paper, we will discuss the regulatory role of acetylcholine in inflammation and remodelling in which we will focus on the role of the airway smooth muscle cell as a target cell for acetylcholine that modulates inflammation and remodelling during respiratory diseases such as asthma and COPD.

  16. Effect of N-acetylcysteine on gas exchange after methacholine challenge and isoprenaline inhalation in the dog. (United States)

    Ueno, O; Lee, L N; Wagner, P D


    N-acetylcysteine (NAC) has antioxidant and possibly mucolytic properties. To determine whether NAC could be of benefit in acute bronchoconstriction induced by methacholine, 12 of 24 anaesthetized dogs (group 1) received NAC i.v. (loading dose 150, then 20 The other 12 (group 2) received diluent. Nebulized methacholine (1%) was then inhaled until arterial oxygen tension (PaO2) fell to a mean of 5.5 kPa, after which isoprenaline 0.5% was inhaled in six dogs of each group to reverse bronchoconstriction. Over the next 3 h we measured total lung resistance, functional residual capacity (FRC), haemodynamic variables, and pulmonary gas exchange for respiratory and inert gases. After methacholine challenge, lung resistance increased and then fell similarly for both groups, but PaO2 was higher in the NAC group (by 0.6-1.9 kPa) throughout the observation period. The ventilation-perfusion distribution measured by inert gas elimination also showed less abnormality in the NAC treated dogs over this time. Mucus was visible during post-mortem in the large airways in about half of the dogs in both groups, with no significant differences between them. These results show that NAC produces a measurable improvement in gas exchange following methacholine challenge (both with and without subsequent isoprenaline therapy) by mechanisms that remain to be determined.

  17. Endotracheal nebulization of N-acetylcysteine increases airway resistance in cats with experimental asthma. (United States)

    Reinero, Carol R; Lee-Fowler, Tekla M; Dodam, John R; Cohn, Leah A; DeClue, Amy E; Guntur, Vamsi P


    N-acetylcysteine (NAC), a mucolytic and antioxidant, is speculated to cause bronchoconstriction in cats when delivered via aerosol. We hypothesized that in cats with experimental asthma, aerosol delivery of NAC (400mg cumulative dose) via an endotracheal tube would increase airflow limitation as measured by ventilator-acquired mechanics. After endotracheal drug delivery, airway resistance and inspiratory plateau pressure (Pplat) measurements were obtained in six mechanically ventilated asthmatic cats. Results demonstrated significantly increased airway resistance (P=0.0007) compared with aerosolized saline control; Pplats were not significantly different (P=0.059). All cats exhibited at least one adverse effect: excessive airway secretions (n=3), spontaneous cough (n=2), unilateral strabismus (n=1) and post-anesthetic death (n=1). No adverse reactions were noted with saline aerosol; cough was noted in one cat with methacholine challenge. In conclusion, airway resistance and adverse reactions were documented in all cats after NAC aerosol delivery. Further studies must be performed to evaluate if it is an effective mucolytic and/or antioxidant in cats and to determine if bronchodilator pre-treatment will negate NAC-induced bronchoconstriction.

  18. Laboratory studies of biological effects of sulfur oxides

    Energy Technology Data Exchange (ETDEWEB)

    Dalbey, W. E.


    Selected results from exposures of laboratory animals to airborne sulfur oxides were briefly summarized. The main observation during acute exposures was reflex bronchoconstriction and a resultant increase in pulmonary resistance. The increase in resistance due to sulfur dioxide (SO/sub 2/) was potentiated by simultaneous exposure to aerosols under conditions which would increase the transfer of sulfur oxides into the respiratory tract and promote transformation to a higher oxidation state, especially one that is acid. Sulfate aerosols, particularly sulfuric acid aerosols, were more potent than SO/sub 2/ in causing bronchoconstriction. Chronic exposure to high concentrations (400 to 650 ppM) of SO/sub 2/ resulted in experimental bronchitis in several species. Longterm exposure to more realistic concentrations of SO/sub 2/ produced little or no changes in respiratory function or morphology. Significant alterations in both pulmonary function and morphology have been reported after chronic exposure to sulfuric acid aerosols. Recent data indicate that changes in the lung may progress after cessation of such exposures.

  19. Inhibitory effect of n-butanol fraction of Moringa oleifera Lam. seeds on ovalbumin-induced airway inflammation in a guinea pig model of asthma. (United States)

    Mahajan, Shailaja G; Banerjee, Aryamitra; Chauhan, Bhupendrasinh F; Padh, Harish; Nivsarkar, Manish; Mehta, Anita A


    Moringaceae, which belongs to the Moringa oleifera Lam. family, is a well-known herb used in Asian medicine as an antiallergic drug. In the present study, the efficacy of the n-butanol extract of the seeds of the plant (MONB) is examined against ovalbumin-induced airway inflammation in guinea pigs. The test drugs (MONB or dexamethasone) are administered orally prior to challenge with aerosolized 0.5% ovalbumin. During the experimental period, bronchoconstriction tests are performed, and lung function parameters are measured. The blood and bronchoalveolar lavage fluid are collected to assess cellular content, and serum is used for cytokine (tumor necrosis factor-alpha, interleukin-4, and interleukin-6) assays. Histamine assays of lung tissue are performed using lung tissue homogenate. The results suggest that in ovalbumin-sensitized model control animals, tidal volume is decreased, respiration rate is increased, and both the total and differential cell counts in blood and bronchoalveolar lavage fluid are increased significantly compared with nonsensitized controls. MONB treatment shows improvement in all parameters except bronchoalveolar lavage tumor necrosis factor-alpha and interleukin-4. Moreover, MONB treatment demonstrates protection against acetylcholine-induced bronchoconstriction and airway inflammation. These results indicate that MONB has an inhibitory effect on airway inflammation. Thus, MONB possesses an antiasthmatic property through modulation of the relationship between Th1/Th2 cytokine imbalances.

  20. Assessing mucus and airway morphology in response to a segmental allergen challenge using OCT (Conference Presentation) (United States)

    Adams, David C.; Miller, Alyssa J.; Holz, Jasmin A.; Szabari, Margit V.; Hariri, Lida P.; Harris, R. Scott; Cho, Jocelyn L.; Hamilos, Daniel L.; Luster, Andrew D.; Medoff, Benjamin D.; Suter, Melissa J.


    Asthma affects hundreds of millions of people worldwide, and the prevalence of the disease appears to be increasing. One of the most important aspects of asthma is the excessive bronchoconstriction that results in many of the symptoms experienced by asthma sufferers, but the relationship between bronchoconstriction and airway morphology is not clearly established. We present the imaging results of a study involving a segmental allergen challenge given to both allergic asthmatic (n = 12) and allergic non-asthmatic (n = 19) human volunteers. Using OCT, we have imaged and assessed baseline morphology in a right upper lobe (RUL) airway, serving as the control, and a right middle lobe (RML) airway, in which the allergen was to be administered. After a period of 24 hours had elapsed following the administration of the allergen, both airways were again imaged and the response morphology assessed. A number of airway parameters were measured and compared, including epithelial thickness, mucosal thickness and buckling, lumen area, and mucus content. We found that at baseline epithelial thickness, mucosal thickness, and mucosal buckling were greater in AAs than ANAs. We also observed statistically significant increases in these values 24 hours after the allergen had been administered for both the ANA and AA sets. In comparison, the control airway which received a diluent showed no statistically significant change.

  1. Emergent structure-function relations in emphysema and asthma. (United States)

    Winkler, Tilo; Suki, Béla


    Structure-function relationships in the respiratory system are often a result of the emergence of self-organized patterns or behaviors that are characteristic of certain respiratory diseases. Proper description of such self-organized behavior requires network models that include nonlinear interactions among different parts of the system. This review focuses on 2 models that exhibit self-organized behavior: a network model of the lung parenchyma during the progression of emphysema that is driven by mechanical force-induced breakdown, and an integrative model of bronchoconstriction in asthma that describes interactions among airways within the bronchial tree. Both models suggest that the transition from normal to pathologic states is a nonlinear process that includes a tipping point beyond which interactions among the system components are reinforced by positive feedback, further promoting the progression of pathologic changes. In emphysema, the progressive destruction of tissue is irreversible, while in asthma, it is possible to recover from a severe bronchoconstriction. These concepts may have implications for pulmonary medicine. Specifically, we suggest that structure-function relationships emerging from network behavior across multiple scales should be taken into account when the efficacy of novel treatments or drug therapy is evaluated. Multiscale, computational, network models will play a major role in this endeavor.

  2. Distribution of airway narrowing responses across generations and at branching points, assessed in vitro by anatomical optical coherence tomography

    Directory of Open Access Journals (Sweden)

    Eastwood Peter R


    Full Text Available Abstract Background Previous histological and imaging studies have shown the presence of variability in the degree of bronchoconstriction of airways sampled at different locations in the lung (i.e., heterogeneity. Heterogeneity can occur at different airway generations and at branching points in the bronchial tree. Whilst heterogeneity has been detected by previous experimental approaches, its spatial relationship either within or between airways is unknown. Methods In this study, distribution of airway narrowing responses across a portion of the porcine bronchial tree was determined in vitro. The portion comprised contiguous airways spanning bronchial generations (#3-11, including the associated side branches. We used a recent optical imaging technique, anatomical optical coherence tomography, to image the bronchial tree in three dimensions. Bronchoconstriction was produced by carbachol administered to either the adventitial or luminal surface of the airway. Luminal cross sectional area was measured before and at different time points after constriction to carbachol and airway narrowing calculated from the percent decrease in luminal cross sectional area. Results When administered to the adventitial surface, the degree of airway narrowing was progressively increased from proximal to distal generations (r = 0.80 to 0.98, P Conclusions Our findings demonstrate that the bronchial tree expresses intrinsic serial heterogeneity, such that narrowing increases from proximal to distal airways, a relationship that is influenced by the route of drug administration but not by structural variations accompanying branching sites.

  3. Physiological Changes at Altitude in Nonasthmatic and Asthmatic Subjects

    Directory of Open Access Journals (Sweden)

    Dianna Louie


    Full Text Available Exercised-induced asthma is not due to exercise itself per se, but rather is due to cooling and/or drying of the airway because of the increased ventilation that accompanies exercise. Travel to high altitudes is accompanied by increased ventilation of cool, often dry, air, irrespective of the level of exertion, and by itself, this could represent an 'exercise' challenge for asthmatic subjects. Exercise-induced bronchoconstriction was measured at sea level and at various altitudes during a two-week trek through the Himalayas in a group of nonasthmatic and asthmatic subjects. The results of this study showed that in mild asthmatics, there was a significant reduction in peak expiratory flow at very high altitudes. Contrary to the authors' hypothesis, there was not a significant additional decrease in peak expiratory flow after exercise in the asthmatic subjects at high altitude. However, there was a significant fall in arterial oxygen saturation postexercise in the asthmatic subjects, a change that was not seen in the nonasthmatic subjects. These data suggest that asthmatic subjects develop bronchoconstriction when they go to very high altitudes, possibly via the same mechanism that causes exercise-induced asthma.

  4. Dynamic model of eicosanoid production with special reference to non-steroidal anti-inflammatory drug-triggered hypersensitivity. (United States)

    Fajmut, Aleš; Emeršič, Tadej; Dobovišek, Andrej; Antić, Nataša; Schäfer, Dirk; Brumen, Milan


    The authors developed a mathematical model of arachidonic acid (AA) degradation to prostaglandins (PGs) and leukotrienes (LTs), which are implicated in the processes of inflammation and hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs). The model focuses on two PGs (PGE2 and PGD2) and one LT (LTC4), their % increases and their ratios. Results are compared with experimental studies obtained from non-asthmatics (NAs), and asthmatics tolerant (ATA) or intolerant (AIA) to aspirin. Simulations are carried out for predefined model populations NA, ATA and three AIA, based on the differences of two enzymes, PG E synthase and/or LTC4-synthase in two states, that is, no-inflammation and inflammation. Their model reveals that the model population with concomitant malfunctions in both enzymes is the most sensitive to NSAIDs, since the duration and the capacity for bronchoconstriction risk are highest after simulated oral dosing of indomethacin. Furthermore, inflammation prolongs the duration of the bronchoconstriction risk in all AIA model populations, and the sensitivity analysis reveals multiple possible scenarios leading to hypersensitivity, especially if inflammatory processes affect the expression of multiple enzymes of the AA metabolic pathway. Their model estimates the expected fold-changes in enzyme activities and gives valuable information for further targeted transcriptomic/proteomic and metabolomic studies.

  5. Ionotropic and Metabotropic Proton-Sensing Receptors Involved in Airway Inflammation in Allergic Asthma

    Directory of Open Access Journals (Sweden)

    Haruka Aoki


    Full Text Available An acidic microenvironment has been shown to evoke a variety of airway responses, including cough, bronchoconstriction, airway hyperresponsiveness (AHR, infiltration of inflammatory cells in the lung, and stimulation of mucus hyperproduction. Except for the participation of transient receptor potential vanilloid-1 (TRPV1 and acid-sensing ion channels (ASICs in severe acidic pH (of less than 6.0-induced cough and bronchoconstriction through sensory neurons, the molecular mechanisms underlying extracellular acidic pH-induced actions in the airways have not been fully understood. Recent studies have revealed that ovarian cancer G protein-coupled receptor 1 (OGR1-family G protein-coupled receptors, which sense pH of more than 6.0, are expressed in structural cells, such as airway smooth muscle cells and epithelial cells, and in inflammatory and immune cells, such as eosinophils and dendritic cells. They function in a variety of airway responses related to the pathophysiology of inflammatory diseases, including allergic asthma. In the present review, we discuss the roles of ionotropic TRPV1 and ASICs and metabotropic OGR1-family G protein-coupled receptors in the airway inflammation and AHR in asthma and respiratory diseases.

  6. Should antihistamines be re-considered as antiasthmatic drugs as adjuvants to anti-leukotrienes? (United States)

    Bartho, Lorand; Benko, Rita


    In spite of histamine mimicking the symptoms of allergic bronchoconstriction and severe anaphylaxis, histamine antagonists most probably represent no effective treatment for these conditions. Anti-leukotrienes proved effective for preventing attacks of allergic asthma. In vitro evidence supports a supra-additive effect of histamine H1 receptor antagonists and anti-leukotrienes in vitro, in asthma models utilizing human bronchi. The same seems to hold true for human allergen provocation tests in vivo. We conclude that combinations of second-generation antihistamines and anti-leukotrienes deserve a large-scale clinical trial for preventing and/or treating attacks of allergic asthma. If useful, these drugs could provide a cost-effective alternative to some recent antiasthmatics. Given that redundant mechanisms may be included in asthma pathophysiology, other combinations (including thromboxane or platelet activating factor antagonists) could also be considered.

  7. Improvement of ventilatory function by spa therapy in patients with intractable asthma.

    Directory of Open Access Journals (Sweden)



    Full Text Available Twenty-five patients with intractable asthma had swimming training in a hot spring pool for 3 months. The subjects were divided into three groups according to their clinical symptoms and ages. Changes of ventilatory function during swimming training were observed in in each group. The ventilatory function test revealed that free swimming training in a hot spring pool for 30 min did not induce bronchoconstriction in any of the groups. The values of ventilatory parameters such as FEV 1.0%, %PEFR, %V50 and %V25 were improved after the 3-month swimming training. The improvement of ventilatory parameters, especially %MMF, %V50 and %V25, by the training was most remarkable in the type II asthma group. The percent increase in %MMF, %V50 and %V25 was highest in patients more than 61 years of age, and higher in patients aged 40 to 60 years than in younger patients.

  8. Airway dysfunction in elite swimmers: prevalence, impact, and challenges

    Directory of Open Access Journals (Sweden)

    Lomax M


    Full Text Available Mitch Lomax Department of Sport and Exercise Science, University of Portsmouth, Portsmouth, UK Abstract: The prevalence of airway dysfunction in elite swimmers is among the highest in elite athletes. The traditional view that swimmers naturally gravitate toward swimming because of preexisting respiratory disorders has been challenged. There is now sufficient evidence that the higher prevalence of bronchial tone disorders in elite swimmers is not the result of a natural selection bias. Rather, the combined effects of repeated chlorine by-product exposure and chronic endurance training can lead to airway dysfunction and atopy. This review will detail the underpinning causes of airway dysfunction observed in elite swimmers. It will also show that airway dysfunction does not prevent success in elite level swimming. Neither does it inhibit lung growth and might be partially reversible when elite swimmers retire from competition. Keywords: exercise, aquatic athletes, bronchoconstriction

  9. The effects of open leaf burning on spirometric measurements in asthma

    Energy Technology Data Exchange (ETDEWEB)

    From, L.J.; Bergen, L.G.; Humlie, C.J. (Beloit Memorial Hospital, WI (United States))


    The purpose of our study was to determine the effects of open leaf burning on asthmatic subjects. Seven subjects with known asthma of varying severity, along with three normal control subjects, were walked 0.5 mile with and without exposure on the same day, under very similar environmental conditions. An acute spirometric broncho-constrictive response was observed within 30 min of exercise with exposure to leaf burning in two of the seven asthmatic subjects. Five of the seven showed an overall drop in parameters measured. No significant change in the FEV1 was seen in the normal subjects with either protocol, nor in the asthmatic subjects during low level exercise alone. The results of our study suggest that open leaf burning under normal community-allowed conditions may represent a significant health hazard for some asthmatic subjects.

  10. Relaxation of soman-induced contracture of airway smooth muscle in vitro. (Reannouncement with new availability information)

    Energy Technology Data Exchange (ETDEWEB)

    Filbert, M.G.; Moore, D.H.; Adler, M.


    A possible role for beta-adrenergic agonists in the management of bronchoconstriction resulting from exposure to anticholinesterase compounds was investigated in vitro in canine tracheal smooth muscle. Norepinephrine, salbutamol and isoproterenol produced partial relaxation of soman-induced contractures. However, the relaxation induced was not sustained; muscle tensions returned to pretreatment levels within minutes despite the continued presence of beta-agonists. Increasing cAMP levels with the non beta-agonist bronchodilators such as thoophylline, a phosphodiesterase inhibitor, or forskolin, a specific stimulator of adenylate cyclase, resulted in more complete and longer lasting relaxation, suggesting that beta-adrenoceptor desensitization may contribute to the failure by beta-agonists to produce sustained relaxation. Nerve agents, Soman, Toxicity, Airway smooth muscle, In vitro, Physiology, Effects.

  11. Nebulised sodium cromoglycate in infancy: airway protection after deterioration. (United States)

    O'Callaghan, C; Milner, A D; Swarbrick, A


    Over a two year period 100 infants with histories of wheeze were challenged with nebulised water. They were sedated and lung function measured by total body plethysmography. Thirteen of the 53 infants who developed bronchoconstriction after challenge with nebulised water were given nebulised sodium cromoglycate and rechallenged with nebulised water. All infants were initially challenged with normal saline, after which there was no significant change in lung function. After challenge with nebulised water and sodium cromoglycate there were significant decreases in specific conductance compared with those found after challenge with normal saline. After rechallenge with nebulised water there was no deterioration in lung function. Although sodium cromoglycate caused a deterioration in lung function in these infants, it protected their airways from challenge with nebulised water. PMID:2111980

  12. Long-Acting Muscarinic Antagonists for Difficult-to-Treat Asthma: Emerging Evidence and Future Directions. (United States)

    Bulkhi, Adeeb; Tabatabaian, Farnaz; Casale, Thomas B


    Asthma is a complex disease where many patients remain symptomatic despite guideline-directed therapy. This suggests an unmet need for alternative treatment approaches. Understanding the physiological role of muscarinic receptors and the parasympathetic nervous system in the respiratory tract will provide a foundation of alternative therapeutics in asthma. Currently, several long-acting muscarinic antagonists (LAMAs) are on the market for the treatment of respiratory diseases. Many studies have shown the effectiveness of tiotropium, a LAMA, as add-on therapy in uncontrolled asthma. These studies led to FDA approval for tiotropium use in asthma. In this review, we discuss how the neurotransmitter acetylcholine itself contributes to inflammation, bronchoconstriction, and remodeling in asthma. We further describe the current clinical studies evaluating LAMAs in adult and adolescent patients with asthma, providing a comprehensive review of the current known physiological benefits of LAMAs in respiratory disease.

  13. Functional high-resolution computed tomography of pulmonary vascular and airway reactions. Experimental results. Funktionelle HR-CT der Lunge. Experimentelle Untersuchungen pulmonaler Gefaess- und Atemwegsreaktionen

    Energy Technology Data Exchange (ETDEWEB)

    Herold, C.J. (Universitaetsklinik fuer Radiodiagnostik, Vienna (Austria) Johns Hopkins Medical Institutions, Baltimore, MD (United States). Dept. of Radiology); Brown, R.H. (Johns Hopkins Medical Institutions, Baltimore, MD (United States). Dept. of Radiology Johns Hopkins Medical Institutions, Baltimore, MD (United States). Dept. of Anesthesiology and Intensive Care Medicine Johns Hopkins Medical Institutions, Baltimore, MD (United States). Dept. of Physiology); Wetzel, R.C.; Herold, S.M. (Johns Hopkins Medical Institutions, Baltimore, MD (United States). Dept. of Anesthesiology and Intensive Care Medicine); Zeerhouni, E.A. (Johns Hopkins Medical Institutions, Baltimore, MD (United States). Dept. of Radiology)


    We describe the use of high-resolution computed tomography (HRCT) for assessment of the function of pulmonary vessels and airways. With its excellent spatial resolution, HRCT is able to demonstrate pulmonary structures as small as 300 [mu]m and can be used to monitor changes following various stimuli. HRCT also provides information about structures smaller than 300 [mu]m through measurement of parenchymal background density. To date, sequential, spiral and ultrafast HRCT techniques have been used in a variety of challenges to gather information about the anatomical correlates of traditional physiological measurements, thus making anatomical-physiological correlation possible. HRCT of bronchial reactivity can demonstrate the location and time course of aerosol-induced broncho-constriction and may show changes not apparent on spirometry. HRCT of the pulmonary vascular system visualized adaptations of vessels during hypoxia and intravascular volume loading and elucidates cardiorespiratory interactions. Experimental studies provide a basis for potential clinical applications of this method. (orig.).

  14. Common causes of dyspnoea in athletes: a practical approach for diagnosis and management

    Directory of Open Access Journals (Sweden)

    James M. Smoliga


    Dyspnoea during exercise is a common chief complaint in athletes and active individuals. It is not uncommon for dyspnoeic athletes to be diagnosed with asthma, “exercise-induced asthma” or exercise-induced bronchoconstriction based on their symptoms, but this strategy regularly leads to misdiagnosis and improper patient management. Dyspnoea during exercise can ultimately be caused by numerous respiratory and nonrespiratory conditions, ranging from nonpathological to potentially fatal in severity. As, such it is important for healthcare providers to be familiar with the many factors that can cause dyspnoea during exercise in seemingly otherwise-healthy individuals and have a general understanding of the clinical approach to this patient population. This article reviews common conditions that ultimately cause athletes to report dyspnoea and associated symptoms, and provides insight for developing an efficient diagnostic plan.

  15. Fatigue of airway obstruction during long-term exposure to allergen aerosol. (United States)

    Zimmermann, I; Curschmann, P; Kowalski, J; Ulmer, W T


    The response to prolonged antigen exposure and the potentiation of airway resistance increase to ACH challenge, after this exposure, were studied on sixteen boxer dogs. One group of animals presented fatigue to A.E. after 3 hours of exposure. This group developed an increased response to ACH aerosol after fatigue to antigen was present. In a second group of dogs, absence of fatigue during prolonged exposure to allergen was observed. A growing tendency of Edyn (as an index of airway resistance) was observed after 5 hours of exposure. The therapeutical influence of bilateral vagus blockade was tested in these last animals. Blockade of nervus vagus released airway obstruction during prolonged allergen exposure and no bronchoconstriction was observed after ACH challenge during blockade.

  16. Role of Asthma Education in the Management of Adult Asthma

    Directory of Open Access Journals (Sweden)

    Johanne Côté


    Full Text Available When a patient is newly diagnosed as having asthma, he or she is often prescribed new medication without getting much information on the disease and its treatment. This article emphasizes the need to educate asthmatics. Asthma treatment should begin with a proper adjustment of the medication, allowing asthmatics to lead a normal life. All asthmatics should be shown how to use their inhalation device properly. They should he knowledgeable about the basic aspects of asthma, airway inflammation and bronchoconstriction, use or medication and early symptoms heralding an asthma attack. Environmental factors that may trigger an asthma attack should be explained. Patients should be able to self-monitor asthma using either symptom severity or a peak flow meter. Because asthma is an unpredictable disease, patients should have a self-action plan to implement when their asthma deteriorates.

  17. Airway responses to eucapnic hyperpnea, exercise, and methacholine in elite swimmers

    DEFF Research Database (Denmark)

    Pedersen, Lise; Winther, S.; Backer, V.;


    Purpose: The International Olympic Committee Medical Commission (IOC-MC) requires athletes to provide the result of an objective test to support a diagnosis of asthma or exercise-induced bronchoconstriction (EIB) if they want to inhale a beta-2-agonist. The purpose of the study was to evaluate...... the airway response to a methacholine challenge and to hyperpnea induced by exercise in the field and in the laboratory or that induced voluntarily by eucapnic hyperpnea in a group of female elite swimmers. Methods: Sixteen female nonasthmatic elite swimmers performed a eucapnic voluntary hyperpnea (EVH...... of diagnosing EIB. We recommend performing the EVH test when diagnosing and evaluating EIB in elite swimmers and if EVH test negative then proceeding to a strenuous LBT Udgivelsesdato: 2008/9...

  18. Airway resistance at maximum inhalation as a marker of asthma and airway hyperresponsiveness

    Directory of Open Access Journals (Sweden)

    O'Connor George T


    Full Text Available Abstract Background Asthmatics exhibit reduced airway dilation at maximal inspiration, likely due to structural differences in airway walls and/or functional differences in airway smooth muscle, factors that may also increase airway responsiveness to bronchoconstricting stimuli. The goal of this study was to test the hypothesis that the minimal airway resistance achievable during a maximal inspiration (Rmin is abnormally elevated in subjects with airway hyperresponsiveness. Methods The Rmin was measured in 34 nonasthmatic and 35 asthmatic subjects using forced oscillations at 8 Hz. Rmin and spirometric indices were measured before and after bronchodilation (albuterol and bronchoconstriction (methacholine. A preliminary study of 84 healthy subjects first established height dependence of baseline Rmin values. Results Asthmatics had a higher baseline Rmin % predicted than nonasthmatic subjects (134 ± 33 vs. 109 ± 19 % predicted, p = 0.0004. Sensitivity-specificity analysis using receiver operating characteristic curves indicated that baseline Rmin was able to identify subjects with airway hyperresponsiveness (PC20 min % predicted, FEV1 % predicted, and FEF25-75 % predicted, respectively. Also, 80% of the subjects with baseline Rmin min > 145% predicted had hyperresponsive airways, regardless of clinical classification as asthmatic or nonasthmatic. Conclusions These findings suggest that baseline Rmin, a measurement that is easier to perform than spirometry, performs as well as or better than standard spirometric indices in distinguishing subjects with airway hyperresponsiveness from those without hyperresponsive airways. The relationship of baseline Rmin to asthma and airway hyperresponsiveness likely reflects a causal relation between conditions that stiffen airway walls and hyperresponsiveness. In conjunction with symptom history, Rmin could provide a clinically useful tool for assessing asthma and monitoring response to treatment.

  19. A Halotyrosine Antibody that Detects Increased Protein Modifications in Asthma Patients

    Energy Technology Data Exchange (ETDEWEB)

    Jin, Hongjun; Hallstrand, Teal S.; Daly, Don S.; Matzke, Melissa M.; Nair, Parameswaran; Bigelow, Diana J.; Pounds, Joel G.; Zangar, Richard C.


    Background-Airway inflammation plays an important pathophysiological role in asthma. Eosinophils produce hypobromite and bromotyrosine while neutrophils produce hypochlorite and chlorotyrosine. Objective-To evaluate halotyrosine modifications of individual airway proteins as a marker of inflammation in asthma using an antibody-based assay. Methods-We developed a novel monoclonal antibody (BTK-94C) that binds halogenated tyrosine residues, and used this antibody in a custom enzyme-linked immunosorbent assay (ELISA) microarray platform to examine halotyrosine levels in 23 proteins in three independent sets of sputum samples (52 samples total). Results-In 15 subjects with either no asthma, or with asthma characterized by high or low sputum eosinophil counts, we found associations between increased halotyrosine levels of at least three proteins and severity of airway hyperresponsiveness (AHR). Treatment with mepolizumab in 17 patients with sputum eosinophilia markedly reduced the sputum eosinophilia and significantly reduced halotyrosine levels in one sputum protein. Further analysis of 10 subjects with neutrophilic asthma and 10 health controls demonstrated a broad increase in halotyrosine in the patients with airway neutrophilia. Conclusions-Significantly higher levels of halotyrosine are associated with asthma in the asthma phenotypes we examined. The halotyrosine levels correlated with indirect AHR in the form of exercise-induced bronchoconstriction. Clinical Implication-An antibody-based assay for tyrosine halogenation in specific proteins may prove useful for assessing airway inflammation in asthma. Capsule Summary-An antibody to measure protein monobrominated tyrosine and other halotyrosine modifications was developed and used to evaluate halogenation in specific proteins in the airways for the first time. Associations were found between levels of halotyrosine and exercise-induced bronchoconstriction, and eosinophil and neutrophil inflammation in sputum from

  20. Protective effects of phosphodiesterase inhibitors on lung function and remodeling in a murine model of chronic asthma

    Directory of Open Access Journals (Sweden)

    Campos H.S.


    Full Text Available The aim of the present study was to compare the efficacy of a novel phosphodiesterase 4 and 5 inhibitor, LASSBio596, with that of dexamethasone in a murine model of chronic asthma. Lung mechanics (airway resistance, viscoelastic pressure, and static elastance, histology, and airway and lung parenchyma remodeling (quantitative analysis of collagen and elastic fiber were analyzed. Thirty-three BALB/c mice were randomly assigned to four groups. In the asthma group (N = 9, mice were immunized with 10 µg ovalbumin (OVA, ip on 7 alternate days, and after day 40 they were challenged with three intratracheal instillations of 20 µg OVA at 3-day intervals. Control mice (N = 8 received saline under the same protocol. In the dexamethasone (N = 8 and LASSBio596 (N = 8 groups, the animals of the asthma group were treated with 1 mg/kg dexamethasone disodium phosphate (0.1 mL, ip or 10 mg/kg LASSBio596 dissolved in dimethyl sulfoxide (0.2 mL, ip 24 h before the first intratracheal instillation of OVA, for 8 days. Airway resistance, viscoelastic pressure and static elastance increased significantly in the asthma group (77, 56, and 76%, respectively compared to the control group. The asthma group presented more intense alveolar collapse, bronchoconstriction, and eosinophil and neutrophil infiltration than the control group. Both LASSBio596 and dexamethasone inhibited the changes in lung mechanics, tissue cellularity, bronchoconstriction, as well as airway and lung parenchyma remodeling. In conclusion, LASSBio596 at a dose of 10 mg/kg effectively prevented lung mechanical and morphometrical changes and had the potential to block fibroproliferation in a BALB/c mouse model of asthma.

  1. Sustained release choline theophyllinate in nocturnal asthma. (United States)

    Rhind, G B; Connaughton, J J; McFie, J; Douglas, N J; Flenley, D C


    Nocturnal wheeze is common in patients with asthma, and slow release theophyllines may reduce symptoms. As theophyllines are stimulants of the central nervous system the effect of 10 days' twice daily treatment with sustained release choline theophyllinate or placebo on symptoms, overnight bronchoconstriction, nocturnal oxygen saturation, and quality of sleep were studied in a double blind crossover study in nine stable patients with nocturnal asthma (five men, four women, age range 23-64 years; forced expiratory volume in one second (FEV1) 0.85-3.8 1; vital capacity 1.95-6.1 1). When treated with the active drug all patients had plasma theophylline concentrations of at least 28 mmol/l (5 micrograms/ml) (peak plasma theophylline concentrations 50-144 mmol/l (9-26 micrograms/ml]. Morning FEV1 was higher when treated with sustained release choline theophyllinate (2.7 (SEM 0.3) 1) than placebo (2.1 (0.3) 1) (p less than 0.01). Both daytime and nocturnal symptoms were reduced when the patients were treated with sustained release choline theophyllinate and subjective quality of sleep was improved (p less than 0.002). When treated with the active drug, however, quality of sleep determined by electroencephalography deteriorated with an increase in wakefulness and drowsiness (p less than 0.05) and a reduction in non-rapid eye movement sleep (p less than 0.005). Treatment with choline theophyllinate had no effect on either the occurrence or the severity of transient nocturnal hypoxaemic episodes or apnoeas or hypopnoeas. In conclusion, sustained release choline theophyllinate prevents overnight bronchoconstriction, but impairs quality of sleep defined by electroencephalography.

  2. Dyspnea assessment and adverse events during sputum induction in COPD

    Directory of Open Access Journals (Sweden)

    Moschandreas Joanna


    Full Text Available Abstract Background The inhalation of normal or hypertonic saline during sputum induction (SI may act as an indirect bronchoconstrictive stimulus leading to dyspnea and lung function deterioration. Our aim was to assess dyspnea and adverse events in COPD patients who undergo SI following a safety protocol. Methods Sputum was induced by normal and hypertonic (4.5% saline solution in 65 patients with COPD of varying severity. In order to minimize saline-induced bronchoconstriction a protocol based on the European Respiratory Society sputum induction Task group report was followed. Dyspnea change was scored using the Borg scale and lung function was assessed by spirometry and oximetry. Results Borg score changes [median(IQR 1.5(0–2] were observed during SI in 40 subjects; 16 patients required temporary discontinuation of the procedure due to dyspnea-general discomfort and 2 did not complete the session due to dyspnea-wheezing. The change in Borg dyspnea score was significantly correlated with oxygen saturation and heart rate changes and with discontinuation of the procedure due to undesired symptoms. 19 subjects presented an hyperresponsive reaction (decline>20% from baseline FEV1. No significant correlation between Borg changes and FEV1decline was found. Patients with advanced COPD presented significantly greater Borg and oxygen saturation changes than patients with less severe disease (p = 0.02 and p = 0.001, respectively. Baseline FEV1, oxygen saturation and 6MWT demonstrated significant diagnostic values in distinguishing subjects who develop an adverse physiologic reaction during the procedure. Conclusion COPD patients undergoing SI following a safety protocol do not experience major adverse events. Dyspnea and oxygen desaturation is more likely to occur in patients with disease in advanced stages, leading to short discontinuation or less frequently to termination of the procedure. Baseline FEV1, oxygen saturation and 6MWT may have a

  3. Eucapnic voluntary hyperventilation as a bronchoprovocation technique: development of a standarized dosing schedule in asthmatics. (United States)

    Argyros, G J; Roach, J M; Hurwitz, K M; Eliasson, A H; Phillips, Y Y


    A variety of dosing schedules have been reported for the hyperventilation method of broncho-provocation testing. To evaluate the effect of challenge technique on the bronchoconstrictive response, we had 16 subjects perform eucapnic voluntary hyperventilation (EVH) with dry, room temperature gas using four different dosing schedules. The hyperventilation challenge dosages included the following: (1) a target minute ventilation (VE) of 20 x FEV1 for 6 min; (2) a target VE of 15 x FEV1 for 12 min; (3) an interrupted challenge with a target VE of 30 x FEV1 for 2 min repeated 3 times; and (4) a target VE of 30 x FEV1 for 6 min. Challenges 2, 3, and 4 gave identical absolute ventilatory challenges (identical factor FEV1 x minutes) but at different VE dosages or time. Challenges 1 and 4 were of identical length, but different target VE. The mean postchallenge fall in FEV1 was 16.6 +/- 10.9%, 11.0 +/- 8.1%, 19.6 +/- 9.9%, and 26.7 +/- 11.3% for challenges 1, 2, 3, and 4, respectively. The response to an identical EVH challenge (FEV1 x 30 for 6 min) was reproducible when performed on separate days. We conclude that the challenge technique used for hyperventilation testing will have a significant impact on the bronchoconstrictive response and must be taken into account when interpreting study results. Tests may be quantitatively comparable over a narrow range of challenge time and VE. We recommend that a 6-min uninterrupted EVH challenge using dry, room temperature gas at a target VE of 30 x FEV1 be adopted as the "standard" challenge.

  4. Effect of Moringa oleifera Lam. seed extract on ovalbumin-induced airway inflammation in guinea pigs. (United States)

    Mahajan, Shailaja G; Mehta, Anita A


    To determine the therapeutic potential of herbal medicine Moringa oleifera Lam. family: Moringaceae in the control of allergic diseases, the efficacy of the ethanolic extract of the seeds of the plant (MOEE) against ovalbumin (OVA)-induced airway inflammation in guinea pigs was examined. During the experimental period, the test drugs (MOEE or dexamethasone) were administered by oral route prior to challenge with aerosolized 0.5% OVA. Bronchoconstriction tests were performed and respiratory parameters (i.e., tidal volume and respiratory rate) were measured. At the end of experiment, blood was collected from each animal to perform total and differential counts and serum was used for assay of IL-4, IL-6, and TNFalpha. Lung lavage fluid (BAL) was collected for estimation of cellular content and cytokine levels. Lung tissue histamine assays were performed using the homogenate of one lobe from each animal; a separate lobe and the trachea were subjected to histopathology to measure the degree of any airway inflammation. The results suggest that in OVA-sensitized control animals that did not receive either drug, tidal volume (V(t)) was decreased, respiration rate (f) was increased, and both the total and differential cell counts in blood and BAL fluid were increased significantly. MOEE-treatment of sensitized hosts resulted in improvement in all parameters except BAL TNFalpha and IL-4. Moreover, MOEE-treatment also showed protection against acetylcholine-induced broncho-constriction and airway inflammation which was confirmed by histological observations. The results of these studies confirm the traditional claim for the usefulness of this herb in the treatment of allergic disorders like asthma.

  5. Gender and perception of dyspnea: The role of the variation in the forced expiratory volume in one second Género y percepción de disnea: el rol de la variación del volumen espiratorio forzado en un segundo

    Directory of Open Access Journals (Sweden)

    Carlos A. Nigro


    Full Text Available During bronchoconstriction women perceive more breathlessness than men. The aims of study were 1 to evaluate if quality of dyspnea in bronchoconstriction was different in women and men 2 to assess if gender difference in the perception of dyspnea could be related to the level of bronchoconstriction. 457 subjects (257 women inhaled methacholine to a 20% decrease in FEV1, or 32 mg/ml. Dyspnea was evaluated using the modified Borg scale and a list of expressions of dyspnea. Borg scores were recorded immediately before the challenge test baseline and at the maximum FEV1 decrease. The prevalence of descriptors of dyspnea reported by women and men was similar. Dyspnea was related to the level of FEV1 (ΔFEV1: OR 1.05, 95%CI 1.01-1.09, p 0.0095, females (OR 2.90, 95%CI 1.33-6.33, p 0.0072, younger subjects (OR 0.93, 95%CI 0.89- 0.97, p 0.0013 and body mass index (BMI (OR 1.11, 95%CI 1.01-1.23, p 0.023. As the FEV1 fell less than 20% from baseline, only the ΔFEV1 was significantly associated with dyspnea (ΔFEV1:OR 1.15, 95%CI 1.07- 1.24, p 0.0002. Instead, if the FEV1 fell higher ≥ 20%, the presence of dyspnea was related to the degree of bronchoconstriction (ΔFEV1: OR 1.04, 95%CI 1.01-1.09, p 0.0187, females (OR 3.02, 95%CI 1.36-6.72, p 0.0067, younger subjects (OR 0.92, 95%CI 0.88-0.96, p 0.0007 and BMI (OR 1.12, 95%CI 1.01-1.23, p 0.023. The quality of dyspnea during the bronchoconstriction was similar in women and men; women showed a higher perception of dyspnea than men only when the FEV1 fell more than 20% from baseline.Durante la broncoconstricción las mujeres perciben más disnea que los hombres. Los objetivos del estudio fueron evaluar: 1 si la calidad de la disnea durante la broncoconstricción fue diferente en mujeres y hombres, 2 si la diferencia entre sexos en la percepción de disnea podría relacionarse al nivel de broncoconstricción. 457 sujetos (257 mujeres inhalaron metacolina hasta un descenso del FEV1 ≥ 20% o 32 mg/ml. La

  6. Clinical evaluation of nedocromil sodium in asthma. (United States)

    Holgate, S T


    The recognition that inflammatory events in the airways play a key role in the pathogenesis of asthma has led to a relentless search for pharmacological agents which modify these processes. Nedocromil sodium (Tilade) represents one such agent. Nedocromil sodium, when inhaled by patients with asthma (0.05-0.50% nebulized, 0.5-4.0 mg m.d.i.), has been shown to inhibit immediate bronchoconstriction provoked by challenges with allergen (10 studies), exercise (five studies), isocapnic hyperventilation, fog and sulphur dioxide (one study each) and adenosine (two studies). With these challenges, inhibition of bronchoconstriction exhibited dose-dependency up to 4 mg, with nedocromil sodium being up to four times more potent than sodium cromoglycate. When inhaled prior to allergen provocation, nedocromil sodium inhibited the late asthmatic reaction; when taken regularly during the pollen season, it attenuated the allergen-induced increase in non-specific bronchial responsiveness. The efficacy of nedocromil sodium (4 mg q.i.d.) in the treatment of clinical asthma was initially shown in four open studies and subsequently confirmed in nine double-blind, placebo-controlled 4-12 week studies on patients with seasonal and perennial asthma. Further clinical trials (eight studies) identified some difficulty in replacing inhaled corticosteroids with nedocromil sodium, especially if the corticosteroids were reduced rapidly (four studies). However, two studies have shown that nedocromil sodium produced further improvement in asthma symptoms when used in addition to bronchodilators and inhaled corticosteroids. Treatment with nedocromil sodium (4 mg q.i.d.) for up to 52 weeks demonstrated a progressive reduction in bronchodilator usage throughout the whole treatment period. During clinical assessment, nedocromil sodium was well tolerated, side-effects being unpleasant taste, nausea and headache. In most cases the adverse reactions were mild and transient, although in approximately 3% of

  7. CysLT2 receptor activation is involved in LTC4-induced lung air-trapping in guinea pigs. (United States)

    Sekioka, Tomohiko; Kadode, Michiaki; Yonetomi, Yasuo; Kamiya, Akihiro; Fujita, Manabu; Nabe, Takeshi; Kawabata, Kazuhito


    CysLT1 receptors are known to be involved in the pathogenesis of asthma. However, the functional roles of CysLT2 receptors in this condition have not been determined. The purpose of this study is to develop an experimental model of CysLT2 receptor-mediated LTC4-induced lung air-trapping in guinea pigs and use this model to clarify the mechanism underlying response to such trapping. Because LTC4 is rapidly converted to LTD4 by γ-glutamyltranspeptidase (γ-GTP) under physiological conditions, S-hexyl GSH was used as a γ-GTP inhibitor. In anesthetized artificially ventilated guinea pigs with no S-hexyl GSH treatment, i.v. LTC4-induced bronchoconstriction was almost completely inhibited by montelukast, a CysLT1 receptor antagonist, but not by BayCysLT2RA, a CysLT2 receptor antagonist. The inhibitory effect of montelukast was diminished by treatment with S-hexyl GSH, whereas the effect of BayCysLT2RA was enhanced with increasing dose of S-hexyl GSH. Macroscopic and histological examination of lung tissue isolated from LTC4-/S-hexyl-GSH-treated guinea pigs revealed air-trapping expansion, particularly at the alveolar site. Inhaled LTC4 in conscious guinea pigs treated with S-hexyl GSH increased both airway resistance and airway hyperinflation. On the other hand, LTC4-induced air-trapping was only partially suppressed by treatment with the bronchodilator salmeterol. Although montelukast inhibition of LTC4-induced air-trapping was weak, treatment with BayCysLT2RA resulted in complete suppression of this air-trapping. Furthermore, BayCysLT2RA completely suppressed LTC4-induced airway vascular hyperpermeability. In conclusion, we found in this study that CysLT2 receptors mediate LTC4-induced bronchoconstriction and air-trapping in S-hexyl GSH-treated guinea pigs. It is therefore believed that CysLT2 receptors contribute to asthmatic response involving air-trapping.

  8. Beta-blockers: friend or foe in asthma?

    Directory of Open Access Journals (Sweden)

    Arboe B


    Full Text Available Bente Arboe, Charlotte Suppli UlrikDepartment of Pulmonary Medicine, Hvidovre Hospital and University of Copenhagen, Hvidovre, DenmarkBackground and aim: Recently, β-blockers have been suggested as a potential maintenance treatment option for asthma. The aim of this review is to provide an overview of the current knowledge of the potential benefits and risks of β-blocker therapy for asthma.Method: Systematic literature review.Results: No significant increase in the number of patients requiring rescue oral corticosteroid for an exacerbation of asthma has been observed after initiation of β-blocker treatment. Patients with mild to moderate reactive airway disease, probably both asthma and chronic obstructive pulmonary disease, may have a limited fall in forced expiratory volume in 1 second (FEV1 following single-dose administration of β-blocker, whereas no change in FEV1 has been reported following long-term administration. In a murine model of asthma, long-term administration of β-blockers resulted in a decrease in airway hyperresponsiveness, suggesting an anti-inflammatory effect. In keeping with this, long-term administration of a nonselective β-blocker to steroid-naïve asthma patients has shown a dose-dependent improvement in airway hyperresponsiveness, and either an asymptomatic fall in FEV1 or no significant change in FEV1. Furthermore, available studies show that bronchoconstriction induced by inhaled methacholine is reversed by salbutamol in patients on regular therapy with a β-blocker. On the other hand, a recent placebo-controlled trial of propranolol and tiotropium bromide added to inhaled corticosteroids revealed no effect on airway hyperresponsiveness and a small, not statistically significant, fall in FEV1 in patients classified as having mild to moderate asthma.Conclusion: The available, although limited, evidence suggests that a dose-escalating model of β-blocker therapy to patients with asthma is well tolerated, does not

  9. Elastase-Induced Parenchymal Disruption and Airway Hyper Responsiveness in Mouse Precision Cut Lung Slices: Toward an Ex vivo COPD Model (United States)

    Van Dijk, Eline M.; Culha, Sule; Menzen, Mark H.; Bidan, Cécile M.; Gosens, Reinoud


    Background: COPD is a progressive lung disease characterized by emphysema and enhanced bronchoconstriction. Current treatments focused on bronchodilation can delay disease progression to some extent, but recovery or normalization of loss of lung function is impossible. Therefore, novel therapeutic targets are needed. The importance of the parenchyma in airway narrowing is increasingly recognized. In COPD, the parenchyma and extracellular matrix are altered, possibly affecting airway mechanics and enhancing bronchoconstriction. Our aim was to set up a comprehensive ex vivo Precision Cut Lung Slice (PCLS) model with a pathophysiology resembling that of COPD and integrate multiple readouts in order to study the relationship between parenchyma, airway functionality, and lung repair processes. Methods: Lungs of C57Bl/6J mice were sliced and treated ex vivo with elastase (2.5 μg/ml) or H2O2 (200 μM) for 16 h. Following treatment, parenchymal structure, airway narrowing, and gene expression levels of alveolar Type I and II cell repair were assessed. Results: Following elastase, but not H2O2 treatment, slices showed a significant increase in mean linear intercept (Lmi), reflective of emphysema. Only elastase-treated slices showed disorganization of elastin and collagen fibers. In addition, elastase treatment lowered both alveolar Type I and II marker expression, whereas H2O2 stimulation lowered alveolar Type I marker expression only. Furthermore, elastase-treated slices showed enhanced methacholine-induced airway narrowing as reflected by increased pEC50 (5.87 at basal vs. 6.50 after elastase treatment) and Emax values (47.96 vs. 67.30%), and impaired chloroquine-induced airway opening. The increase in pEC50 correlated with an increase in mean Lmi. Conclusion: Using this model, we show that structural disruption of elastin fibers leads to impaired alveolar repair, disruption of the parenchymal compartment, and altered airway biomechanics, enhancing airway contraction

  10. Exploiting the relationship between birefringence and force to measure airway smooth muscle contraction with PS-OCT (Conference Presentation) (United States)

    Adams, David C.; Hariri, Lida P.; Holz, Jasmin A.; Szabari, Margit V.; Harris, R. Scott; Cho, Jocelyn L.; Hamilos, Daniel L.; Luster, Andrew D.; Medoff, Benjamin D.; Suter, Melissa J.


    The ability to observe airway dynamics is fundamental to forming a complete understanding of pulmonary diseases such as asthma. We have previously demonstrated that Optical Coherence Tomography (OCT) can be used to observe structural changes in the airway during bronchoconstriction, but standard OCT lacks the contrast to discriminate airway smooth muscle (ASM) bands- ASM being responsible for generating the force that drives airway constriction- from the surrounding tissue. Since ASM in general exhibits a greater degree of birefringence than the surrounding tissue, a potential solution to this problem lies in the implementation of polarization sensitivity (PS) to the OCT system. By modifying the OCT system so that it is sensitive to the birefringence of tissue under inspection, we can visualize the ASM with much greater clarity and definition. In this presentation we show that the force of contraction can be indirectly measured by an associated increase in the birefringence signal of the ASM. We validate this approach by attaching segments of swine trachea to an isometric force transducer and stimulating contraction, while simultaneously measuring the exerted force and imaging the segment with PS-OCT. We then show how our results may be used to extrapolate the force of contraction of closed airways in absence of additional measurement devices. We apply this technique to assess ASM contractility volumetrically and in vivo, in both asthmatic and non-asthmatic human volunteers.

  11. Life-threatening asthma attack during prolonged fingolimod treatment: case report

    Directory of Open Access Journals (Sweden)

    Zecca C


    Full Text Available Chiara Zecca,1,* Matteo Caporro,1,* Sandor Györik,2 Claudio Gobbi11Neurocenter of Southern Switzerland, Department of Neurology, Ospedale Regionale di Lugano, Lugano, Switzerland; 2Department of Internal Medicine, Ospedale Regionale di Bellinzona, Bellinzona, Switzerland*These authors contributed equally to this workBackground: Fingolimod (FTY mediates bronchoconstriction by interacting with sphingosine-1-phosphate receptors. The majority of the reported adverse respiratory events occur during the first weeks of treatment.Case presentation: A 49-year-old woman developed a life-threatening asthma attack after 6 months of continuous FTY treatment. The adverse event required prolonged hospitalization, and the patient recovered without sequelae after FTY interruption. A history of previous airway hyperreactivity and a concurrent viral respiratory infection possibly acted as predisposing factors.Conclusion: This first description of a severe, life-threatening asthma attack during prolonged FTY treatment suggests the need for long-term clinical surveillance, especially in patients with known predisposing factors.Keywords: multiple sclerosis, bronchial hyper-reactivity

  12. Inhalers and nebulizers: which to choose and why. (United States)

    Pedersen, S


    It is obvious that many factors should be considered when an inhaler is prescribed. Based upon the information discussed above, a rational inhaler strategy could be as follows: (1) Children valve system (and a face mask for the children) for the delivery of all drugs. When they are severely obstructed, some may need a nebulizer. If the patient cannot be taught the correct use of a spacer, a nebulizer should be prescribed. (2) Children > or = 5 years and adults are prescribed a spacer or a Turbuhaler for the administration of inhaled corticosteroids and a dry powder inhaler (preferably multiple dose) or a breath-actuated MDI for other drugs. If these alternatives are not available or the patient prefers, a conventional MDI can be used (preferably not for other corticosteroids than fluticasone propionate) provided that careful tuition is given. Fluticasone dipropionate may be given by DPI, Spacer or MDI. (3) Nebulizers are mainly reserved for severe acute attacks of bronchoconstriction. With this approach, most patients can be taught effective inhaler use with a minimum of instructional time. Finally, it must always be remembered to consider the patient's wish, since prescription of an inhaler which the physician likes but the patient does not is likely to reduce compliance.

  13. Acute inhalation of ozone stimulates bronchial C-fibers and rapidly adapting receptors in dogs

    Energy Technology Data Exchange (ETDEWEB)

    Coleridge, J.C.G.; Coleridge, H.M.; Schelegle, E.S.; Green, J.F. (Univ. of California, Davis (United States) Univ. of California, San Francisco (United States))


    To identify the afferents responsible for initiating the vagally mediated respiratory changes evoked by acute exposure to ozone, the authors recorded vagal impulses in anesthetized, open-chest, artificially ventilated dogs and examined the pulmonary afferent response to ozone (2--3 ppM in air) delivered to the lower trachea for 20--60 min. Bronchial C-fibers (BrCs) were the lung afferents most susceptible to ozone, the activity of 10 of 11 BrCs increasing from 0.2 [+-] 0.2 to 4.6 [+-] 1.3 impulses/s within 1--7 min of ozone exposure. Ten of 15 rapidly adapting receptors (RARs) were stimulated by ozone, their activity increasing from 1.5 [+-] 0.4 to 4.7 [+-] 0.7 impulses/s. Stimulation of RARs (but not of BrCs) appeared secondary to the ozone-induced reduction of lung compliance because it was abolished by hyperinflation of the lungs. Ozone had little effect on pulmonary C-fibers or slowly adapting pulmonary stretch receptors. The authors' results suggest that both BrCs and RARs contribute to the tachypnea and bronchoconstriction evoked by acute exposure to ozone when vagal conduction is intact and that BrCs alone are responsible for the vagally mediated tachypnea that survives vagal cooling to 7[degrees]C. 23 refs., 5 figs.

  14. Nonspecific airway reactivity in a mouse model of asthma

    Energy Technology Data Exchange (ETDEWEB)

    Collie, D.D.; Wilder, J.A.; Bice, D.E.


    Animal models are indispensable for studies requiring an intact immune system, especially for studying the pathogenic mechanisms in atopic diseases, regulation of IgE production, and related biologic effects. Mice are particularly suitable and have been used extensively for such studies because their immune system is well characterized. Further, large numbers of mutants or inbred strains of mice are available that express deficiencies of individual immunologic processes, inflammatory cells, or mediator systems. By comparing reactions in such mice with appropriate control animals, the unique roles of individual cells or mediators may be characterized more precisely in the pathogenesis of atopic respiratory diseases including asthma. However, given that asthma in humans is characterized by the presence of airway hyperresponsiveness to specific and nonspecific stimuli, it is important that animal models of this disease exhibit similar physiologic abnormalities. In the past, the size of the mouse has limited its versatility in this regard. However, recent studies indicate the feasibility of measuring pulmonary responses in living mice, thus facilitating the physiologic evaluation of putative mouse models of human asthma that have been well charcterized at the immunologic and patholigic level. Future work will provide details of the morphometry of the methacholine-induced bronchoconstriction and will further seek to determine the relationship between cigarette smoke exposure and the development of NS-AHR in the transgenic mouse model.

  15. Review: Implications of air pollution effects on athletic performance (United States)

    Pierson, William E.; Covert, David S.; Koenig, Jane Q.; Namekata, Tsukasa; Kim, Yoon Shin

    Both controlled human studies and observational studies suggest air pollution adversely affects athletic performance during both training and competition. The air pollution dosage during exercise is much higher than during rest because of a higher ventilatory rate and both nasal and oral breathing in the former case. For example, SO 2 which is a highly water soluble gas, is almost entirely absorbed in the upper respiratory tract during nasal breathing. However, with oral pharyngeal breathing, the amount of sulfur dioxide that is absorbed is significantly less, and with exercise and oral pharyngeal breathing a significant decrease in upper airway absorption occurs, resulting in a significantly larger dosage of this pollutant being delivered to the tracheobronchial tree. Recently, several controlled human studies have shown that the combination of exercise and pollutant exposure (SO 2 or O 3) caused a marked bronchoconstriction and reduced ventilatory flow when compared with pollution exposure at rest. In a situation like the Olympic Games where ms and mm often determine success of athletes, air pollution can be an important factor in affecting their performance. This paper examines possible impacts of air pollution on athletic competition.

  16. [Osmolarity of solutions used in nebulization]. (United States)

    Portel, L; Tunon de Lara, J M; Vernejoux, J M; Weiss, I; Taytard, A


    Inhaled medications are widely used in patients suffering from bronchial diseases. Beside their pharmacological properties, nebulised solutions have physico-chemical characteristics that can alter bronchial reactivity. Non-isotonic solutions can induce a bronchial hyperresponsiveness and/or a severe bronchonconstriction. Nevertheless, multiple drugs are used for nebulisation despite their unknown osmolarity. The aim of this study was to measure the tonicity of drug solutions commonly used for nebulisation in patients suffering from bronchial disease. Drug solutions were prepared either according to manufacturer recommendations or by diluting the stock in 5 ml of NaCl (0.9%) or H2CO3 (0.14%). Although bronchodilatator solutions (i.e. salbutamol, terbulatine, ipratropium bromide) were nearly isotonic, some drugs prepared for nebulisation had either a very high (e.g. mesna, netilmicine) or a very low (e.g. gomenol, sodium cromoglycate) tonicity. These values may be responsible for bronchoconstriction. Some hypertonic solutions, prepared with drugs such as acetylcytein or netilmycin, are not commercialised for nebulisation but are commonly used for aerosol therapy. In addition, solutions initially isotonic could become significantly hypertonic towards the end of nebulisation. Taken together, these results suggest that non-isotonic solutions should be used with caution specially in patients with bronchial hyperresponsiveness, even when aerosol therapy is prescribed for upper airways.

  17. Effects of Flavin7 on allergen induced hyperreactivity of airways

    Directory of Open Access Journals (Sweden)

    Franova S


    Full Text Available Abstract Some studies have suggested that the polyphenolic compounds might reduce the occurrence of asthma symptoms. The aim of our experiments was to evaluate the effects of 21 days of the flavonoid Flavin7 administration on experimentally induced airway inflammation in ovalbumin-sensitized guinea pigs. We assessed tracheal smooth muscle reactivity by an in vitro muscle-strip method; changes in airway resistance by an in vivo plethysmographic method; histological picture of tracheal tissue; and the levels of interleukin 4 (IL-4, and interleukin 5 (IL-5 in bronchoalveolar lavage fluid (BALF. Histological investigation of tracheal tissue and the concentrations of the inflammatory cytokines IL-4 and IL-5 in BALF were used as indices of airway inflammation. Administration of Flavin7 caused a significant decrease of specific airway resistance after histamine nebulization and a decline in tracheal smooth muscle contraction amplitude in response to bronchoconstricting mediators. Flavin7 minimized the degree of inflammation estimated on the basis of eosinophil calculation and IL-4 and IL-5 concentrations. In conclusion, administration of Flavin7 showed bronchodilating and anti-inflammatory effects on allergen-induced airway inflammation.

  18. Acid stress in the pathology of asthma. (United States)

    Ricciardolo, Fabio L M; Gaston, Benjamin; Hunt, John


    Although alteration of airway pH may serve an innate host defense capacity, it also is implicated in the pathophysiology of obstructive airway diseases. Acid-induced asthma appears in association with gastroesophageal reflux after accidental inhalation of acid (fog, pollution, and workplace exposure) and in the presence of altered airway pH homeostasis. Endogenous and exogenous exposures to acids evoke cough, bronchoconstriction, airway hyperreactivity, microvascular leakage, and heightened production of mucous, fluid, and nitric oxide. Abnormal acidity of the airways is reflected in exhaled breath assays. The intimate mechanisms of acid-induced airway obstruction are dependent on activation of capsaicin-sensitive sensory nerves. Protons activate these nerves with the subsequent release of tachykinins (major mediators of this pathway) that, in conjunction with kinins, nitric oxide, oxygen radicals, and proteases, modulate diverse aspects of airway dysfunction and inflammation. The recognition that acid stress might initiate or exacerbate airway obstructive symptomatology has prompted the consideration of new therapies targeting pH homeostasis.

  19. Asthma Management in Sickle Cell Disease

    Directory of Open Access Journals (Sweden)

    Esteban Gomez


    Full Text Available Asthma is a common comorbid factor in sickle cell disease (SCD. However, the incidence of asthma in SCD is much higher than expected compared to rates in the general population. Whether “asthma” in SCD is purely related to genetic and environmental factors or rather is the consequence of the underlying hemolytic and inflammatory state is a topic of recent debate. Regardless of the etiology, hypoxemia induced by bronchoconstriction and inflammation associated with asthma exacerbations will contribute to a cycle of sickling and subsequent complications of SCD. Recent studies confirm that asthma predisposes to complications of SCD such as pain crises, acute chest syndrome, and stroke and is associated with increased mortality. Early recognition and aggressive standard of care management of asthma may prevent serious pulmonary complications and reduce mortality. However, data regarding the management of asthma in SCD is very limited. Clinical trials are needed to evaluate the effectiveness of current asthma therapy in patients with SCD and coincident asthma, while mechanistic studies are needed to delineate the underlying pathophysiology.

  20. Bronchial Thermoplasty in Asthma

    Directory of Open Access Journals (Sweden)

    Wayne Mitzner


    Full Text Available In this review we discuss the potential of a new procedure, termed Bronchial Thermoplasty to prevent serious consequences resulting from excessive airway narrowing. The most important factor in minimizing an asthmatic attack is limiting the degree of smooth muscle shortening. The premise that airway smooth muscle can be either inactivated or obliterated without any long-term alteration of other lung tissues, and that airway function will remain normal, albeit with reduced bronchoconstriction, has now been demonstrated in dogs, a subset of normal subjects, and mild asthmatics. Bronchial Thermoplasty may thus develop into a useful clinical procedure to effectively impair the ability for airway smooth muscle to reach the levels of pathologic narrowing that characterizes an asthma attack. It may also enable more successful treatment of asthma patients who are unresponsive to more conventional therapies. Whether this will remain stable for the lifetime of the patient still remains to be determined, but at the present time, there are no indications that the smooth muscle contractility will return. This successful preliminary experience showing that Bronchial Thermoplasty could be safely performed in patients with asthma has led to an ongoing clinical trial at a number of sites in Europe and North America designed to examine the effectiveness of this procedure in subjects with moderately severe asthma.

  1. Biomarkers for Gastroesophageal Reflux in Respiratory Diseases

    Directory of Open Access Journals (Sweden)

    Össur Ingi Emilsson


    Full Text Available Gastroesophageal reflux (GER is commonly associated with respiratory symptoms, either through a vagal bronchoconstrictive reflex or through microaspiration of gastric contents. No diagnostic test is available, however, to diagnose when respiratory illnesses are caused by GER and when not, but research in this field has been moving forward. Various biomarkers in different types of biosamples have been studied in this context. The aim of this review is to summarize the present knowledge in this field. GER patients with respiratory diseases seem to have a different biochemical profile from similar patients without GER. Inflammatory biomarkers differ in asthmatics based on GER status, tachykinins are elevated in patients with GER-related cough, and bile acids are elevated in lung transplant patients with GER. However, studies on these biomarkers are often limited by their small size, methods of analysis, and case selections. The two pathogenesis mechanisms are associated with different respiratory illnesses and biochemical profiles. A reliable test to identify GER-induced respiratory disorders needs to be developed. Bronchoalveolar lavage is too invasive to be of use in most patients. Exhaled breath condensate samples need further evaluation and standardization. The newly developed particles in exhaled air measurements remain to be studied further.

  2. Effects of inspiratory resistance, inhaled beta-agonists and histamine on canine tracheal blood flow

    Energy Technology Data Exchange (ETDEWEB)

    Kelly, W.T.; Baile, E.M.; Brancatisano, A.; Pare, P.D.; Engel, L.A. (Dept. of Respiratory Medicine, Westmead Hospital, Westmead, NSW (Australia))


    Tracheobronchial blood flow is potentially important in asthma as it could either influence the clearance of mediators form the airways, thus affecting the duration and severity of bronchoispasm, or enhance oedema formation with a resultant increase in airflow obstruction. In anaesthetized dogs, spontaneously breathing via a tracheostomy, we investigated the effects of three interventions which are relevant to acute asthma attacks and could potentially influence blood flow and its distribution to the mucosa and remaining tissues of the trachea: (1) increased negative intrathoracic pressure swings (-25[+-]1 cmH[sub 2]O) induced by an inspiratory resistance; (2) variable inhaled doses of a beta-adrenoceptor-agonist (terbutaline); and (3) aerosolized histamine sufficient to produce a threefold increase in pulmonary resistance. Microspheres labelled with different radioisotopes were used to measure blood flow. Resistive breathing did not influence tracheobronchial blood flow. Following a large dose of terbutaline, mucosal blood flow (Qmb) increased by 50%. After inhaled histamine, Qmb reached 265% of the baseline value. We conclude that, whereas increased negative pressure swings do not influence tracheobronchial blood flow or its distribution, inhalation of aerosolized terbutaline, corresponding to a conventionally nebulized dose, increases mucosal blood flow. Our results also confirm that inhaled histamine, in a dose sufficient to produce moderate bronchoconstriction, increases tracheal mucosal blood flow in the area of deposition. (au).


    Institute of Scientific and Technical Information of China (English)

    TAO Meng-Fei; REN Tao; LIANG Yong-Jie


    Objective To investigate the effects of antihistamine agents, loratadine and ketotifen, on the model of exercise-induced asthma in guinea pigs with lipopolysaccharide ( LPS) and metyapone. Methods Nineteen guinea pigs were injected peritoneolly with LPS (1mg/kg, i. p. ) and metyapone ( 50mg/kg, i. p. ). Then they were randomized into 3 groups. The control group ( n =7) did not take any drug, ketotifen group ( n =6) adminisd-1 ) for 4 days. On the fifth day, lung resistance (RL) and dynamic compliance of respiratory system (Cdyn) of 3 groups were measured before and after exercise challenge. The total number of leukocytes in bronchoalveolar lavage fluid (BALF) from 3 groups was counted and differentiated cell type count was measured. Morphometric examination of the animal lungs was performed. Results In control group, RLincreased and Cdyn decreased significantly after exercise challenge. In ketotifen group and loratadine group with no change. There was a significant increase in the number of neutrophils, macrophages and eosinophils in BALF from control group. The infiltration of neutrophils in the bronchial mucosa was shown in control group in the morphometric study. Conclusion Loratadine and ketotifen can inhibit the exercise-indaced bronchoconstriction in guinea pigs pretreated with LPS and metyrapone. Inhibiting the formation of inflammation in airway may be the therapeutic mechanism of these H-1 receptor antagonists.

  4. Evidence for homogeneity of thromboxane A2 receptor using structurally different antagonists. (United States)

    Swayne, G T; Maguire, J; Dolan, J; Raval, P; Dane, G; Greener, M; Owen, D A


    Nine structurally dissimilar thromboxane antagonists (SQ 29548, ICI 185282, AH 23848, BM 13505 (Daltroban), BM 13177 (Sulotroban), SK&F 88046, L-636499, L-640035 and a Bayer compound SK&F 47821) were studied for activity as thromboxane A2 receptor antagonists. The assays used were inhibition of responses induced by the thromboxane mimetic, U46619, on human washed platelet aggregation, rabbit platelet aggregation, rabbit aortic strip contraction, anaesthetised guinea-pig bronchoconstriction, and a radio-labelled ligand (125I-PTA-OH) binding assay as a measure of affinity for the human platelet receptor. The results of the present study, with activities spanning at least four orders of magnitude along with statistically significant correlations (at least P less than 0.01), strongly suggests that between assays, antagonists and species a homogenous population of thromboxane A2 receptors exists. This finding is in contrast to those of a close series of 13-azapinane antagonists studied by other workers which have suggested receptor heterogeneity.

  5. Effect of montelukast on platelet activating factor- and tachykinin induced mucus secretion in the rat

    Directory of Open Access Journals (Sweden)

    Groneberg David A


    Full Text Available Abstract Background Platelet activating factor and tachykinins (substance P, neurokinin A, neurokinin B are important mediators contributing to increased airway secretion in the context of different types of respiratory diseases including acute and chronic asthma. Leukotriene receptor antagonists are recommended as add-on therapy for this disease. The cys-leukotriene-1 receptor antagonist montelukast has been used in clinical asthma therapy during the last years. Besides its inhibitory action on bronchoconstriction, only little is known about its effects on airway secretions. Therefore, the aim of this study was to evaluate the effects of montelukast on platelet activating factor- and tachykinin induced tracheal secretory activity. Methods The effects of montelukast on platelet activating factor- and tachykinin induced tracheal secretory activity in the rat were assessed by quantification of secreted 35SO4 labelled mucus macromolecules using the modified Ussing chamber technique. Results Platelet activating factor potently stimulated airway secretion, which was completely inhibited by the platelet activating factor receptor antagonist WEB 2086 and montelukast. In contrast, montelukast had no effect on tachykinin induced tracheal secretory activity. Conclusion Cys-leukotriene-1 receptor antagonism by montelukast reverses the secretagogue properties of platelet activating factor to the same degree as the specific platelet activating factor antagonist WEB 2086 but has no influence on treacheal secretion elicited by tachykinins. These results suggest a role of montelukast in the signal transduction pathway of platelet activating factor induced secretory activity of the airways and may further explain the beneficial properties of cys-leukotriene-1 receptor antagonists.

  6. Respiratory toxicity of repeated exposure to particles produced by traffic and sugar cane burning. (United States)

    Mazzoli-Rocha, Flavia; Carvalho, Giovanna M C; Lanzetti, Manuella; Valença, Samuel S; Silva, Luiz F F; Saldiva, Paulo H N; Zin, Walter A; Faffe, Débora S


    We compared the toxicity of subchronic exposure to equivalent masses of particles from sugar cane burning and traffic. BALB/c mice received 3 intranasal instillations/week during 1, 2 or 4 weeks of either distilled water (C1, C2, C4) or particles (15μg) from traffic (UP1, UP2, UP4) or biomass burning (BP1, BP2, BP4). Lung mechanics, histology and oxidative stress were analyzed 24h after the last instillation. In all instances UP and BP groups presented worse pulmonary elastance, airway and tissue resistance, alveolar collapse, bronchoconstriction and macrophage influx into the lungs than controls. UP4, BP2 and BP4 presented more alveolar collapse than UP1 and BP1, respectively. UP and BP had worse bronchial and alveolar lesion scores than their controls; BP4 had greater bronchial lesion scores than UP4. Catalase was higher in UP4 and BP4 than in C4. In conclusion, biomass particles were more toxic than those from traffic after repeated exposures.

  7. Functional

    Directory of Open Access Journals (Sweden)

    Fedoua Gandia


    Full Text Available The study was carried out to investigate the effects of inhaled Mg alone and associated with F in the treatment of bronchial hyperresponsiveness. 43 male Wistar rats were randomly divided into four groups and exposed to inhaled NaCl 0.9%, MeCh, MgSO4 and MgF2. Pulmonary changes were assessed by means of functional tests and quantitative histological examination of lungs and trachea. Results revealed that delivery of inhaled Mg associated with F led to a significant decrease of total lung resistance better than inhaled Mg alone (p < 0.05. Histological examinations illustrated that inhaled Mg associated with F markedly suppressed muscular hypertrophy (p = 0.034 and bronchoconstriction (p = 0.006 in MeCh treated rats better than inhaled Mg alone. No histological changes were found in the trachea. This study showed that inhaled Mg associated with F attenuated the main principle of the central components of changes in MeCh provoked experimental asthma better than inhaled Mg alone, potentially providing a new therapeutic approach against asthma.

  8. Inhibitory effect of sodium cromoglycate on pulmonary responses to histamine administered after indomethacin in anaesthetized guinea-pigs. (United States)

    Mitchell, H. W.


    1. Histamine (2-4 micrograms kg-1 i.v.) increased airways resistance (Raw) and decreased dynamic lung compliance (Cdyn) in urethane-anaesthetized guinea-pigs. The effects on Raw were almost abolished by atropine (0.1 mg kg-1 i.v.) and reduced by vagal cooling (11-16 degrees C). 2. Histamine-induced changes in Raw and Cdyn were significantly (P less than 0.05) enhanced by indomethacin (1 mg kg-1 i.v.). 3. In animals not treated with indomethacin, exposure to an aerosol containing sodium cromoglycate (0.01-2% for 30 s) failed to affect subsequent (3 min) histamine-induced bronchoconstriction. 4. Administration of an aerosol containing low (0.01-0.2%) concentrations of sodium cromoglycate had no effect on the enhanced responses (i.e. hyperreactivity) seen after indomethacin. However, more concentrated sodium cromoglycate aerosols (greater than 0.2%) reduced or abolished the hyperreactivity to histamine seen after indomethacin. 5. It was concluded that sodium cromoglycate can prevent the development of hyperreactivity to histamine, possibly by interacting with some mechanism utilized by both histamine and indomethacin in this model. PMID:3134970

  9. Airway Responsiveness: Role of Inflammation, Epithelium Damage and Smooth Muscle Tension

    Directory of Open Access Journals (Sweden)

    K. I. Gourgoulianis


    Full Text Available The purpose of this study was the effect of epithelium damage on mechanical responses of airway smooth muscles under different resting tension. We performed acetylcholine (ACh (10-5M-induced contraction on tracheal strips from 30 rabbits in five groups (0.5, 1, 1.5, 2 and 2.5 g before and after epithelium removal. At low resting tension (0.5-1.5g, the epithelium removal decreased the ACh-induced contractions. At 2g resting tension, the epithelium removal increased the ACh-induced contractions of airways with intact epithelium about 20%. At 2.5 g resting tension, the elevation of contraction is about 25% (p<0.01. Consequently, after epithelium loss, the resting tension determines the airway smooth muscles responsiveness. In asthma, mediators such as ACh act on already contracted inflammatory airways, which results in additional increase of contraction. In contrast, low resting tension, a condition that simulates normal tidal breathing, protects from bronchoconstriction even when the epithelium is damaged.

  10. Application of the Virtual Bronchoscopy in Children with Suspected Aspiration of the Foreign Body - Case Report

    Directory of Open Access Journals (Sweden)

    Kostic Gordana


    Full Text Available In diagnosing the aspiration of the foreign body (AFB in children most important are: medical history, clinical signs and positive radiography of the lungs. Common dilemmas in the diff erential diagnosis are life-threatening asthma attacks or difficult pneumonia. Conventional rigid bronchoscopy (RB is not recommended as a routine method. Virtual bronchoscopy (VB can be a diagnostic tool for solving dilemmas. Fiber-optic bronchoscopy (FOB has a therapeutic stake in severe cases. Herein, we describe a girl, at the age of 6, who was hospitalized due to rapid bronchoconstriction and based on the anamnesis, clinical symptoms and physical fi ndings the suspicion was that she aspirated the foreign body. Due to the poor general condition and possible sequel, the idea of RB was dropped out. Multidetector computed tomography of the chest and VB was performed and AFB was not found. Due to positive epidemiological situation, virus H1N1 was excluded. FOB established that the foreign body does not exist in the airways. During bronchoscopy numerous castings are aspirated from the peripheral airways which lead to faster final recovery. With additional procedures, the diagnosis of asthma was confirmed and for girl that was the first attack. Along with inhaled corticosteroids as prevention she feels well.

  11. Persistent and Unusual Respiratory Findings after Prolonged Glutaraldehyde Exposure

    Directory of Open Access Journals (Sweden)

    S Copeland


    Full Text Available Glutaraldehyde is commonly used in endoscopy labs to clean and disinfect instruments. It can cause direct irritation of the skin and the upper and lower airways. Health care workers are also at risk for the development of irritant-induced or sensitizer-induced occupational asthma when exposed to this chemical. Herein, we report on a patient who had frequent exposures to glutaraldehyde over one year while working in an endoscopy lab and developed chronic upper and lower respiratory tract symptoms. Multiple spirometric tests during her evaluation revealed variable results including restrictive pattern with a response to bronchodilators, obstructive pattern with a paradoxic bronchoconstrictive response to bronchodilators, and obstructive pattern with a partial response to bronchodilators. These results indicate that the distribution of inflammation and bronchial responsiveness can vary in a single patient with glutaraldehyde-induced occupational asthma. Therefore, the evaluation may be more difficult than might be expected in patients with occupational asthma, and some patients will need multiple pulmonary function tests to characterize their airway disease.

  12. Regadenoson use in patients with chronic obstructive pulmonary disease: the state of current knowledge

    Directory of Open Access Journals (Sweden)

    Golzar Y


    Full Text Available Yasmeen Golzar,1,2 Rami Doukky1,21Division of Adult Cardiology, John H Stroger Jr, Hospital of Cook County, 2Division of Cardiology, Rush University Medical Center, Chicago, IL, USAAbstract: Stress testing is challenging in patients with chronic obstructive pulmonary disease (COPD. Functional capacity is generally decreased in this patient population, limiting patients' ability to achieve physiologic stress through exercise. Additionally, due to emphysematous changes, COPD patients tend to have poor acoustic windows that impair the quality and therefore diagnostic accuracy of stress echocardiography techniques. Pharmacologic stress myocardial perfusion imaging (MPI testing is also problematic, particularly due to the concern for adenosine-induced bronchoconstriction with conventional vasodilator stress agents. Regadenoson, a selective A2A adenosine receptor agonist, has gained popularity due to its ease of administration and improved patient experience in the general population. The literature describing the experience with regadenoson in COPD patients, though limited, is rapidly growing and reassuring. This review summarizes the pharmacology and clinical application of this novel stress agent and presents the available data on the safety and tolerability of its use in COPD patients.Keywords: chronic obstructive pulmonary disease, COPD, regadenoson, myocardial perfusion imaging, safety, tolerability, asthma, emphysema

  13. Interventional pulmonology for asthma and emphysema: bronchial thermoplasty and bronchoscopic lung volume reduction. (United States)

    Miller, Russell J; Murgu, Septimiu D


    Emphysema and asthma are responsible for economic and social burden. Altering the natural course of these diseases is a field of intense research. The National Emphysema Treatment Trial showed that lung volume reduction surgery (LVRS) could significantly reduce both morbidity and mortality in properly selected patients. LVRS is seldom performed, however, due to the high morbidity associated with the surgery. Numerous bronchoscopic interventions have been introduced with the goal of providing the clinical benefits of LVRS without the surgical complications. Thus far, these modalities have not produced the results once hoped. However, through active modification of both technique and patient selection, the role of minimally invasive modalities in the treatment of emphysema continues to evolve. Bronchial thermoplasty (BT) is a method of delivering controlled heat to airway mucosa with the goal of reducing airway smooth muscle mass and hence bronchoconstriction. In patients suffering from asthma who cannot achieve control with standard medical care, BT has been shown to be safe and improves symptoms, with long lasting benefit. BT does not seem to affect traditional markers of asthma severity such as forced expiratory volume in 1 second and questions remain regarding proper patient selection for this therapy and its true physiologic effects. This article is a review of bronchoscopic modalities for emphysema and asthma.

  14. Ambient particulate matter air pollution and cardiopulmonary diseases. (United States)

    Thurston, George; Lippmann, Morton


    Population exposures to ambient outdoor particulate matter (PM) air pollution have been assessed to represent a major burden on global health. Ambient PM is a diverse class of air pollution, with characteristics and health implications that can vary depending on a host of factors, including a particle's original source of emission or formation. The penetration of inhaled particles into the thorax is dependent on their deposition in the upper respiratory tract during inspiration, which varies with particle size, flow rate and tidal volume, and in vivo airway dimensions. All of these factors can be quite variable from person to person, depending on age, transient illness, cigarette smoke and other short-term toxicant exposures that cause transient bronchoconstriction, and occupational history associated with loss of lung function or cumulative injury. The adverse effects of inhaled PM can result from both short-term (acute) and long-term (chronic) exposures to PM, and can range from relatively minor, such as increased symptoms, to very severe effects, including increased risk of premature mortality and decreased life expectancy from long-term exposure. Control of the most toxic PM components can therefore provide major health benefits, and can help guide the selection of the most human health optimal air quality control and climate change mitigation policy measures. As such, a continued improvement in our understanding of the nature and types of PM that are most dangerous to health, and the mechanism(s) of their respective health effects, is an important public health goal.

  15. T(H)2 cytokines modulate the IL-9R expression on human neutrophils. (United States)

    Dragon, Stéphane; Takhar, Manrit Kaur; Shan, Lianyu; Hayglass, Kent T; Simons, F Estelle; Gounni, Abdelilah S


    Interleukin (IL)-9 is associated with key pathological features of asthma such as airway hyperresponsiveness, bronchoconstriction and mucus production. Inflammatory responses mediated by IL-9 rely on the expression of the IL-9R which has been reported on lung epithelial cells, T lymphocytes and recently on airway granulocyte infiltrates. In this study, we assessed the regulatory and constitutive cell surface expression of the IL-9Ralpha in unfractionated and purified human neutrophils from atopic asthmatics, atopic non-asthmatics and healthy normal controls. We demonstrate that T(H)2 cytokines (IL-4 or IL-13) and granulocyte macrophage-colony stimulating factor (GM-CSF) up-regulated mRNA and cell surface expression levels of the IL-9Ralpha in primary human and HL-60 differentiated neutrophils. Pharmacological inhibition of NF-kappaB did not affect T(H)2-mediated IL-9Ralpha expression in human neutrophils although IFN-gamma and IL-10 down-regulated IL-9Ralpha expression when co-incubated with IL-4, IL-13 or GM-CSF. Collectively, our results reveal a regulatory function for IFN-gamma and IL-10 on modulating the inducible IL-9Ralpha expression levels on peripheral blood neutrophils by T(H)2 cytokines.

  16. Pharmacogenomics of Prostaglandin and Leukotriene Receptors (United States)

    Cornejo-García, José A.; Perkins, James R.; Jurado-Escobar, Raquel; García-Martín, Elena; Agúndez, José A.; Viguera, Enrique; Pérez-Sánchez, Natalia; Blanca-López, Natalia


    Individual genetic background together with environmental effects are thought to be behind many human complex diseases. A number of genetic variants, mainly single nucleotide polymorphisms (SNPs), have been shown to be associated with various pathological and inflammatory conditions, representing potential therapeutic targets. Prostaglandins (PTGs) and leukotrienes (LTs) are eicosanoids derived from arachidonic acid and related polyunsaturated fatty acids that participate in both normal homeostasis and inflammatory conditions. These bioactive lipid mediators are synthesized through two major multistep enzymatic pathways: PTGs by cyclooxygenase and LTs by 5-lipoxygenase. The main physiological effects of PTGs include vasodilation and vascular leakage (PTGE2); mast cell maturation, eosinophil recruitment, and allergic responses (PTGD2); vascular and respiratory smooth muscle contraction (PTGF2), and inhibition of platelet aggregation (PTGI2). LTB4 is mainly involved in neutrophil recruitment, vascular leakage, and epithelial barrier function, whereas cysteinyl LTs (CysLTs) (LTC4, LTD4, and LTE4) induce bronchoconstriction and neutrophil extravasation, and also participate in vascular leakage. PTGs and LTs exert their biological functions by binding to cognate receptors, which belong to the seven transmembrane, G protein-coupled receptor superfamily. SNPs in genes encoding these receptors may influence their functionality and have a role in disease susceptibility and drug treatment response. In this review we summarize SNPs in PTGs and LTs receptors and their relevance in human diseases. We also provide information on gene expression. Finally, we speculate on future directions for this topic. PMID:27708579

  17. Airway responses to sulfate and sulfuric acid aerosols in asthmatics. An exposure-response relationship. (United States)

    Utell, M J; Morrow, P E; Speers, D M; Darling, J; Hyde, R W


    Epidemiologic studies support an association between elevated levels of sulfates and increased symptoms in asthmatics. To determine if these pollutants produce airway responses, 17 asthmatics inhaled the following sulfates: sodium bisulfate, ammonium sulfate, ammonium bisulfate (NH4HSO4), or sulfuric acid (H2SO4) aerosols with an aerodynamic diameter of 0.80 micron at concentrations of 100 micrograms/m3, 450 micrograms/m3, and 1,000 micrograms/m3. A sodium chloride (NaCl) aerosol of similar characteristics, administered by double-blind randomization, served as a control. Subjects breathed these aerosols for a 16-minute period via a mouthpiece. Deposition studies showed 54 to 65% retention of the inhaled aerosols. At the 1,000 micrograms/m3 concentration, the Threshold Limit Value for occupational exposure, H2SO4 and NH4HSO4 inhalation produced significant reductions in specific airway conductance (SGaw) (p less than 0.05) and forced expiratory volume in one second (p less than 0.01) compared with NaCl or pre-exposure values. At the 450 micrograms/m3 concentration, only H2SO4 inhalation produced a significant reduction in SGaw (p less than 0.01). At 100 micrograms/m3, a level 3 to 5 times greater than peak urban levels, no significant change in airway function occurred after any sulfate exposure. These data indicate that asthmatics demonstrate bronchoconstriction after brief exposure to common acidic sulfate pollutants.

  18. Diagnostic values of combination of free running asthma screening test and total serum allergen IgE level in children with asthma

    Institute of Scientific and Technical Information of China (English)

    Chen Xin; Li Yong; Zeng Meiying


    Background A free running asthma screening test is usually used for screening exercise-induced bronchoconstriction.The total serum allergen IgE level can reveal the patient's atopy characteristics.Our study is to evaluate the diagnostic values of the combination of the two tests in asthmatic children and compare this new diagnostic method with the Intemational Study of Asthma and Allergies in Childhood (ISSAC) questionnaires and the bronchial provocation test,which are popular diagnostic tool for pediatric asthma.Methods A total of 773 school children were recruited in this study.The children's asthma was diagnosed by means of a combination of the free running asthma screening test and total serum allergen IgE level.The new diagnostic method value was assessed using receiver operating characteristic (ROC) curves and compared with other diagnostic tools such as ISSAC questionnaires and the bronchial provocation test.Results The AUC of this new diagnostic method was higher than 0.9.When the cut-off value of total serum allergen IgE level was ≥47 KU/L,the sensitivity and the specificity were 71.4% and 85.1%,respectively,which were better than those of either the ISSAC questionnaires or bronchial provocation test.Conclusion The combination of the free running asthma screening test and total serum allergen IgE level may be an effective diagnostic tool for children's asthma.

  19. Differential Gene Expression Profiles and Selected Cytokine Protein Analysis of Mediastinal Lymph Nodes of Horses with Chronic Recurrent Airway Obstruction (RAO Support an Interleukin-17 Immune Response.

    Directory of Open Access Journals (Sweden)

    Alexandra Korn

    Full Text Available Recurrent airway obstruction (RAO is a pulmonary inflammatory condition that afflicts certain mature horses exposed to organic dust particulates in hay. Its clinical and pathological features, manifested by reversible bronchoconstriction, excessive mucus production and airway neutrophilia, resemble the pulmonary alterations that occur in agricultural workers with occupational asthma. The immunological basis of RAO remains uncertain although its chronicity, its localization to a mucosal surface and its domination by a neutrophilic, non-septic inflammatory response, suggest involvement of Interleukin-17 (IL-17. We examined global gene expression profiles in mediastinal (pulmonary-draining lymph nodes isolated from RAO-affected and control horses. Differential expression of > 200 genes, coupled with network analysis, supports an IL-17 response centered about NF-κB. Immunohistochemical analysis of mediastinal lymph node sections demonstrated increased IL-17 staining intensity in diseased horses. This result, along with the finding of increased IL-17 concentrations in lymph node homogenates from RAO-affected horses (P = 0.1 and a down-regulation of IL-4 gene and protein expression, provides additional evidence of the involvement of IL-17 in the chronic stages of RAO. Additional investigations are needed to ascertain the cellular source of IL-17 in this equine model of occupational asthma. Understanding the immunopathogenesis of this disorder likely will enhance the development of therapeutic interventions beneficial to human and animal pulmonary health.

  20. Airways obstruction in asthmatics induced by body cooling. (United States)

    Chen, W Y; Horton, D J


    Pulmonary and thermoregulatory reactions to body cooling were studied in eight asthmatic and five normal subjects. The cooling was achieved by a cold shower at water temperature (T) of 15 degrees C for 1 min, followed by exposing the wet body to a high wind generated by a fan for another minute. The skin T, oral T and pulmonary functions were measured before and after cooling. After the cooling, skin T fell a mean of 7 degrees in all subjects and the oral T fell 0.5 degrees in the normals and 0.7 degrees in the asthmatics. In asthmatics, the post-cooling forced expiratory volume in 1 s (FEV1) and maximal mid-expiratory flow (MMEF) fell significantly (P less than .05) to a mean of 79% and 72%of baseline, respectively, and thoracic gas volume (TGV) and airway resistance (Raw) increased significantly to 133% and 198% of baseline, respectively. In normal subjects a small but significant increase in Raw was found. No obstruction developed in the asthmatics after a warm shower at 37 degrees or after breathing the cold shower mist. It is suggested that it is body cooling which leads first to vasoconstriction and then cooling of respiratory mucosa that initiates bronchoconstriction in asthmatics.


    Directory of Open Access Journals (Sweden)

    José Antonio Cornejo-García


    Full Text Available Individual genetic background together with environmental effects are thought to be behind many human complex diseases. A number of genetic variants, mainly single nucleotide polymorphisms (SNPs, have been shown to be associated with various pathological and inflammatory conditions, representing potential therapeutic targets. Prostaglandins (PTGs and leukotrienes (LTs are eicosanoids derived from arachidonic acid and related polyunsaturated fatty acids that participate in both normal homeostasis and inflammatory conditions. These bioactive lipid mediators are synthesised through two major multistep enzymatic pathways: PTGs by cyclooxygenase and LTs by 5-lipoxygenase. The main physiological effects of PTGs include vasodilation and vascular leakage (PTGE2; mast cell maturation, eosinophil recruitment and allergic responses (PTGD2; vascular and respiratory smooth muscle contraction (PTGF2, and inhibition of platelet aggregation (PTGI2. LTB4 is mainly involved in neutrophil recruitment, vascular leakage, and epithelial barrier function, whereas cysteinyl LTs (CysLTs (LTC4, LTD4 and LTE4 induce bronchoconstriction and neutrophil extravasation, and also participate in vascular leakage. PTGs and LTs exert their biological functions by binding to cognate receptors, which belong to the seven transmembrane, G protein-coupled receptor superfamily. SNPs in genes encoding these receptors may influence their functionality and have a role in disease susceptibility and drug treatment response. In this review we summarize SNPs in PTGs and LTs receptors and their relevance in human diseases. We also provide information on gene expression. Finally, we speculate on future directions for this topic.

  2. Sulfur: its clinical and toxicologic aspects. (United States)

    Komarnisky, Lioudmila A; Christopherson, Robert J; Basu, Tapan K


    Although there is no known dietary requirement for inorganic sulfur, it is an essential element for all animal species in as much as they all require the sulfur-containing amino acid methionine. There are three predominate forms of organic sulfur in animals and humans: 1). the thiomethyl of methionine residues in protein; 2). the sulfhydryl disulfides of protein; and 3). the compounds containing ester or amide bound sulfates of glycosaminoglycans, steroids, and many xenobiotic metabolites. Thus, sulfur becomes an important constituent of amino acids, proteins, enzymes, vitamins and other biomolecules. Unlike mammalian species, plants can use inorganic sulfur and synthesize methionine from which are synthesized all the other important sulfur compounds. Hence, sulfur deficiency occurs mainly when plants are grown in sulfur-depleted soils and when humans and animals consume low-protein diets. In recent times, however, the increasing prevalence of refining petroleum and smelting sulfur compounds of metallic minerals into free metals are having a large impact on the balance of sulfur in the environment. Sulfur toxicity is associated mainly with high levels of the element and its toxic volatile substances in the environment. Sulfur dioxide (SO(2)), a major air pollutant, may adversely affect animal and human health by causing bronchitis, bronchoconstriction, and increased pulmonary resistance.

  3. Rosa canina as an adjunctive treatment of asthma: A hypothesis

    Directory of Open Access Journals (Sweden)

    Samin Hamidi


    Full Text Available Asthma is one of the most common chronic disorders and about 7% of the US population suffers from asthma. Initial response to allergy is associated with mediators like histamine, prostaglandin (PG D2 and leukotriene (LT C4. In asthmatic patients, 5-lipo-oxygenase (5-LO pathway produces more LTC4 than the healthy people. Also, pro-inflammatory factors like interleukin (IL-1, IL-6 and Tumor Necrosis Factor (TNF-α play a remarkable role in bronchoconstriction. The common asthma medications are associated with a number of unwanted side effects, especially throughout long term treatment. Herbal medication is an alternative treatment for asthma and the plants are rich sources of antioxidants that intensively reduce the activity of free radicals. Among several herbs, Rosa canina (RC is a potent anti-inflammatory remedy which contains a number of well-known antioxidants including vitamin C, quercetin, hesperidin, rutin and some other therapeutic compounds. The aim of this study was to review the scientific evidences supporting the probable influence of Rosa canina on asthma. Keywords: Asthma; Rosa canina; Anti-inflammatory

  4. Inhibitory effects of putative peptidic urotensin-II receptor antagonists on urotensin-II-induced contraction of cat isolated respiratory smooth muscle. (United States)

    Behm, David J; Ao, Zhaohui; Camarda, Valeria; Aiyar, Nambi V; Johns, Douglas G; Douglas, Stephen A


    Urotensin-II is purported to influence pulmonary function by modulating smooth muscle tone/growth. In the present study, Northern blot and reverse transcription polymerase chain reaction (RT-PCR) analysis indicated the presence of UT receptor mRNA in cat trachea, bronchi and lung parenchyma. Urotensin-II contracted cat isolated trachea and bronchi with similar potencies (pEC(50)s 8.61+/-0.07-8.81+/-0.10). Contractile efficacies ranged from 19+/-9% to 63+/-11% KCl in the primary and secondary bronchi. The peptidic UT receptor antagonists BIM-23127, SB-710411 and GSK248451 (7.18+/-0.12, 7.52+/-0.08 and 9.05+/-0.16 cat recombinant UT pK(i)s) inhibited urotensin-II-induced contraction of cat isolated trachea with pK(b)s 6.36+/-0.11, 6.74+/-0.07 and 9.27+/-0.12, respectively. As such, feline lung contains significant amounts of UT mRNA and this receptor appears to be functionally coupled to bronchoconstriction (the peptidic tool compound GSK248451 representing a sub-nanomolar inhibitor of such effects). These findings suggest that the cat represents a suitable species for future studies designed to assess the effects of the urotensin-II receptor on pulmonary (patho)physiology.

  5. The role of platelets in the pathophysiology of asthma. (United States)

    Kornerup, K N; Page, C P


    The incidence of asthma is on the increase worldwide, yet the pathogenesis of this disease is still not fully understood. Many recent drug trials have had disappointing results, thus fuelling the need for more research to be undertaken in this area. Substantial evidence suggests an important role for platelets in various inflammatory diseases, including atherosclerosis, rheumatoid arthritis, eczema, allergic rhinitis and asthma. In asthma, platelets have been found to actively participate in most of its main features, including bronchial hyperresponsiveness, bronchoconstriction, airway inflammation and airway remodelling. It has recently become clear that platelet-release products, as well as the expression of adhesion molecules on the platelet surface and the ability to undergo chemotaxis, are all involved in these processes. This review focuses on both experimental and clinical studies available to date that have investigated the role of platelets in the pathophysiology of asthma. Taken together, the evidence points toward platelets being an attractive new target in the area of asthma research; a target with much-needed novel therapeutic potential.

  6. Patient perspectives in the management of asthma: improving patient outcomes through critical selection of treatment options

    Directory of Open Access Journals (Sweden)

    Nicola Scichilone


    Full Text Available Nicola Scichilone, Adele Contino, Giovanni Battista Figlioli, Giuseppe Paglino, Vincenzo BelliaDipartimento di Medicina, Pneumologia, Fisiologia e Nutrizione Umana (DIMPEFINU, University of Palermo, Palermo, ItalyAbstract: Asthma is a chronic inflammatory disorder of the airways that requires long-term treatment, the goal of which is to control clinical symptoms for extended periods with the least possible amount of drugs. International guidelines recommend the addition of an inhaled long-acting beta2-agonist (LABA to a low- to medium-dose inhaled corticosteroid (ICS when low doses of ICS fail to control asthma symptoms. The fixed combined administration of ICS/LABA improves patient compliance, reducing the risk of therapy discontinuation. The relative deposition pattern of the inhaled drug to the target site is the result of a complex interaction between the device used, the aerosol formulation and the patient’s adherence to therapy. Different inhalation devices have been introduced in clinical practice over time. The new hydrofluoroalkane (HFA solution aerosols allow for the particle size to be modified, thus leading to deeper penetration of the medication into the lung. The Modulite® technology allows for the manipulation of inhaled HFA-based solution formulations, such as the fixed beclomethasone/formoterol combination, resulting in a uniform treatment of inflammation and bronchoconstriction. The success of any anti-asthmatic treatment depends on the choice of the correct device and the adherence to therapy.Keywords: asthma, therapy, inhalers, compliance

  7. Comparison of Glucocorticoid (Budesonide) and Antileukotriene (Montelukast) Effect in Patients with Bronchial Asthma Determined with Body Plethysmography (United States)

    Lajqi, Njomza; Ilazi, Ali; Kastrati, Bashkim; Islami, Hilmi


    Objective: Effect of glucocorticoids-budesonide and antileukotriene–montelukast in patients with bronchial asthma and bronchial increased reactivity was studied in this work. Methods: Parameters of the lung function are determined with Body plethysmography. Raw and ITGV were registered and specific resistance (SRaw) was also calculated. Results: Results of this research, in patients with bronchial asthma, indicate that glucocorticoids – budesonide (Pulmicort; 2 × 2 mg inh) has significant action (p< 0.01) on reduction of the specific resistance (SRaw) of airways, applied to the same patients 3 days after administration of montelukast, at home (2 × 10 mg). Three days after administration of the montelukast, antileukotriene medicine, at home, on the fourth day same patients administered a capsule of montelukast, 10 mg dose per os, and significantly (p < 0.05) reduced the increased bronchomotor tonus; and the effect of the control with salbutamol (beta2-adrenergic agonist) is effective in removal of the increased bronchomotor tonus, causing significant decrease of the resistance (Raw), respectively of the specific resistance (SRaw), (p < 0, 01). Conclusion: This suggests that the bronchodilator effect of glucocorticoids is more powerful than of the leukotriene, because glucocorticoids terminate the early stage of chemical mediator release (prostaglandins PgD2, SRS, and leukotriene LTC4, LTD4, LTE4 and Cytokinins also etc.) as powerful bronchoconstriction substances, whilst antileukotriene substances does not have this feature. PMID:26862243

  8. Respirable antisense oligonucleotides: a new drug class for respiratory disease

    Directory of Open Access Journals (Sweden)

    Tanaka Makoto


    Full Text Available Abstract Respirable antisense oligonucleotides (RASONs, which attenuate specific disease-associated mRNAs, represent a new class of respiratory therapeutics with considerable potential. RASONs overcome previous obstacles that have impeded the development of antisense therapeutics targeting diseases in other organ systems. RASONs are delivered directly to the target tissue via inhalation; their uptake seems to be enhanced by cationic properties inherent in pulmonary surfactant, and, because of the markedly different target properties of mRNA and proteins, they can have very long durations of effect compared with traditional drugs targeting the protein of the same gene. RASONs contain chemical modifications that decrease their degradation by cellular nucleases. However, total insensitivity to nucleases is probably not an optimal design criterion for RASONs, because moderate nuclease sensitivity can prevent their systemic delivery, decreasing the potential for systemic toxicity. EPI-2010 is a 21-mer phosphorothioate RASON that attenuates bronchoconstriction, inflammation and surfactant depletion in preclinical models of human asthma, has a duration of effect of seven days, and seems to undergo minimal systemic delivery.

  9. The Quintiles Prize Lecture 2004: The identification of the adenosine A2B receptor as a novel therapeutic target in asthma (United States)

    Holgate, Stephen T


    Adenosine is a powerful bronchoconstrictor of asthmatic, but not normal, airways. In vitro studies on isolated human mast cells and basophils revealed that adenosine and selective analogues augmented inflammatory mediator release from mast cells by stimulating A2 receptors. Pharmacological blockade of mast cell mediator release in vivo also attenuated adenosine-induced bronchoconstriction, as did theophylline, by adenosine A2 receptor antagonism. Further in vitro studies revealed that the asthmatic response to adenosine is likely to be mediated via the A2B subtype which is selectively antagonised by enprofylline. Studies in animal models, especially mice, have shown a close synergistic interaction between adenosine, Th2 and airway remodelling responses. The recent description of A2B receptors on human airway smooth muscle cells that mediate cytokine and chemokine release and induce differentiation of fibroblasts into myofibroblasts strengthens the view that adenosine maybe more than an inflammatory mediator in asthma but also participates in airway wall remodelling in this disease. These data have provided a firm basis for developing adenosine A2B receptor antagonists as a new therapeutic approach to this disease. PMID:15980878

  10. The Quintiles Prize Lecture 2004. The identification of the adenosine A2B receptor as a novel therapeutic target in asthma. (United States)

    Holgate, Stephen T


    Adenosine is a powerful bronchoconstrictor of asthmatic, but not normal, airways. In vitro studies on isolated human mast cells and basophils revealed that adenosine and selective analogues augmented inflammatory mediator release from mast cells by stimulating A(2) receptors. Pharmacological blockade of mast cell mediator release in vivo also attenuated adenosine-induced bronchoconstriction, as did theophylline, by adenosine A(2) receptor antagonism. Further in vitro studies revealed that the asthmatic response to adenosine is likely to be mediated via the A(2B) subtype which is selectively antagonised by enprofylline. Studies in animal models, especially mice, have shown a close synergistic interaction between adenosine, Th2 and airway remodelling responses. The recent description of A(2B) receptors on human airway smooth muscle cells that mediate cytokine and chemokine release and induce differentiation of fibroblasts into myofibroblasts strengthens the view that adenosine maybe more than an inflammatory mediator in asthma but also participates in airway wall remodelling in this disease. These data have provided a firm basis for developing adenosine A(2B) receptor antagonists as a new therapeutic approach to this disease.

  11. Mast cell adenosine receptors function: a focus on the A3 adenosine receptor and inflammation

    Directory of Open Access Journals (Sweden)

    Noam eRudich


    Full Text Available Adenosine is a metabolite, which has long been implicated in a variety of inflammatory processes. Inhaled adenosine provokes bronchoconstriction in asthmatics or chronic obstructive pulmonary disease (COPD patients, but not in non-asthmatics. This hyper responsiveness to adenosine appears to be mediated by mast cell activation. These observations have marked the receptor that mediates the bronchoconstrictor effect of adenosine on mast cells, as an attractive drug candidate. Four subtypes (A1, A2a, A2b and A3 of adenosine receptors have been cloned and shown to display distinct tissue distributions and functions. Animal models have firmly established the ultimate role of the A3 adenosine receptor (A3R in mediating hyper responsiveness to adenosine in mast cells, although the influence of the A2b adenosine receptor was confirmed as well. In contrast, studies of the A3R in humans have been controversial. In this review, we summarize data on the role of different adenosine receptors in mast cell regulation of inflammation and pathology, with a focus on the common and distinct functions of the A3R in rodent and human mast cells. The relevance of mouse studies to the human is discussed.

  12. β2 agonists in athletes. An ergogenic aid? = β2 agonistas en deportistas. ¿Una ayuda ergogénica?

    Directory of Open Access Journals (Sweden)

    Ospina Uribe, Carlos Fernando


    Full Text Available Asthma is a chronic disorder of the airways with bronchial hyperresponsiveness and bronchoconstriction. Exercise can trigger asthma symptoms; this condition is known as exerciseinduced bronchospasm (EIB. Asthma is common in Olympic athletes who therefore use β2 agonists to prevent and treat its episodes. These drugs are preferably supplied by inhalation. In sports, the use of β2 agonists is restricted by anti-doping regulation, arguing that these drugs have the potential to improve physical performance, which can result in a competitive advantage. β2 agonists are prohibited by the WADA (World Anti-Doping Agency, except salbutamol (maximum dose: 1.600 μg over 24 hours and salmeterol. Oral administration of salbutamol can induce ergogenic effects in athletes. It has been documented that when given orally β2 agonists can improve performance in endurance disciplines, increase muscle strength and improve anaerobic power. However, according to scientific evidence, inhaled β2 agonists do not have a relevant performance-enhancing effect in nonasthmatic athletes.

  13. Percutaneous exposure to the nerve agent VX: Efficacy of combined atropine, obidoxime and diazepam treatment. (United States)

    Joosen, Marloes J A; van der Schans, Marcel J; van Helden, Herman P M


    The nerve agent VX is most likely to enter the body via liquid contamination of the skin. After percutaneous exposure, the slow uptake into the blood, and its slow elimination result in toxic levels in plasma for a period of several hours. Consequently, this has implications for the development of toxic signs and for treatment onset. In the present study, clinical signs, toxicokinetics and effects on respiration, electroencephalogram and heart rate were investigated in hairless guinea pigs after percutaneous exposure to 500 microg/kg VX. We found that full inhibition of AChE and partial inhibition of BuChE in blood were accompanied by the onset of clinical signs, reflected by a decline in respiratory minute volume, bronchoconstriction and a decrease in heart rate. Furthermore, we investigated the therapeutic efficacy of a single dose of atropine, obidoxime and diazepam, administered at appearance of first clinical signs, versus that of repetitive dosing of these drugs on the reappearance of signs. A single shot treatment extended the period to detrimental physiological decline and death for several hours, whereas repetitive administration remained effective as long as treatment was continued. In conclusion, percutaneous VX poisoning showed to be effectively treatable when diagnosed on time and when continued over the entire period of time during which VX, in case of ineffective decontamination, penetrates the skin.

  14. Fullerene carbon-70 derivatives dampen anaphylaxis and allergic asthma pathogenesis in mice (United States)

    Norton, Sarah Brooke

    Fullerenes are carbon nanospheres that can be solublized by the addition of polar chemical groups to the carbon cage, forming fullerene derivatives. One specifically derivatized fullerene compound, termed C 70-Tetragylocolate (C70-TGA), has been shown to stabilize mast cell responses in vitro thus we hypothesized it may have an effect on mast cell-driven diseases such as asthma and systemic anaphylaxis. To observe the effects of C70-TGA on systemic anaphylaxis, mice were subjected to a model of passive systemic anaphylaxis. In this model, mice were injected with DNP-specific IgE 16 hours prior to challenge, then treated with C 70-TGA. Immediately prior to DNP challenge, mice were subjected to a second injection of C70-TGA. Following DNP challenge, body temperature was recorded and blood was collected for quantitation of histamine levels. Treatment with C70-TGA significantly reduced body temperature drop associated with systemic anaphylaxis and serum histamine levels. To observe the effects of C70-TGA on chronic features of asthma in vivo, we utilized a heavily MC influenced model of asthma pathogenesis. Mice were sensitized by intraperitoneal (i.p.) injection of ovalbumin (OVA) in saline, challenged intranasally (i.n.) with OVA, and one of two treatment strategies was pursued. In one, C70-TGA was given i.n. throughout disease development. In the other, C70-TGA was given following an initial set of challenges to allow disease to develop prior to treatment; mice were then re-challenged with OVA to assess the effect on established disease. We found that C70-TGA treatment significantly reduced airway inflammation and eosinophilia and dramatically reduced bronchoconstriction in either model. Cytokines IL-4 and IL-5 and serum IgE levels are significantly reduced in C70-TGA treated animals. Interestingly, we also saw an increase in the anti-inflammatory eicosanoid 11, 12-epoxyeicosatreinoic acid (11,12-EET) in the BAL fluid, suggesting the involvement of this mediator in

  15. Chronobiology and chronotherapy of allergic rhinitis and bronchial asthma. (United States)

    Smolensky, Michael H; Lemmer, Bjoern; Reinberg, Alain E


    Study of the chronobiology of allergic rhinitis (AR) and bronchial asthma (BA) and the chronopharmacology and chronotherapy of the medications used in their treatment began five decades ago. AR is an inflammatory disease of the upper airway tissue with hypersensitivity to specific environmental antigens, resulting in further local inflammation, vasomotor changes, and mucus hypersecretion. Symptoms include sneezing, nasal congestion, and runny and itchy nose. Approximately 25% of children and 40% of adults in USA are affected by AR during one or more seasons of the year. The manifestation and severity of AR symptoms exhibit prominent 24-h variation; in most persons they are worse overnight or early in the morning and often comprise nighttime sleep, resulting in poor daytime quality of life, compromised school and work performance, and irritability and moodiness. BA is also an inflammatory medical condition of the lower airways characterized by hypersensitivity to specific environmental antigens, resulting in greater local inflammation as well as bronchoconstriction, vasomotor change, and mucus hypersecretion. In USA an estimated 6.5 million children and 15.7 million adults have BA. The onset and worsening of BA are signaled by chest wheeze and/or croupy cough and difficult and labored breathing. Like AR, BA is primarily a nighttime medical condition. AR is treated with H1-antagonist, decongestant, and anti-inflammatory (glucocorticoid and leukotriene receptor antagonist and modifier) medications. Only H1-antagonist AR medications have been studied for their chronopharmacology and potential chronotherapy. BA is treated with some of the same medications and also theophylline and beta2-agonists. The chronopharmacology and chronotherapy of many classes of BA medications have been explored. This article reviews the rather extensive knowledge of the chronobiology of AR and BA and the chronopharmacology and chronotherapy of the various medications used in their treatment.

  16. ASM-024, a piperazinium compound, promotes the in vitro relaxation of β2-adrenoreceptor desensitized tracheas. (United States)

    Israël-Assayag, Evelyne; Beaulieu, Marie-Josée; Cormier, Yvon


    Inhaled β2-adrenoreceptor agonists are widely used in asthma and chronic obstructive pulmonary disease (COPD) for bronchoconstriction relief. β2-Adrenoreceptor agonists relax airway smooth muscle cells via cyclic adenosine monophosphate (cAMP) mediated pathways. However, prolonged stimulation induces functional desensitization of the β2-adrenoreceptors (β2-AR), potentially leading to reduced clinical efficacy with chronic or prolonged administration. ASM-024, a small synthetic molecule in clinical stage development, has shown activity at the level of nicotinic receptors and possibly at the muscarinic level and presents anti-inflammatory and bronchodilator properties. Aerosolized ASM-024 reduces airway resistance in mice and promotes in-vitro relaxation of tracheal and bronchial preparations from animal and human tissues. ASM-024 increased in vitro relaxation response to maximally effective concentration of short-acting beta-2 agonists in dog and human bronchi. Although the precise mechanisms by which ASM-024 promotes airway smooth muscle (ASM) relaxation remain unclear, we hypothesized that ASM-024 will attenuate and/or abrogate agonist-induced contraction and remain effective despite β2-AR tachyphylaxis. β2-AR tachyphylaxis was induced with salbutamol, salmeterol and formoterol on guinea pig tracheas. The addition of ASM-024 relaxed concentration-dependently intact or β2-AR desensitized tracheal rings precontracted with methacholine. ASM-024 did not induce any elevation of intracellular cAMP in isolated smooth muscle cells; moreover, blockade of the cAMP pathway with an adenylate cyclase inhibitor had no significant effect on ASM-024-induced guinea pig trachea relaxation. Collectively, these findings show that ASM-024 elicits relaxation of β2-AR desensitized tracheal preparations and suggest that ASM-024 mediates smooth muscle relaxation through a different target and signaling pathway than β2-adrenergic receptor agonists. These findings suggest ASM-024

  17. Could the gene coding for human uteroglobin (clara cell 10 kDa protein) be a candidate gene for atopy?

    Energy Technology Data Exchange (ETDEWEB)

    Mukherjee, A.B.; Peri, A.; Miele, L. [SDG, Bethesda, MD (United States)] [and others


    It has been proposed that human immune response to allergens is genetically determined. Most of these allergic responses are directed to environmental proteins and are mediated by immunoglobulin E (IgE). These allergic disorders (eg. allergic asthma) are commonly known as atopy. IgE activates phospholipase A{sub 2} (PLA{sub 2}) which hydrolyzes cell membrane phospholipids generating free fatty acids, such as arachidonic acid (AA). AA is utilized as the substrate for the generation of pro-inflammatory eicosanoids and platelet activating factor (PAF). These agents can cause inflammation as well as bronchoconstriction, hallmarks of asthma. IgE-induced mast cell degranulation and accumulation of basophils and eosinophils in the lung are also characteristic immunological processes commonly found in atopic asthma. Recent investigations suggest that a group I PLA{sub 2} may be associated with the secretory granules of these cells. An inverse relationship between the levels of eicosanoids and hUG has been found in the nasopharyngeal lavage fluid of children with viral infections of the upper respiratory tract, often a precipitating factor in asthma. Results of genetic linkage studies mapped a putative atopy gene in human chromosome 11q{sup 13}, the same region in which we localized the hUG gene. Moreover, a genetic linkage between atopic IgE responses and chromosome 11q{sup 13} has been reported. In addition, hUG is: (i) a potent inhibitor of PLA{sub 2} activity, (ii) a potent antiinflammatory/immunomodulatory and antichemotactic protein and has a hitherto undetermined receptor-mediated activity. Taken together, these findings suggest that a mutation either in the hUG or its receptor genes may manifest symptoms characteristic of atopy. Hence, we raise the question whether hUG is a candidate gene for this disease.

  18. Ginger (Zingiber officinale) as an Analgesic and Ergogenic Aid in Sport: A Systemic Review. (United States)

    Wilson, Patrick B


    Ginger is a popular spice used to treat a variety of maladies, including pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used by athletes to manage and prevent pain; unfortunately, NSAIDs contribute to substantial adverse effects, including gastrointestinal (GI) dysfunction, exercise-induced bronchoconstriction, hyponatremia, impairment of connective tissue remodeling, endurance competition withdrawal, and cardiovascular disease. Ginger, however, may act as a promoter of GI integrity and as a bronchodilator. Given these potentially positive effects of ginger, a systematic review of randomized trials was performed to assess the evidence for ginger as an analgesic and ergogenic aid for exercise training and sport. Among 7 studies examining ginger as an analgesic, the evidence indicates that roughly 2 g·d(-1) of ginger may modestly reduce muscle pain stemming from eccentric resistance exercise and prolonged running, particularly if taken for a minimum of 5 days. Among 9 studies examining ginger as an ergogenic aid, no discernable effects on body composition, metabolic rate, oxygen consumption, isometric force generation, or perceived exertion were observed. Limited data suggest that ginger may accelerate recovery of maximal strength after eccentric resistance exercise and reduce the inflammatory response to cardiorespiratory exercise. Major limitations to the research include the use of untrained individuals, insufficient reporting on adverse events, and no direct comparisons with NSAID ingestion. While ginger taken over 1-2 weeks may reduce pain from eccentric resistance exercise and prolonged running, more research is needed to evaluate its safety and efficacy as an analgesic for a wide range of athletic endeavors.

  19. Airway Responsiveness to Psychological Processes in Asthma and Health

    Directory of Open Access Journals (Sweden)

    Thomas eRitz


    Full Text Available Psychosocial factors have been found to impact airway pathophysiology in respiratory disease with considerable consistency. Influences on airway mechanics have been studied particularly well. The goal of this article is to review the literature on airway responses to psychological stimulation, discuss potential pathways of influence, and present a well-established emotion-induction paradigm to study airway obstruction elicited by unpleasant stimuli. Observational studies have found systematic associations between lung function and daily mood changes. The laboratory –based paradigm of bronchoconstrictive suggestion has been used successfully to elicit airway obstruction in a substantial proportion of asthmatic individuals. Other studies have demonstrated an enhancement of airway responses to standard airway challenges with exercise, allergens, or methacholine. Standardized emotion-induction techniques have consistently shown airway constriction during unpleasant stimulation, with surgery, blood and injury stimuli being particularly powerful. Findings with various forms of stress induction have been more mixed. A number of methodological factors may account for variability across studies, such as choice of measurement technique, temporal association between stimulation and measurement, and the specific quality and intensity of the stimulus material, in particular the extent of implied action-orientation. Research has also begun to elucidate physiological processes associated with psychologically induced airway responses, with vagal excitation and ventilatory influences being the most likely candidate pathways, whereas the role of specific central nervous system pathways and inflammatory processes has been less studied. The technique of emotion-induction using films has the potential to become a standardized challenge paradigm for the further exploration of airway hyperresponsiveness mediated by central nervous system processes.

  20. New insights into the relationship between airway inflammation and asthma. (United States)

    Wardlaw, A J; Brightling, C E; Green, R; Woltmann, G; Bradding, P; Pavord, I D


    Asthma is a condition characterized by variable airflow obstruction, airway hyper-responsiveness (AHR) and airway inflammation which is usually, but not invariably, eosinophilic. Current thoughts on the pathogenesis of asthma are focused on the idea that it is caused by an inappropriate response of the specific immune system to harmless antigens, particularly allergens such as cat dander and house dust mite, that result in Th2-mediated chronic inflammation. However, the relationship between inflammation and asthma is complex, with no good correlation between the severity of inflammation, at least as measured by the number of eosinophils, and the severity of asthma. In addition, there are a number of conditions, such as eosinophilic bronchitis and allergic rhinitis, in which there is a Th2-mediated inflammatory response, but no asthma, as measured by variable airflow obstruction or AHR. Bronchoconstriction can also occur without obvious airway inflammation, and neutrophilic inflammation can in some cases be associated with asthma. When we compared the immunopathology of eosinophilic bronchitis and asthma, the only difference we observed was that, in asthma, the airway smooth muscle (ASM) was infiltrated by mast cells, suggesting that airway obstruction and AHR are due to an ASM mast cell myositis. This observation emphasizes that the features that characterize asthma, as opposed to bronchitis, are due to abnormalities in smooth muscle responsiveness, which could be intrinsic or acquired, and that inflammation is only relevant in that it leads to these abnormalities. It also emphasizes the importance of micro-localization as an organizing principle in physiological responses to airway inflammation. Thus, if inflammation is localized to the epithelium and lamina propria, then the symptoms of bronchitis (cough and mucus hypersecretion) result, and it is only if the ASM is involved -- for reasons that remain to be established -- that asthma occurs.

  1. Change of bronchial hyperresponsiveness in asthmatic children

    Directory of Open Access Journals (Sweden)

    Stojković-Anđelković Anđelka


    Full Text Available Introduction. Bronchial hyperresponsiveness (BHR is a factor in predicting bronchial asthma independently of inflammation markers. Objective. The aims were to determine the frequency and important predictive facts of BHR and the effect of prophylaxis by Global Initiative for Asthma (GINA and National Asthma Education and Prevention Program (NAEPP on BHR in asthmatic children. Methods. BHR in 106 children was evaluated by the bronchoprovocation test with methacholine. Results. The prevalence rate of symptomatic BHR is 18% for crucial point of PC20=4.1±3.03 mg/ml and PD20=3.22±2.59 μmol methacholine. On average asthmatic children express moderate BHR, which persists even two years after administering prophylaxis. After two years bronchial reactivity is significantly smaller, the change of FEV1 is significantly smaller, the velocity of change of slope dose response curve (sDRC is faster and the provocative concentration of methacholine that causes wheezing is 2-3 times lower. A mild sDRC shows milder bronchoconstriction after two years. The fast change of bronchial reactivity in 41% of asthmatic children is contributed to aero-pollution with sulfur dioxide and/ or, possible insufficient and/or inadequate treatment during two years of administering prophylaxis. A simultaneous effect of allergens from home environment and grass and tree pollens and of excessive aero-pollution on children’s airways is important in the onset of symptomatic BHR. After two years of treatment by GINA and NAEPP children do not show asthma symptoms or show mild asthma symptoms, however bronchial sensitivity remains unchanged. Conclusion. Optimal duration of anti-inflammatory treatment in asthmatic children who show moderate bronchial hyperresponsiveness should be longer than two years.

  2. Organophosphorus pesticides decrease M2 muscarinic receptor function in guinea pig airway nerves via indirect mechanisms.

    Directory of Open Access Journals (Sweden)

    Becky J Proskocil

    Full Text Available BACKGROUND: Epidemiological studies link organophosphorus pesticide (OP exposures to asthma, and we have shown that the OPs chlorpyrifos, diazinon and parathion cause airway hyperreactivity in guinea pigs 24 hr after a single subcutaneous injection. OP-induced airway hyperreactivity involves M2 muscarinic receptor dysfunction on airway nerves independent of acetylcholinesterase (AChE inhibition, but how OPs inhibit neuronal M2 receptors in airways is not known. In the central nervous system, OPs interact directly with neurons to alter muscarinic receptor function or expression; therefore, in this study we tested whether the OP parathion or its oxon metabolite, paraoxon, might decrease M2 receptor function on peripheral neurons via similar direct mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: Intravenous administration of paraoxon, but not parathion, caused acute frequency-dependent potentiation of vagally-induced bronchoconstriction and increased electrical field stimulation (EFS-induced contractions in isolated trachea independent of AChE inhibition. However, paraoxon had no effect on vagally-induced bradycardia in intact guinea pigs or EFS-induced contractions in isolated ileum, suggesting mechanisms other than pharmacologic antagonism of M2 receptors. Paraoxon did not alter M2 receptor expression in cultured cells at the mRNA or protein level as determined by quantitative RT-PCR and radio-ligand binding assays, respectively. Additionally, a biotin-labeled fluorophosphonate, which was used as a probe to identify molecular targets phosphorylated by OPs, did not phosphorylate proteins in guinea pig cardiac membranes that were recognized by M2 receptor antibodies. CONCLUSIONS/SIGNIFICANCE: These data indicate that neither direct pharmacologic antagonism nor downregulated expression of M2 receptors contributes to OP inhibition of M2 function in airway nerves, adding to the growing evidence of non-cholinergic mechanisms of OP neurotoxicity.

  3. Airway hyperresponsiveness induced by repeated esophageal infusion of HCl in guinea pigs. (United States)

    Cheng, Yan-Mei; Cao, Ai-Li; Zheng, Jian-Pu; Wang, Hong-Wei; Sun, Yong-Shun; Liu, Chun-Fang; Zhang, Bei-Bei; Wang, Yi; Zhu, Sheng-Liang; Wu, Da-Zheng


    Gastroesophageal reflux is a common disorder closely related to chronic airway diseases, such as chronic cough, asthma, chronic bronchitis, and chronic obstructive disease. Indeed, gastroesophageal acid reflux into the respiratory tract causes bronchoconstriction, but the underlying mechanisms have still not been clarified. This study aimed to elucidate functional changes of bronchial smooth muscles (BSMs) isolated from guinea pigs in an animal model of gastroesophageal reflux. The marked airway inflammation, hyperresponsiveness and remodeling were observed after guinea pigs were exposed to intraesophageal HCl infusion for 14 days. In addition, contractile responses to acetylcholine (ACh), KCl, electrical field stimulation, and extracellular Ca(2+) were greater in guinea pigs infused with HCl compared with control groups. The L-type voltage-dependent Ca(2+) channels (L-VDCC) blocker, nicardipine, significantly inhibited ACh- and Ca(2+)-enhanced BSM contractions in guinea pigs infused with HCl. The Rho-kinase inhibitor, Y27632, attenuated ACh-enhanced BSM contractions in guinea pigs infused with HCl. Moreover, mRNA and protein expressions for muscarinic M2 and M3 receptors, RhoA, and L-VDCC in BSM were detected by real-time PCR and Western blot. Expressions of mRNA and protein for muscarinic M3 receptors, RhoA, and L-VDCC were greater than in BSM of HCl-infused guinea pigs, whereas levels of muscarinic M2 receptors were unchanged. We demonstrate that acid infusion to the lower esophagus and, subsequently, microaspiration into the respiratory tract in guinea pigs leads to airway hyperresponsiveness and overactive BSM. Functional and molecular results indicate that overactive BSM is the reason for enhancement of extracellular Ca(2+) influx via L-VDCC and Ca(2+) sensitization through Rho-kinase signaling.

  4. Detrimental effects of albuterol on airway responsiveness requires airway inflammation and is independent of β-receptor affinity in murine models of asthma

    Directory of Open Access Journals (Sweden)

    Aimi Steven


    Full Text Available Abstract Background Inhaled short acting β2-agonists (SABA, e.g. albuterol, are used for quick reversal of bronchoconstriction in asthmatics. While SABA are not recommended for maintenance therapy, it is not uncommon to find patients who frequently use SABA over a long period of time and there is a suspicion that long term exposure to SABA could be detrimental to lung function. To test this hypothesis we studied the effect of long-term inhaled albuterol stereoisomers on immediate allergic response (IAR and airway hyperresponsiveness (AHR in mouse models of asthma. Methods Balb/C mice were sensitized and challenged with ovalbumin (OVA and then we studied the IAR to inhaled allergen and the AHR to inhaled methacholine. The mice were pretreated with nebulizations of either racemic (RS-albuterol or the single isomers (S- and (R-albuterol twice daily over 7 days prior to harvest. Results We found that all forms of albuterol produced a significant increase of IAR measured as respiratory elastance. Similarly, we found that AHR was elevated by albuterol. At the same time a mouse strain that is intrinsically hyperresponsive (A/J mouse was not affected by the albuterol isomers nor was AHR induced by epithelial disruption with Poly-L-lysine affected by albuterol. Conclusions We conclude that long term inhalation treatment with either isomer of albuterol is capable of precipitating IAR and AHR in allergically inflamed airways but not in intrinsically hyperresponsive mice or immunologically naïve mice. Because (S-albuterol, which lacks affinity for the β2-receptor, did not differ from (R-albuterol, we speculate that isomer-independent properties of the albuterol molecule, other than β2-agonism, are responsible for the effect on AHR.

  5. Critical analysis of studies concerning reports of respiratory sensitization to certain wood dusts. (United States)

    Williams, P Brock


    Studies have been published reporting that exposures to certain wood dusts are sensitizing, resulting in respiratory symptoms in susceptible individuals. Many of the publications in this field are case reports that collectively have a number of important shortcomings. Illuminating these should further our understanding of whether respiratory sensitization results from occupational exposure to particular wood dusts. The aim of this study was to critically review and understand the evidence to date regarding reported respiratory sensitization in connection with wood dusts from oak, beech, pine, ash, and western red cedar. Publications dealing with these commercially important woods in North America have been selected from the Pubmed/Medline database (1966 to the present) using the key word, wood dust. These articles, along with supporting references on procedures and techniques, are reviewed according to the strengths and weaknesses of evidence and conclusions presented. Evidence from skin testing, specific immunoglobulin E measurements, and basophil histamine release tests suggests that reported symptoms are not likely to be immunologically derived. Because of methodological problems, challenge tests with specific wood dusts do not support the conclusion that reactions to certain wood dusts are specific. Experiments with nonspecific bronchoconstrictive agents indicate that a number of study subjects possess hyperresponsive airways. Thus, select individuals can demonstrate various respiratory symptoms in the woodworking industry, but any specificity or direct cause is currently unproved. Current studies do not support that exposure to wood dusts from a number of common North American wood species causes immunologic sensitization in woodworkers. Rather, symptoms reported in some studies of exposed workers seem to follow the paradigm for nonspecific respiratory responses in individuals with hyperresponsive airways.

  6. The effects of aminophylline infusion in the treatment of children with acute asthma exacerbation. Evaluation with {sup 81m}Kr ventilation scintigraphy

    Energy Technology Data Exchange (ETDEWEB)

    Matsubara, Yasuko; Shimada, Takao [Jikei Univ., Tokyo (Japan). School of Medicine


    The use of intravenous aminophylline in the treatment of children with acute asthma remains controversial. Most authors suggest that aminophylline be used with caution because of its poor efficacy with adverse reactions and instead recommend other drugs, such as {beta}{sub 2}-adrenergic agonists and glucocorticoids. However other studies have reported the benefits of aminophylline, and current Japanese guidelines for the management of asthma recommend its use. Here, we have evaluated the efficacy of aminophylline infusion in children with acute asthma exacerbations. Twenty children with acute asthma exacerbations were given an infusion of 5 mg/kg of aminophylline over 5 minutes, 30 minutes after the same volume of normal saline had been infused as a control. {sup 81m}Kr ventilation scintigraphy was done sequentially, and lung function was measured with spirometry before and after each infusion. Side effects were also evaluated with a questionnaire. Ventilation images obtained with {sup 81m}Kr scintigraphy, which initially showed widespread ventilatory defects caused by bronchoconstriction, decreased 54.9% after aminophylline infusion (p<0.0001). Ventilatory defects, caused by both central and peripheral airway disturbances and confirmed with the {sup 81m}Kr bolus inhalation procedure, also showed significant improvement (p<0.0001). These improvement were accompanied by improvements in lung function as assessed with forced expiratory volume in 1 second (p<0.01) and maximum expiratory flow rates at 25% (p<0.001) and 50% (p<0.001). No serious adverse reactions were recognized in any subjects. Our results show that aminophylline is a useful bronchodilator which decreased ventilatory imbalance and improves lung function in both central and peripheral airways. (author)

  7. RSD931, a novel anti-tussive agent acting on airway sensory nerves. (United States)

    Adcock, J J; Douglas, G J; Garabette, M; Gascoigne, M; Beatch, G; Walker, M; Page, C P


    1 The anti-tussive effects, of the local anaesthetic, lidocaine and carcainium chloride (RSD931) have been investigated in guinea-pigs and rabbits. 2 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% (Plidocaine 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% (PLidocaine 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 (PLidocaine at 10.0 mg ml(-1) also significantly (P0.05) 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 (PLidocaine also significantly (Pactions of RSD931 are mediated via inhibition of discharges in Adelta-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.

  8. Technetium-99m DTPA inhalation scintigraphy in patients treated with fluoxetine and maprotiline: preliminary results

    Energy Technology Data Exchange (ETDEWEB)

    Kaya, G.C.; Durak, H.; Oezdogan, Oe.; Sayit, E.; Degirmenci, B.; Derebek, E. [Dokuz Eyluel Univ., Izmir (Turkey). School of Medicine; Yemez, B.; Turhal, Ue. [Dept. of Psychiatry, Dokuz Eylul Univ. School of Medicine, Izmir (Turkey)


    Drug-metabolising enzymatic activities have been detected in tracheobronchiolar, bronchiolar and alveolar regions in the lungs. Induction of phospholipidosis by amine drugs such as clorphentermine has also been shown. This study aimed to investigate the effect of fluoxetine and maprotiline, which contain amine groups in their structure, on pulmonary epithelial membrane permeability. Twenty-seven patients (mean age 36{+-}12 years) with various psychiatric problems, of whom 17 were treated with fluoxetine and 10 with maprotiline, were included in this study. Technetium-99m diethylene triamine penta-acetic acid (DTPA) aerosol inhalation scintigraphy was performed before and after 4-6 weeks of therapy. Following the inhalation of 1480 MBq {sup 99m}Tc-DTPA for 3 min, lung images in a 64 x 64 matrix were obtained every minute for 30 min. Regions of interest were drawn around the periphery of the lungs and on the major airways. Clearance half-times (T{sub 1/2}) were calculated by placing a mono-exponential fit on the curves. Penetration index (PI) was calculated on the first-minute image. There was no difference between the clearance rates of {sup 99m}Tc-DTPA before and after therapy for either the fluoxetine or the maprotiline group. After therapy, a significant decrease in PI was found in patients treated with fluoxetine (PI values before and after therapy: 0.53{+-}0.03 and 0.49{+-}0.05 respectively, P{<=}0.05). This finding might have been due to the induction of increased synaptic serotonin (5-HT) by fluoxetine, which acts by inhibiting the re-uptake of 5-HT on presynaptic membranes. Bronchoconstriction of small and medium airways may be caused by direct and indirect effects of 5-HT on smooth muscle contraction. (orig.)

  9. The role of ozone exposure in the epidemiology of asthma

    Energy Technology Data Exchange (ETDEWEB)

    Balmes, J.R. [Univ. of California, San Francisco, CA (United States)


    Asthma is a clinical condition characterized by intermittent respiratory symptoms, nonspecific airway hyperresponsiveness, and reversible airway obstruction. Although the pathogenesis of asthma is incompletely understood, it is clear that airway inflammation is a paramount feature of the condition. Because inhalation of ozone by normal, healthy subjects causes increased airway responsiveness and inflammation, it is somewhat surprising that most controlled human exposure studies that have involved asthmatic subjects have not shown them to be especially sensitive to ozone. The acute decrement in lung function that is the end point traditionally used to define sensitivity to ozone in these studies may be due more to neuromuscular mechanisms limiting deep inspiration than to bronchoconstriction. The frequency of asthma attacks following ozone exposures may be a more relevant end point. Epidemiologic studies, rather than controlled human exposure studies, are required to determine whether ozone pollution increases the risk of asthma exacerbations. Asthma affects approximately 10 million people in the United States and, thus, the answer to this question is of considerable public health importance. Both the prevalence and severity of asthma appear to be increasing in many countries. Although increased asthma morbidity and mortality are probably of multifactorial etiology, a contributory role of urban air pollution is plausible. The epidemiologic database to support an association between asthma and ozone exposure is limited, but the results of several studies suggest such an association. Some potential approaches to further investigation of the relationship between asthma and ozone, including those that would link controlled human exposures to population-based studies, are considered. 57 refs.

  10. Associations between criteria air pollutants and asthma

    Energy Technology Data Exchange (ETDEWEB)

    Koren, H.S. [Environmental Protection Agency, Chapel Hill, NC (United States)


    The evidence that asthma is increasing in prevalence is becoming increasingly compelling. This trend has been demonstrated in the United States, the United Kingdom, New Zealand, Australia, and several other Western countries. In the US, the increase is largest in the group under 18 years of age. There is mounting evidence that certain environmental air pollutants are involved in exacerbating asthma. This is based primarily on epidemiologic studies and more recent clinical studies. The U.S. Clean Air Act of 1970 provides special consideration to the class of outdoor air pollutants referred to as criteria pollutants, including O{sub 3}, sulfur dioxide (SO{sub 2}), particulate matter (PM), NO{sub x}, CO, and Pb. Standards for these pollutants are set by the US EPA with particular concern for populations at risk. Current evidence suggests that asthmatics are more sensitive to the effects of O{sub 3}, SO{sub 2} PM, and NO{sub 2}, and are therefore at risk. High SO{sub 2} and particulate concentrations have been associated with short-term increases in morbidity and mortality in the general population during dramatic air pollution episodes in the past. Controlled exposure studies have clearly shown that asthmatics are sensitive to low levels of SO{sub 2}. Exercising asthmatics exposed to SO{sub 2} develop bronchoconstriction within minutes, even at levels of 0.25 ppm. Responses are modified by air temperature, humidity, and exercise level. Recent epidemiologic studies have suggested that exposure to Pm is strongly associated with morbidity and mortality in the general population and that hospital admissions for bronchitis and asthma were associated with PM{sub 10} levels. In controlled clinical studies, asthmatics appear to be no more reactive to aerosols than healthy subjects. Consequently, it is difficult to attribute the increased mortality observed in epidemiologic studies to specific effects demonstrated in controlled human studies. 106 refs., 1 fig., 1 tab.

  11. Budesonide/formoterol and formoterol provide similar rapid relief in patients with acute asthma showing refractoriness to salbutamol

    Directory of Open Access Journals (Sweden)

    Lombardi DM


    Full Text Available Abstract Background To compare the efficacy and safety of budesonide/formoterol (Symbicort® with formoterol (Oxis® in the treatment of patients with acute asthma who showed evidence of refractoriness to short-acting β2-agonist therapy. Methods In a 3 hour, randomized, double-blind study, a total of 115 patients with acute asthma (mean FEV1 40% of predicted normal and a refractory response to salbutamol (mean reversibility 2% of predicted normal after inhalation of 400 μg, were randomized to receive either budesonide/formoterol (320/9 μg, 2 inhalations at t = -5 minutes and 2 inhalations at 0 minutes [total dose 1280/36 μg] or formoterol (9 μg, 2 inhalations at t = -5 minutes and 2 inhalations at 0 minutes [total dose 36 μg]. The primary efficacy variable was the average FEV1 from the first intake of study medication to the measurement at 90 minutes. Secondary endpoints included changes in FEV1 at other timepoints and change in respiratory rate at 180 minutes. Treatment success, treatment failure and patient assessment of the effectiveness of the study medication were also measured. Results FEV1 increased after administration of the study medication in both treatment groups. No statistically significant difference between the treatment groups was apparent for the primary outcome variable, or for any of the other efficacy endpoints. There were no statistically significant between-group differences for treatment success, treatment failure or patient assessment of medication effectiveness. Both treatments were well tolerated. Conclusion Budesonide/formoterol and formoterol provided similarly rapid relief of acute bronchoconstriction in patients with asthma who showed evidence of refractoriness to a short-acting β2-agonist.

  12. Effect of lignocaine, sodium cromoglycate, and ipratropium bromide in exercise-induced asthma (United States)

    Tullett, WM; Patel, KR; Berkin, KE; Kerr, JW


    Eight patients with exercise-induced asthma participated in a single-blind trial comparing the protective effects of inhaled lignocaine (estimated dose 48 mg), sodium cromoglycate (estimated dose 12 mg), and ipratropium bromide (estimated dose 120 μg). Saline was used as control. Effects were assessed from the mean maximal percentage fall in forced expiratory volume in one second (FEV1) and maximal mid-expiratory flow rates (MMFR) after they had run on a treadmill for eight minutes. There was no significant change in baseline FEV1 or MMFR before each agent was given. Saline, lignocaine, and sodium cromoglycate did not alter the mean baseline FEV1 or MMFR significantly. Ipratropium caused bronchodilatation with an increase of 16·3% in the mean FEV1 (p<0·001) and of 43·4% in the mean MMFR (p<0·05). After exercise the maximal percentage falls in FEV1 (means and SEM) after saline, lignocaine, sodium cromoglycate, and ipratropium bromide were 38·1% (5·0), 34·5% (6·1), 11·3% (3·7), and 19·3% (7·4) respectively. Similarly, the mean maximal falls in MMFR after saline, lignocaine, sodium cromoglycate, and ipratropium bromide were 54·4% (5·2), 52·9% (7·7), 23·6% (6·6), and 32·1% (10·5) respectively. The inhibitory effects of sodium cromoglycate and ipratropium bromide were significant whereas lignocaine failed to produce an effect. These results suggest that mediator release is an important factor in exercise-induced asthma and that in some patients the effects of the mediators may be on the postsynaptic muscarinic receptors. Local anaesthesia of sensory vagal receptors, on the other hand, does not prevent exercise asthma and these receptors do not appear to have any important role in exercise-induced bronchoconstriction. PMID:6218645

  13. Antigen-induced bronchial anaphylaxis in actively sensitized guinea-pigs: effect of long-term treatment with sodium cromoglycate and aminophylline. (United States)

    Andersson, P.; Bergstrand, H.


    1 The effects of long-term treatment with sodium cromoglycate (SCG) and aminophylline on antigen-induced bronchoconstriction have been studied in guinea-pigs actively sensitized according to two different regimens (one producing IgE- and IgG-like antibodies and the other producing exclusively IgG-like antibodies). 2 Treatment for three weeks with SCG (10 mg/kg) and aminophylline (10, 30 or 60 mg/kg) led to a decreased bronchial response capacity which persisted even three days after treatment ceased. In this respect SCG was effective only in guinea-pigs sensitized to produce at least partly IgE-like antibodies; aminophylline was effective in guinea-pigs sensitized to produce both IgE and/or IgG antibodies. 3 The results in vivo with SCG were reflected in vitro by a reduced capacity of chopped lung tissue to release histamine at antigen challenge; lungs from animals treated with aminophylline did not show reduced histamine releasing capacity. 4 Acute treatment with atropine was shown to reduce significantly the antigen-induced bronchial contraction in guinea-pigs sensitized to produce both IgE- and IgG-antibodies. No effect of atropine was seen on an IgG-mediated anaphylaxis. 5 Increased reactivity to methacholine but not to histamine was seen in guinea-pigs sensitized to produce both IgG- and IgE-antibodies. Long-term treatment with SCG did not affect this hyperreactivity to methacholine. 6 Decreased reactivity to isoprenaline was found in isolated tracheae taken from guinea-pigs sensitized to produce both IgE- and IgG-like antibodies compared to unsensitized guinea-pigs. Long-term treatment with SCG, but not with aminophylline, reversed this decreased reactivity. PMID:6170376

  14. Involvement of glutamate in transmission of afferent constrictive inputs from the airways to the nucleus tractus solitarius in ferrets. (United States)

    Haxhiu, M A; Yamamoto, B; Dreshaj, I A; Bedol, D; Ferguson, D G


    In this study, we identified the neurons within nucleus tractus solitarius (nTS) activated by stimulation of airway sensory systems and examined the expression of AMPA receptor subtype(s) by these cells. We also investigated the possible involvement of endogenously released glutamate and AMPA receptors in the transmission of excitatory inputs from the sensory system of the respiratory tract to the neurons of the nTS. In these experiments we used: (1) immunodetection of c-fos encoded protein (cFos) expression to identify the nTS neurons activated by the stimulation of the airway sensory system; (2) receptor immunochemistry and confocal microscopy to determine the receptor(s) expressed by activated nTS neurons; (3) microdialysis to measure glutamate release, and (4) physiological measurements to examine the effects of selective receptor blockers, and thereby define the role of the glutamate and AMPA glutamatergic receptor subtype(s) in reflexly induced airway constriction. The results showed that activation of airway sensory receptors, by inhalation of aerosolized histamine or capsaicin, induced cFos expression in a subset of nTS neurons that also expressed the AMPA subtype of glutamate receptors. Furthermore, activation of sensory bronchoconstrictive receptors induced glutamate release within nTS, and blockade of the AMPA receptor subtype within nTS inhibited reflexly increased cholinergic outflow to the airways. These data indicate for the first time that glutamate and AMPA receptor signaling pathways are involved in the transmission of afferent inputs from the airways to the nTS, and in mediating reflex airway constriction.

  15. A multi-scale approach to airway hyperresponsiveness: from molecule to organ

    Directory of Open Access Journals (Sweden)

    Anne-Marie eLauzon


    Full Text Available Airway hyperresponsiveness (AHR, a characteristic of asthma that involves an excessive reduction in airway caliber, is a complex mechanism reflecting multiple processes that manifest over a large range of length and time scales. At one extreme, molecular interactions determine the force generated by airway smooth muscle (ASM. At the other, the spatially distributed constriction of the branching airways leads to breathing difficulties. Similarly, asthma therapies act at the molecular scale while clinical outcomes are determined by lung function. These extremes are linked by events operating over intermediate scales of length and time. Thus, AHR is an emergent phenomenon that limits our understanding of asthma and confounds the interpretation of studies that address physiological mechanisms over a limited range of scales. A solution is a modular computational model that integrates experimental and mathematical data from multiple scales. This includes, at the molecular scale, kinetics and force production of actin-myosin contractile proteins during cross-bridge and latch-state cycling; at the cellular scale, Ca2+ signaling mechanisms that regulate ASM force production; at the tissue scale, forces acting between contracting ASM and opposing viscoelastic tissue that determine airway narrowing; at the organ scale, the topographic distribution of ASM contraction dynamics that determine mechanical impedance of the lung. At each scale, models are constructed with iterations between theory and experimentation to identify the parameters that link adjacent scales. This modular model establishes algorithms for modeling over a wide range of scales and provides a frame-work for the inclusion of other responses such as inflammation or therapeutic regimes. The goal is to develop this lung model so that it can make predictions about bronchoconstriction and identify the pathophysiologic mechanisms having the greatest impact on AHR and its therapy.

  16. Flowmetric comparison of respiratory inductance plethysmography and pneumotachography in horses. (United States)

    Hoffman, A; Kuehn, H; Riedelberger, K; Kupcinskas, R; Miskovic, M B


    Respiratory inductance plethysmographic (RIP) and pneumotachographic (Pn) flows were compared dynamically in horses with bronchoconstriction. On a breath-by-breath basis, RIP was normalized to inspiratory volume from Pn, and peak [peak of subtracted final exhalation waveform (SFE(max))] and selected area [integral of subtracted final waveform during first 25% of exhaled volume (SFE(int))] differences between RIP and Pn flows during early expiration were measured in three settings: 1) healthy horses (n = 8) undergoing histamine bronchoprovocation; 2) horses with naturally occurring lower airway obstruction (AO) (n = 7); and 3) healthy horses (n = 6) given lobeline. HCl to induce hyperpnea. In setting 1, histamine challenge induced a dose-dependent increase in SFE(max) and SFE(int) differences. A test index of airway reactivity (interpolated histamine dose that increased SFE(max) by 35%) closely correlated (r(s) = 0.93, P = 0.001) with a conventional index (histamine dose that induced a 35% decrease in dynamic compliance). In setting 2, in horses with AO, SFE(max) and SFE(int) were markedly elevated, and their absolute values correlated significantly (P < 0.005) with pulmonary resistance and the maximum change in transpulmonary pressure. The effects of bronchodilator treatment on the SFE(max) and SFE(int) were also highly significant (P < 0.0001). In setting 3, hyperpnea, but not tachypnea, caused significant (P < 0.01) increases in SFE(max) but not in SFE(int). In conclusion, dynamic comparisons between RIP and Pn provide a defensible method for quantifying AO during tidal breathing, without the need for invasive instrumentation.

  17. The potential role of omega-3 fatty acids supplements in increasing athletic performance

    Directory of Open Access Journals (Sweden)

    Șerban GLIGOR


    Full Text Available Polyunsaturated omega-3 and omega-6 fatty acids are essential fatty acids that cannot be produced by the body itself and therefore must be provided through nutrition. Omega-6 and particularly omega-3 fatty acids have important roles in the organism, contributing to the maintenance and promotion of health. The optimal proportion of omega-6/omega-3 fatty acids is 2:1, or even better 1:1. They are involved in normal growth and development, play a role in the prevention of coronary and cardiovascular diseases, of diabetes mellitus, of arterial hypertension, arthritis and cancer. Omega-3 fatty acids mainly have an anti-inflammatory effect, but also act as hypolipidemic and antithrombotic agents. A potential role of omega-3 fatty acids is that of increasing physical performance. Their role in the physical activity refers on one side to the global health of athletes and on the other side to their anti-inflammatory effect, as high intensity physical exercise induces increased free-radical production and microtraumas, with the induction of an inflammatory status. The anti-inflammatory effect of these fatty acids manifests through an increased production of endogenous antioxidant enzymes, through decreasing the production of prostaglandins metabolites, decreasing the production of leukotriene B4, etc. They are also effective on reducing muscle pain post eccentric exercise and on decreasing the severity of bronchoconstriction induced by exercise, as well as improving pulmonary function variables. In conclusion it seems that supplementing diets with omega-3 fatty acids, apart from having benefic effects on health and on the prevention and management of certain affections, proves to be a beneficial for physical activity and athletic performance.

  18. Termoplastia brônquica: relato do primeiro tratamento endoscópico de asma na América Latina Bronchial thermoplasty: report on the first endoscopic treatment for asthma in Latin America

    Directory of Open Access Journals (Sweden)

    Adalberto Sperb Rubin


    Full Text Available A termoplastia brônquica é um novo procedimento broncoscópico que libera energia por radiofreqüência nas vias aéreas, com potencial redução da broncoconstrição causada pela contratura da musculatura lisa. Relatamos o caso de um homem de 48 anos, portador de asma persistente moderada, submetido à termoplastia brônquica. O tratamento aumentou o volume expiratório forçado no primeiro segundo, aumentou o número de dias livres de sintomas, reduziu o uso da medicação de resgate e melhorou o escore no questionário de Juniper Asthma Quality of Life Scale. A termoplastia brônquica foi bem tolerada e segura. Esta foi a primeira termoplastia brônquica na América Latina, com resultados estimulantes após 12 meses quanto ao seu potencial benefício em asmáticos pouco controlados.Bronchial thermoplasty is a new bronchoscopic procedure that delivers radiofrequency energy to the airway and potentially reduces the smooth muscle-mediated bronchoconstriction. We report the case of a 48-year-old man with persistent moderate asthma submitted to bronchial thermoplasty. The treatment increased the forced expiratory volume in one second, increased the number of symptom-free days, reduced the use of relief medications, and improved the Juniper Asthma Quality of Life Scale score. In this patient, bronchial thermoplasty was well tolerated and safe. This was the first bronchial thermoplasty performed in Latin America. At 12 months after the procedure, the results were encouraging in terms of its potential benefits in patients with difficult-to-control asthma.

  19. Bioequivalence of two formulations of montelukast sodium 4 mg oral granules in healthy adults. (United States)

    Fey, Constanze; Thyroff-Friesinger, Ursula; Jones, Spencer


    Montelukast is an effective and well-tolerated treatment for the prophylaxis and chronic treatment of asthma, acute prevention of exercise-induced bronchoconstriction and symptomatic relief of seasonal allergic rhinitis and perennial allergic rhinitis. The aim of the study was to compare bioavailability, and characterise the pharmacokinetic profile and safety of Sandoz generic montelukast 4 mg oral granules relative to Singulair(®) mini (Merck, Sharp & Dohme). An open-label, randomised, single-dose, two-treatment, two-period, two-sequence, two-way crossover bioequivalence study was conducted in healthy male volunteers aged 18-55 years, under fasting conditions. The duration of the clinical part of the trial was ≈ 11 days. Montelukast levels in plasma were quantified using a validated liquid chromatography tandem mass spectrometry method, and pharmacokinetic parameters calculated from the drug concentration-time profile using a non-compartmental model. A total of 40 subjects completed both study periods. The ratio test/reference of geometric least squares means was calculated for both formulations of montelukast for the In-transformed pharmacokinetic parameters; the 90% confidence intervals (CIs) were within the pre-defined limits of 80.00-125.00%: 92.2% (90% CI: 87.42-97.30%) for Cmax, 98.1% (90% CI: 94.49-101.81%) for AUC0-t and 97.6% (90% CI: 94.14-101.27%) for AUC0-∞. Two study subjects each reported one mild adverse event: dyspepsia (possibly related to study medication) and throat pain (not considered related to study medication). Sandoz montelukast 4 mg oral granules are bioequivalent to Singulair(®) 4 mg mini oral granules, with a similar safety profile. This suggests that these two preparations can be considered interchangeable in clinical practice.

  20. Antagonist profile of ibodutant at the tachykinin NK2 receptor in guinea pig isolated bronchi. (United States)

    Santicioli, Paolo; Meini, Stefania; Giuliani, Sandro; Lecci, Alessandro; Maggi, Carlo Alberto


    In this study we have characterized the pharmacological profile of the non-peptide tachykinin NK2 receptor antagonist ibodutant (MEN15596) in guinea pig isolated main bronchi contractility. The antagonist potency of ibodutant was evaluated using the selective NK2 receptor agonist [βAla(8)]NKA(4-10)-mediated contractions of guinea pig isolated main bronchi. In this assay ibodutant (30, 100 and 300nM) induced a concentration-dependent rightward shift of the [βAla(8)]NKA(4-10) concentration-response curves without affecting the maximal contractile effect. The analysis of the results yielded a Schild-plot linear regression with a slope not different from unity (0.95, 95% c.l. 0.65-1.25), thus indicating a surmountable behaviour. The calculated apparent antagonist potency as pKB value was 8.31±0.05. Ibodutant (0.3-100nM), produced a concentration-dependent inhibition of the nonadrenergic-noncholinergic (NANC) contractile response induced by electrical field stimulation (EFS) of intrinsic airway nerves in guinea pig isolated main bronchi. At the highest concentration tested (100nM) ibodutant almost abolished the EFS-induced bronchoconstriction (95±4% inhibition), the calculated IC50 value was 2.98nM (95% c.l. 1.73-5.16nM). In bronchi from ovalbumin (OVA) sensitized guinea pigs ibodutant (100nM) did not affect the maximal contractile response to OVA, but completely prevented the slowing in the fading of the motor response induced by phosphoramidon pretreatment linked to the endogenous neurokinin A release. Altogether, the present study demonstrate that ibodutant is a potent NK2 receptor antagonist in guinea pig airways.

  1. Effects of Sodium Cromoglycate on Iranian Asthmatic Subjects Without Exposure to any Bronchoconstrictor agent. (United States)

    Mombeini, Tajmah; Zahedpoure-Anaraki, Mohammad Reza; Dehpour, Ahmad Reza


    Cromolyn sodium, a mast cell stabilizing agent, provides an immediate protective effect against the exercise-induced bronchoconstriction while being used before the exercise. However, cromolyn is ineffective in reversing asthmatic bronchospasm; it is used as a maintenance therapy and has a prophylactic role in chronic asthma. The purpose of this study was to determine the extent of change in baseline lung function tests following a single dose of cromolyn sodium in adult asthmatics. Forty volunteers (33 women and 7 men) with moderate to severe persistent asthma were randomly assigned to receive 20 mg cromolyn, 40 mg cromolyn or cromolyn-placebo. The percent of improvement in lung function parameters was compared among the groups, during 1 h of inhalation. Low dose of cromolyn induced more improvement in most lung function parameters such as forced expiratory flow volume in one second, forced vital capacity and peak expiratory flow compared with other groups. After 15 min, the improvement percentage of baseline forced expiratory flow volume in one second was 3.35 ± 1.5, for sodium cromoglycate-20 mg group compared with 0.98 ± 1.43 and - 0.68 ± 1.2 for sodium cromoglycate-placebo and sodium cromoglycate-40 mg, groups respectively. However, the differences between means were not significant. Furthermore, based on the definition of American Thoracic Society (ATS) for a "significant post-bronchodilator response" developed in a few patients 15 min after the inhalation of 20 mg cromolyn sodium. It is suggested that probably the inhalation of 20 mg of cromolyn sodium could immediately improve the lung function in few adults with asthma.

  2. Ozone-Induced Hypertussive Responses in Rabbits and Guinea Pigs. (United States)

    Clay, Emlyn; Patacchini, Riccardo; Trevisani, Marcello; Preti, Delia; Branà, Maria Pia; Spina, Domenico; Page, Clive


    Cough remains a major unmet clinical need, and preclinical animal models are not predictive for new antitussive agents. We have investigated the mechanisms and pharmacological sensitivity of ozone-induced hypertussive responses in rabbits and guinea pigs. Ozone induced a significant increase in cough frequency and a decrease in time to first cough to inhaled citric acid in both conscious guinea pigs and rabbits. This response was inhibited by the established antitussive drugs codeine and levodropropizine. In contrast to the guinea pig, hypertussive responses in the rabbit were not inhibited by bronchodilator drugs (β2 agonists or muscarinic receptor antagonists), suggesting that the observed hypertussive state was not secondary to bronchoconstriction in this species. The ozone-induced hypertussive response in the rabbit was inhibited by chronic pretreatment with capsaicin, suggestive of a sensitization of airway sensory nerve fibers. However, we could find no evidence for a role of TRPA1 in this response, suggesting that ozone was not sensitizing airway sensory nerves via activation of this receptor. Whereas the ozone-induced hypertussive response was accompanied by a significant influx of neutrophils into the airway, the hypertussive response was not inhibited by the anti-inflammatory phosphodiesterase 4 inhibitor roflumilast at a dose that clearly exhibited anti-inflammatory activity. In summary, our results suggest that ozone-induced hypertussive responses to citric acid may provide a useful model for the investigation of novel drugs for the treatment of cough, but some important differences were noted between the two species with respect to sensitivity to bronchodilator drugs.

  3. Protective effect of levodropropizine against cough induced by inhalation of nebulized distilled water in patients with obstructive lung disease. (United States)

    Bariffi, F; Tranfa, C; Vatrella, A; Ponticiello, A


    Levodropropizine is a recently developed, peripherally active antitussive agent which is widely used in clinical practice. In order to obtain further information on the spectrum of activity of this compound in experimental clinical models, a double-blind controlled study was carried out to evaluate the potential effect of the drug against cough and bronchoconstriction induced by inhalation of an ultrasonically nebulized solution of distilled water in patients with obstructive lung disease. Twenty patients were randomly divided into two groups, which received levodropropizine (60 mg t.i.d.) or placebo respectively for 7 consecutive days. Parameters evaluated at baseline and on the last day of treatment included (i) results of respiratory function tests (FEV1, IVC, FVC, TIFF, PEF, MEF75, MEF50, MEF25) performed before the stimulation test with nebulized water; (ii) total number of coughs during a 2-hour period after the stimulation test; (iii) bronchial responsiveness, quantified by calculating the volume of nebulized water required to induce a 20% reduction of FEV1 below the basal level. At pretreatment, the tussive response was very similar in the two groups. A significant decrease in number of coughs (from 34.4 +/- 8.4 at baseline to 15.6 +/- 4.9 post-treatment, p less than 0.01) was observed after administration of levodropropizine, whereas placebo treatment produced no significant effect (number of coughs: 29.6 +/- 4.9 at baseline vs 24.8 +/- 9.6 post-treatment, N.S.). Bronchial responsiveness decreased significantly (compared to baseline) in both treatment groups, without any significant difference between drug and placebo. Respiratory function tests were not significantly affected by either treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. Mechanisms of aldehyde-induced bronchial reactivity: role of airway epithelium

    Energy Technology Data Exchange (ETDEWEB)

    Leikauf, G.D. (Department of Environmental Health, University of Cincinnati Medical Center, OH (United States))


    To investigate the relative irritant potencies of inhaled aldehydes, guinea pigs were exposed to formaldehyde or acrolein and specific total pulmonary resistance and bronchial reactivity to intravenous acetylcholine were assessed. The mechanisms associated with these responses were investigated by analyzing morphologic and biochemical changes in airway epithelial cells after in vivo and in vitro exposures. Immediately after exposure to formaldehyde or acrolein, specific resistance increased transiently and returned to control values within 30 to 60 minutes. Bronchial hyperreactivity, assessed by the acetylcholine dose necessary to double resistance, increased and became maximal two to six hours after exposure to at least 9 parts per million2 (ppm) formaldehyde or at least 1 ppm acrolein for two hours. The effect of exposure to 3 ppm formaldehyde for two hours was less than the effect of exposure to 1 ppm formaldehyde for eight hours; thus, extended exposures produced a disproportionate heightening of bronchial reactivity. Bronchial hyperreactivity often persisted for longer than 24 hours. Increases in three bronchoconstrictive eicosanoids, prostaglandin F2 alpha, thromboxane B2, and leukotriene C4, occurred immediately after exposure, whereas an influx of neutrophils into lavage fluid occurred 24 hours later. Histological examination of the tracheal epithelium and lamina propria also demonstrated a lack of inflammatory cell infiltration. Treatment with leukotriene synthesis inhibitors and receptor antagonists inhibited acrolein-induced hyperreactivity, supporting a causal role for these compounds in this response. Acrolein also stimulated eicosanoid release from bovine epithelial cells in culture. However, the profile of metabolites formed differed from that found in lavage fluid after in vivo exposure.

  5. Transglutaminase 2, a novel regulator of eicosanoid production in asthma revealed by genome-wide expression profiling of distinct asthma phenotypes.

    Directory of Open Access Journals (Sweden)

    Teal S Hallstrand

    Full Text Available BACKGROUND: A frequent manifestation of asthma, exercise-induced bronchoconstriction (EIB, occurs in 30-50% of asthmatics and is characterized by increased release of inflammatory eicosanoids. The objective of this study was to identify genes differentially expressed in EIB and to understand the function of these genes in the biology of asthma. METHODOLOGY/PRINCIPAL FINDINGS: Genome-wide expression profiling of airway leukocytes and epithelial cells obtained by induced sputum was conducted in two groups of subjects with asthma with and without EIB (n = 7 per group, at baseline and following exercise challenge. Based on the results of the gene expression study, additional comparisons were made with a normal control group (n = 10. Localization studies were conducted on epithelial brushings and biopsies from an additional group of asthmatics with EIB (n = 3. Genes related to epithelial repair and mast cell infiltration including beta-tryptase and carboxypeptidase A3 were upregulated by exercise challenge in the asthma group with EIB. A gene novel to asthma pathogenesis, transglutaminase 2 (TGM2, was the most differentially expressed at baseline between the groups. In vivo studies confirmed the increased expression of TGM2 in airway cells and airway lining fluid, and demonstrate that TGM2 is avidly expressed in the asthmatic airway epithelium. In vitro studies using recombinant human enzymes reveal that TGM2 augments the enzymatic activity of secreted phospholipase A(2 (PLA(2 group X (sPLA(2-X, an enzyme recently implicated in asthma pathogenesis. CONCLUSIONS/SIGNIFICANCE: This study found that TGM2, a mediator that is novel to asthma pathogenesis, is overexpressed in asthmatic airways and functions to increase sPLA(2-X enzymatic activity. Since PLA(2 serves as the first rate-limiting step leading to eicosanoid formation, these results suggest that TGM2 may be a key initiator of the airway inflammatory cascade in asthma.

  6. In vivo adenosine A(2B) receptor desensitization in guinea-pig airway smooth muscle: implications for asthma. (United States)

    Breschi, Maria Cristina; Blandizzi, Corrado; Fogli, Stefano; Martinelli, Cinzia; Adinolfi, Barbara; Calderone, Vincenzo; Camici, Marcella; Martinotti, Enrica; Nieri, Paola


    This study was aimed at characterizing the role of adenosine receptor subtypes in the contractility modulation of guinea-pig airway smooth muscle in normal and pathological settings. In vitro and in vivo experiments were performed by testing selective agonists and antagonists on isolated tracheal smooth muscle preparations and pulmonary inflation pressure, respectively, under normal conditions or following ovalbumin-induced allergic sensitization. In normal and sensitized animals, the adenosine A(2A)/A(2B) receptor agonist, NECA, evoked relaxing responses of isolated tracheal preparations precontracted with histamine, and such an effect was reversed by the adenosine A(2B) antagonist, MRS 1706, in the presence or in the absence of epithelium. The expression of mRNA coding for adenosine A(2B) receptors was demonstrated in tracheal specimens. In vitro desensitization with 100 microM NECA markedly reduced the relaxing effect of the agonist. In vivo NECA or adenosine administration to normal animals inhibited histamine-mediated bronchoconstriction, while these inhibitory effects no longer occurred in sensitized guinea-pigs. Adenosine plasma levels were significantly higher in sensitized than normal animals. In conclusion, our data demonstrate that: (i) adenosine A(2B) receptors are responsible for the relaxing effects of adenosine on guinea-pig airways; (ii) these receptors can undergo rapid adaptive changes that may affect airway smooth muscle responsiveness to adenosine; (iii) ovalbumin-induced sensitization promotes a reversible inactivation of adenosine A(2B) receptors which can be ascribed to homologous desensitization. These findings can be relevant to better understand adenosine functions in airways as well as mechanisms of action of asthma therapies targeting the adenosine system.

  7. Cooling-induced contraction in ovine airways smooth muscle. (United States)

    Mustafa, S M; Pilcher, C W; Williams, K I


    The mechanism of cold-induced bronchoconstriction is poorly understood. This prompted the present study whose aim was to determine the step-wise direct effect of cooling on smooth muscle of isolated ovine airways and analyse the role of calcium in the mechanisms involved. Isolated tracheal strips and bronchial segments were suspended in organ baths containing Krebs' solution for isometric tension recording. Tissue responses during stepwise cooling from 37 to 5 degrees C were examined. Cooling induced a rapid and reproducible contraction proportional to cooling temperature in ovine tracheal and bronchial preparations which was epithelium-independent. On readjustment to 37 degrees C the tone returned rapidly to basal level. Maximum contraction was achieved at a temperature of 5 degrees C for trachea and 15 degrees C for bronchiole. Cooling-induced contractions (CIC) was resistant to tetrodotoxin (1; 10 micrometer), and not affected by the muscarinic antagonist atropine (1 micrometer) or the alpha-adrenergic antagonist phentolamine (1 micrometer), or the histamine H1-antagonist mepyramine (1 micrometer) or indomethacin (1 micrometer). Ca2+ antagonists (nifedipine and verapamil) and Mn2+ raised tracheal but not bronchiolar tone and augmented CIC. Incubation in Ca2+-free, EGTA-containing Krebs' solution for 5 min had no effect on CIC, although it significantly reduced KCl-induced contraction by up to 75%. Cooling inhibited Ca2+ influx measured using 45Ca2+ uptake. Caffeine (100 micrometer) significantly inhibited CIC. The results show that cooling-induced contractions do not appear to involve activation of nerve endings, all surface reception systems or Ca2+ influx. However, CIC is mainly dependent on release of intracellular Ca2+.

  8. Suppression of ovalbumin-induced Th2-driven airway inflammation by β-sitosterol in a guinea pig model of asthma. (United States)

    Mahajan, Shailaja G; Mehta, Anita A


    In the present study, the efficacy of β-sitosterol isolated from an n-butanol extract of the seeds of the plant Moringa oleifera (Moringaceae) was examined against ovalbumin-induced airway inflammation in guinea pigs. All animals (except group I) were sensitized subcutaneously and challenged with aerosolized 0.5% ovalbumin. The test drugs, β-sitosterol (2.5mg/kg) or dexamethasone (2.5mg/kg), were administered to the animals (p.o.) prior to challenge with ovalbumin. During the experimental period (on days 18, 21, 24 and 29), a bronchoconstriction test (0.25% acetylcholine for 30s) was performed and lung function parameters (tidal volume and respiration rate) were measured for each animal. On day 30, blood and bronchoalveolar lavaged fluid were collected to assess cellular content, and serum was collected for cytokine assays. Lung tissue was utilized for a histamine assay and for histopathology. β-sitosterol significantly increased the tidal volume (V(t)) and decreased the respiration rate (f) of sensitized and challenged guinea pigs to the level of non-sensitized control guinea pigs and lowered both the total and differential cell counts, particularly eosinophils and neutrophils, in blood and bronchoalveolar lavaged fluid. Furthermore, β-sitosterol treatment suppressed the increase in cytokine levels (TNFα, IL-4 and IL-5), with the exception of IL-6, in serum and in bronchoalveolar lavaged fluid detected in model control animals. Moreover, treatment with β-sitosterol protected against airway inflammation in lung tissue histopathology. β-sitosterol possesses anti-asthmatic actions that might be mediated by inhibiting the cellular responses and subsequent release/synthesis of Th2 cytokines. This compound may have therapeutic potential in allergic asthma.

  9. Cough and exhaled nitric oxide levels: what happens with exercise? (United States)

    Petsky, Helen L; Kynaston, Jennifer Anne; McElrea, Margaret; Turner, Catherine; Isles, Alan; Chang, Anne B


    Cough associated with exertion is often used as a surrogate marker of asthma. However, to date there are no studies that have objectively measured cough in association with exercise in children. Our primary aim was to examine whether children with a pre-existing cough have an increase in cough frequency during and post-exercise. We hypothesized that children with any coughing illness will have an increase in cough frequency post-exercise regardless of the presence of exercise-induced broncho-constriction (EIB) or atopy. In addition, we hypothesized that Fractional exhaled nitric oxide (FeNO) levels decreases post-exercise regardless of the presence of EIB or atopy. Children with chronic cough and a control group without cough undertook an exercise challenge, FeNO measurements and a skin prick test, and wore a 24-h voice recorder to objectively measure cough frequency. The association between recorded cough frequency, exercise, atopy, and presence of EIB was tested. We also determined if the change in FeNO post exercise related to atopy or EIB. Of the 50 children recruited (35 with cough, 15 control), 7 had EIB. Children with cough had a significant increase in cough counts (median 7.0, inter-quartile ranges, 0.5, 24.5) compared to controls (2.0, IQR 0, 5.0, p = 0.028) post-exercise. Presence of atopy or EIB did not influence cough frequency. FeNO level was significantly lower post-exercise in both groups but the change was not influenced by atopy or EIB. Cough post-exertion is likely a generic response in children with a current cough. FeNO level decreases post-exercise irrespective of the presence of atopy or EIB. A larger study is necessary confirm or refute our findings.

  10. Cough and exhaled nitric oxide levels: What happens with exercise?

    Directory of Open Access Journals (Sweden)

    Helen ePetsky


    Full Text Available Cough associated with exertion is often used as a surrogate marker of asthma. However, to date there are no studies that have objectively measured cough in association with exercise in children. Our primary aim was to examine whether children with a pre-existing cough have an increase in cough frequency during and post-exercise. We hypothesised that children with any coughing illness will have an increase in cough frequency post-exercise regardless of the presence of exercise induced broncho-constriction (EIB or atopy. In addition, we hypotheised that FeNO levels decreases post-exercise regardless of the presence of EIB or atopy.Children with chronic cough and a control group without cough undertook an exercise challenge, FeNO measurements and a skin prick test and wore a 24-hour voice recorder to objectively measure cough frequency. The association between recorded cough frequency, exercise, atopy and presence of EIB was tested. We also determined if the change in FeNO post exercise related to atopy or EIB.Of the 50 children recruited (35 with cough, 15 control, 7 had EIB. Children with cough had a significant increase in cough counts (median 7.0, IQR 0.5, 24.5 compared to controls (2.0, IQR 0, 5.0, p=0.028 post-exercise. Presence of atopy or EIB did not influence cough frequency. FeNO level was significantly lower post-exercise in both groups but the change was not influenced by atopy or EIB. Cough post-exertion is likely a generic response in children with a current cough. FeNO level decreases post-exercise irrespective of the presence of atopy or EIB. A larger study is necessary confirm or refute our findings.

  11. Inhibitory effects of cryptoporus polysaccharide on airway constriction, eosinophil release, and chemotaxis in guinea pigs

    Institute of Scientific and Technical Information of China (English)

    Xiao-yan ZHAO; Qiang-min XIE; Ji-qiang CHEN; Chuan-kui KE


    AIM: To study effects of cryptoporus polysaccharide (CP) on antigen-induced bronchoconstriction, eosinophil peroxidase (EPO) release in vivo, and on platelet activating factor (PAF)-induced eosinophil chemotaxis in vitro in guinea pig. METHODS: The asthma model of guinea pig was formed with ovalbumin (OVA). The changes of lung resistance (RL) and dynamic lung compliance (Cdyn), EPO level in bronchoalveolar lavage fluids (BALF) and eosinophil migration were determined. RESULTS: Pretreatment of CP at doses of 3, 9, and 27 mg/kg by intragastric gavage (ig), qd for 10 d, inhibited early asthma response in a dose-dependent manner. Inhibitory rates of mean increase value from 1 to 30 min of RL were 34.8 %, 74.4 % (P<0.05), and 79.6 % (P<0.05), respectively. Inhibitory rate of mean reduction value of Cdyn were 22.9 %, 40.5 % (P<0.01), and 66.5 % (P<0.01), respectively.Pretreatment of CP at doses of 3, 9, and 27 mg/kg also inhibited late asthma response, and the reduction of EPO level in BALF were 3.1%, 16.9 % (P<0.01), and 20.1% (P<0.01), respectively. The inhibitory rates of CP at concentrations of 0.13, 1.3, 13, 130 nmol/L to eosinophil migration induced by PAF were 6.8 %, 17.2 % (P<0.05),29.6 % (P<0.01), and 35.9 % (P<0.01). CONCLUSION: CP protects lung against increase of RL and reduction of Cdyn, decreases EPO level in the asthma model, and inhibits eosinophil chemotaxis induced by PAF. The results suggest that CP may be a novel antiinflammatory agent for the treatment of asthma and allergic diseases.

  12. Activation of Transient Receptor Potential Ankyrin-1 by Insoluble Particulate Material and Association with Asthma. (United States)

    Deering-Rice, Cassandra E; Shapiro, Darien; Romero, Erin G; Stockmann, Chris; Bevans, Tatjana S; Phan, Quang M; Stone, Bryan L; Fassl, Bernhard; Nkoy, Flory; Uchida, Derek A; Ward, Robert M; Veranth, John M; Reilly, Christopher A


    Inhaled irritants activate transient receptor potential ankyrin-1 (TRPA1), resulting in cough, bronchoconstriction, and inflammation/edema. TRPA1 is also implicated in the pathogenesis of asthma. Our hypothesis was that particulate materials activate TRPA1 via a mechanism distinct from chemical agonists and that, in a cohort of children with asthma living in a location prone to high levels of air pollution, expression of uniquely sensitive forms of TRPA1 may correlate with reduced asthma control. Variant forms of TRPA1 were constructed by mutating residues in known functional elements and corresponding to single-nucleotide polymorphisms in functional domains. TRPA1 activity was studied in transfected HEK-293 cells using allyl-isothiocynate, a model soluble electrophilic agonist; 3,5-ditert butylphenol, a soluble nonelectrophilic agonist and a component of diesel exhaust particles; and insoluble coal fly ash (CFA) particles. The N-terminal variants R3C and R58T exhibited greater, but not additive, activity with all three agonists. The ankyrin repeat domain-4 single nucleotide polymorphisms E179K and K186N exhibited decreased response to CFA. The predicted N-linked glycosylation site residues N747A and N753A exhibited decreased responses to CFA, which were not attributable to differences in cellular localization. The pore-loop residue R919Q was comparable to wild-type, whereas N954T was inactive to soluble agonists but not CFA. These data identify roles for ankyrin domain-4, cell surface N-linked glycans, and selected pore-loop domain residues in the activation of TRPA1 by insoluble particles. Furthermore, the R3C and R58T polymorphisms correlated with reduced asthma control for some children, which suggest that TRPA1 activity may modulate asthma, particularly among individuals living in locations prone to high levels of air pollution.

  13. Oxidative stress and airway mucus hypersecretion%氧化应激与支气管哮喘气道黏液高分泌研究进展

    Institute of Scientific and Technical Information of China (English)

    谢桃; 李国平


    哮喘是一种以支气管收缩可逆性、肺部炎症及气道重塑为特点的慢性气道炎症性疾病.黏液过度分泌导致气道阻塞、肺功能下降、气道重塑和感染增加.过度的活性氧/活性氮(ROS/RNS)产生造成气道炎症,气道高反应性,气道微血管高通透性和气道黏液高分泌,以及组织损伤和形态的改变.减轻氧化应激或增加抗氧化能够减轻气道嗜酸粒细胞,减少黏液分泌,减轻支气管高反应性.本文就氧化应激与哮喘气道黏液高分泌的关系作一综述.%Asthma is a bronchoconstriction reversibility,lung inflammation and airway remodeling for characteristics of chronic airway inflammatory disease.Excessive mucus secretion lead to obstruction of the airway,lung function decline,airway remodeling and increase infection.Excessive reactive oxygen species/reactive nitrogen species (ROS/RNS)produce cause airway inflammation,airway responsieness,airway microvascular high permeability and high airway mucus secretion,and tissue damage and the change of the form.Reduce oxidative stress or increase antioxidant that can reduce airway eosinophils,reduce mucus secretion,reduce bronchial high reaction.Oxidative stress and asthma airway mucus secretion relationship high application were introduced in this paper.

  14. [Physical exercise and bronchial asthma]. (United States)

    Endre, László


    An article was published in the Lancet in 1935 about the therapy of asthmatic patients, using a special breathing exercise (the authors used a control group, too). Swimming, as a complementary therapy for asthmatic children, was first recommended in 1968, by authors from the United States. In Hungary, regular swimming training for asthmatic children is in use since August, 1981. As the result of this exercise, the physical fitness of asthmatic children (using this method regularly for years) increased dramatically, and it is much better compared to that found in the non asthmatic, non swimming children of the same age group. The requirement for asthma medication decreased, and the severity of their disease significantly decreased, also. On the other hand, asthma is not a rarity even among elite athletes. It is most frequent in the endurance sports (for example in Northern Europe among cross-country skiers its prevalence is between 14-54%, among long distance runners 15-24%, and among swimmers 13-44%). The possible reason is related to the fact that elite athletes inspire 200 liter air/minute (mostly through the mouth). Air pollution and allergens can penetrate in the lower respiratory tract. The air causes cooling and drying of the mucosa of the airways and, as a consequence, mediators are liberated which produce oedema of the mucosa, and bronchoconstriction. Beta-2-receptor agonists inhalation can prevent (or decrease significantly) this phenomenon. These agents are used regularly by elite athletes, too. The non-medical possibilities for prevention include wearing a special mask, frequent ventilation of the swimming pool's air, consumption of omega-3-fatty acid, and inhalation of dry salt (very small, and very clear sodiumchloride particles).

  15. Impaired Bronchoprotection Is Not Induced by Increased Smooth Muscle Mass in Chronic Treatment In Vivo with Formoterol in Asthmatic Mouse Model

    Directory of Open Access Journals (Sweden)

    W Luo


    Full Text Available Objective: Inhaling β2-adrenoceptor agonist is first-line asthma treatment, which is used for both acute relief and prevention of bronchoconstriction. However, chronic use of β-agonists results in impaired bronchoprotection and increasing occurrences of severe asthma exacerbation, even death in clinical practice. The mechanism of β-adrenoceptor hyposensitivity has not been thoroughly elucidated thus far. Bronchial smooth muscle contraction induces airway narrowing and also mediates airway inflammation. Moreover, bronchial smooth muscle mass significantly increases in asthmatics. We aimed to establish an asthmatic model that demonstrated that formoterol induced impaired bronchoprotection and to see whether increased smooth muscle mass played a role in it. Methods: We combined routine allergen challenging (seven weeks with repeated application of formoterol, formoterol plus budesonide or physiological saline in allergen-sensitized BALB/c mouse. The bronchoprotection mediated by β-agonist was measured in five consecutive weeks. Smooth muscle mass was shown by morphometric analysis, and α-actin expression was detected by western blot. Results: The trend of bronchoprotection was wavy in drug interventional groups, which initially increased and then decreased. Chronic treatment with formoterol significantly impaired bronchoprotection. According to the morphometric analysis and α-actin expression, no significant difference was detected in smooth muscle mass in all groups. Conclusion: This experiment successfully established that a chronic asthmatic mouse model, which manifested typical features of asthmatic patients, with chronic use of formoterol, results in a loss of bronchoprotection. No significant difference was detected in smooth muscle mass in all groups, which implied some subcellular signalling changes may be the key points.

  16. Increased B Cell ADAM10 in Allergic Patients and Th2 Prone Mice.

    Directory of Open Access Journals (Sweden)

    Lauren Folgosa Cooley

    Full Text Available ADAM10, as the sheddase of the low affinity IgE receptor (CD23, promotes IgE production and thus is a unique target for attenuating allergic disease. Herein, we describe that B cell levels of ADAM10, specifically, are increased in allergic patients and Th2 prone WT mouse strains (Balb/c and A/J. While T cell help augments ADAM10 expression, Balb WT B cells exhibit increased ADAM10 in the naïve state and even more dramatically increased ADAM10 after anti-CD40/IL4 stimulation compared C57 (Th1 prone WT B cells. Furthermore, ADAM17 and TNF are reduced in allergic patients and Th2 prone mouse strains (Balb/c and A/J compared to Th1 prone controls. To further understand this regulation, ADAM17 and TNF were studied in C57Bl/6 and Balb/c mice deficient in ADAM10. C57-ADAM10B-/- were more adept at increasing ADAM17 levels and thus TNF cleavage resulting in excess follicular TNF levels and abnormal secondary lymphoid tissue architecture not noted in Balb-ADAM10B-/-. Moreover, the level of B cell ADAM10 as well as Th context is critical for determining IgE production potential. Using a murine house dust mite airway hypersensitivity model, we describe that high B cell ADAM10 level in a Th2 context (Balb/c WT is optimal for disease induction including bronchoconstriction, goblet cell metaplasia, mucus, inflammatory cellular infiltration, and IgE production. Balb/c mice deficient in B cell ADAM10 have attenuated lung and airway symptoms compared to Balb WT and are actually most similar to C57 WT (Th1 prone. C57-ADAM10B-/- have even further reduced symptomology. Taken together, it is critical to consider both innate B cell levels of ADAM10 and ADAM17 as well as Th context when determining host susceptibility to allergic disease. High B cell ADAM10 and low ADAM17 levels would help diagnostically in predicting Th2 disease susceptibility; and, we provide support for the use ADAM10 inhibitors in treating Th2 disease.

  17. Comparing the cardiovascular therapeutic indices of glycopyrronium and tiotropium in an integrated rat pharmacokinetic, pharmacodynamic and safety model

    Energy Technology Data Exchange (ETDEWEB)

    Trifilieff, Alexandre; Ethell, Brian T. [Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB (United Kingdom); Sykes, David A. [Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB (United Kingdom); School of Life Sciences, Queen' s Medical Centre, University of Nottingham, Nottingham, NG7 2UH (United Kingdom); Watson, Kenny J.; Collingwood, Steve [Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB (United Kingdom); Charlton, Steven J. [Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB (United Kingdom); School of Life Sciences, Queen' s Medical Centre, University of Nottingham, Nottingham, NG7 2UH (United Kingdom); Kent, Toby C., E-mail: [Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB (United Kingdom)


    Long acting inhaled muscarinic receptor antagonists, such as tiotropium, are widely used as bronchodilator therapy for chronic obstructive pulmonary disease (COPD). Although this class of compounds is generally considered to be safe and well tolerated in COPD patients the cardiovascular safety of tiotropium has recently been questioned. We describe a rat in vivo model that allows the concurrent assessment of muscarinic antagonist potency, bronchodilator efficacy and a potential for side effects, and we use this model to compare tiotropium with NVA237 (glycopyrronium bromide), a recently approved inhaled muscarinic antagonist for COPD. Anaesthetized Brown Norway rats were dosed intratracheally at 1 or 6 h prior to receiving increasing doses of intravenous methacholine. Changes in airway resistance and cardiovascular function were recorded and therapeutic indices were calculated against the ED{sub 50} values for the inhibition of methacholine-induced bronchoconstriction. At both time points studied, greater therapeutic indices for hypotension and bradycardia were observed with glycopyrronium (19.5 and 28.5 fold at 1 h; > 200 fold at 6 h) than with tiotropium (1.5 and 4.2 fold at 1 h; 4.6 and 5.5 fold at 6 h). Pharmacokinetic, protein plasma binding and rat muscarinic receptor binding properties for both compounds were determined and used to generate an integrated model of systemic M{sub 2} muscarinic receptor occupancy, which predicted significantly higher M{sub 2} receptor blockade at ED{sub 50} doses with tiotropium than with glycopyrronium. In our preclinical model there was an improved safety profile for glycopyrronium when compared with tiotropium. - Highlights: • We use an in vivo rat model to study CV safety of inhaled muscarinic antagonists. • We integrate protein and receptor binding and PK of tiotropium and glycopyrrolate. • At ED{sub 50} doses for bronchoprotection we model systemic M{sub 2} receptor occupancy. • Glycopyrrolate demonstrates lower M

  18. The lungs need to be deflated: effects of glycopyrronium on lung hyperinflation in COPD patients. (United States)

    Sanguinetti, Claudio M


    disease that needs a chronic bronchodilation by decreasing the mechanic stress of the airways determined by repeated bronchoconstriction and increasing patient's adherence to treatment plan with better clinical results. Several studies demonstrated that glycopyrronium is able to positively and significantly decrease lung hyperinflation, symptoms, and improve psycho-physical status of COPD patients, with a low rate of adverse events, similar to that of placebo.

  19. Investigation of the bioequivalence of montelukast chewable tablets after a single oral administration using a validated LC-MS/MS method

    Directory of Open Access Journals (Sweden)

    Zaid AN


    Full Text Available Abdel Naser Zaid,1 Murad N Abualhasan,1 David G Watson,2 Ayman Mousa,3 Nadia Ghazal,4 Rana Bustami5 1Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine; 2Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK; 3R&D Department, Avalon Pharma (Middle East Pharmaceutical Industries Co. Ltd., Riyadh, Kingdom of Saudi Arabia; 4Naratech Pharmaceutical Consultancy, 5Pharmaceutical Research Unit, Amman, Jordan Background: Montelukast (MT is a leukotriene D4 antagonist. It is an effective and safe medicine for the prophylaxis and treatment of chronic asthma. It is also used to prevent acute exercise-induced bronchoconstriction and as a symptomatic relief of seasonal allergic rhinitis and perennial allergic rhinitis.Objective: The aim of this study was to evaluate the bioequivalence (BE of two drug products: generic MT 5 mg chewable tablets versus the branded drug Singulair® pediatric 5 mg chewable tablets among Mediterranean volunteers.Methods: An open-label, randomized two-period crossover BE design was conducted in 32 healthy male volunteers with a 9-day washout period between doses and under fasting conditions. The drug concentrations in plasma were quantified by using a newly developed and fully validated liquid chromatography tandem mass spectrometry method, and the pharmacokinetic parameters were calculated using a non-compartmental model. The ratio for generic/branded tablets using geometric least squares means was calculated for both the MT products.Results: The relationship between concentration and peak area ratio was found to be linear within the range 6.098–365.855 ng/mL. The correlation coefficient (R2 was always greater than 0.99 during the course of the validation. Statistical comparison of the main pharmacokinetic parameters showed no significant difference between the generic and branded products. The point estimates (ratios of

  20. Reproducibility of the airway response to an exercise protocol standardized for intensity, duration, and inspired air conditions, in subjects with symptoms suggestive of asthma

    Directory of Open Access Journals (Sweden)

    Anderson Sandra D


    Full Text Available Abstract Background Exercise testing to aid diagnosis of exercise-induced bronchoconstriction (EIB is commonly performed. Reproducibility of the airway response to a standardized exercise protocol has not been reported in subjects being evaluated with mild symptoms suggestive of asthma but without a definite diagnosis. This study examined reproducibility of % fall in FEV1 and area under the FEV1 time curve for 30 minutes in response to two exercise tests performed with the same intensity and duration of exercise, and inspired air conditions. Methods Subjects with mild symptoms of asthma exercised twice within approximately 4 days by running for 8 minutes on a motorized treadmill breathing dry air at an intensity to induce a heart rate between 80-90% predicted maximum; reproducibility of the airway response was expressed as the 95% probability interval. Results Of 373 subjects challenged twice 161 were positive (≥10% fall FEV1 on at least one challenge. The EIB was mild and 77% of subjects had 1 and 19.3% (72 positive on both challenges. The remaining 23.9% of subjects had only one positive test. The 95% probability interval for reproducibility of the % fall in FEV1 and AUC0-30 min was ± 9.7% and ± 251% for all 278 adults and ± 13.4% and ± 279% for all 95 children. The 95% probability interval for reproducibility of % fall in FEV1 and AUC0-30 min for the 72 subjects with two tests ≥10% fall FEV1 was ± 14.6% and ± 373% and for the 34 subjects with two tests ≥15% fall FEV1 it was ± 12.2% and ± 411%. Heart rate and estimated ventilation achieved were not significantly different either on the two test days or when one test result was positive and one was negative. Conclusions Under standardized, well controlled conditions for exercise challenge, the majority of subjects with mild symptoms of asthma demonstrated agreement in test results. Performing two tests may need to be considered when using exercise to exclude or diagnose EIB, when

  1. Pulmonary function responses to ozone in smokers with a limited smoking history

    Energy Technology Data Exchange (ETDEWEB)

    Bates, Melissa L., E-mail: [Interdisciplinary Graduate Degree Program in Physiology, Pennsylvania State University, University Park, PA 16802 (United States); Department of Pediatrics, Critical Care Division, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792 (United States); John Rankin Laboratory of Pulmonary Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792 (United States); Brenza, Timothy M. [Department of Chemical Engineering, Pennsylvania State University, University Park, PA 16802 (United States); Ben-Jebria, Abdellaziz [Interdisciplinary Graduate Degree Program in Physiology, Pennsylvania State University, University Park, PA 16802 (United States); Department of Chemical Engineering, Pennsylvania State University, University Park, PA 16802 (United States); Bascom, Rebecca [Division of Pulmonary, Allergy and Critical Care Medicine, Penn State College of Medicine, Hershey, PA 17033 (United States); Eldridge, Marlowe W. [Department of Pediatrics, Critical Care Division, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792 (United States); John Rankin Laboratory of Pulmonary Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792 (United States); Department of Kinesiology, University of Wisconsin-Madison, Madison, WI 53792 (United States); Department of Bioengineering, University of Wisconsin-Madison, Madison, WI 53792 (United States); Ultman, James S. [Interdisciplinary Graduate Degree Program in Physiology, Pennsylvania State University, University Park, PA 16802 (United States); Department of Chemical Engineering, Pennsylvania State University, University Park, PA 16802 (United States)


    In non-smokers, ozone (O{sub 3}) inhalation causes decreases in forced expiratory volume (FEV{sub 1}) and dead space (V{sub D}) and increases the slope of the alveolar plateau (S{sub N}). We previously described a population of smokers with a limited smoking history that had enhanced responsiveness to brief O{sub 3} boluses and aimed to determine if responsiveness to continuous exposure was also enhanced. Thirty smokers (19 M, 11 F, 24 ± 4 years, 6 ± 4 total years smoking,4 ± 2 packs/week) and 30 non-smokers (17 M, 13 F, 25 ± 6 years) exercised for 1 h on a cycle ergometer while breathing 0.30 ppm O{sub 3}. Smokers and non-smokers were equally responsive in terms of FEV{sub 1} (− 9.5 ± 1.8% vs − 8.7 ± 1.9%). Smokers alone were responsive in terms of V{sub D} (− 6.1 ± 1.2%) and S{sub N} (9.1 ± 3.4%). There was no difference in total delivered dose. Dead space ventilation (V{sub D}/V{sub T}) was not initially different between the two groups, but increased in the non-smokers (16.4 ± 2.8%) during the exposure, suggesting that the inhaled dose may be distributed more peripherally in smokers. We also conclude that these cigarette smokers retain their airway responsiveness to O{sub 3} and, uniquely, experience changes in V{sub D} that lead to heterogeneity in airway morphometry and an increase in S{sub N}. - Highlights: • We previously found lung function responses to O{sub 3} bolus exposure in smokers. • Here, we describe their responsiveness to continuous O{sub 3} exposure with exercise. • Spirometry and capnography were used to assess pulmonary function changes. • Enhanced bronchoconstriction in smokers increases parenchymal delivery of O{sub 3}.

  2. Intoxication aiguë sévère par les pesticides organophosphorés: à propos de 28 cas

    Directory of Open Access Journals (Sweden)

    Ali Derkaoui


    une insuffisance respiratoire de mécanismes multiples: encombrement bronchique réalisant une véritable noyade interne, bronchoconstriction, paralysie des muscles respiratoires, œdème pulmonaire d’évolution gravissime

  3. Effect of Cromoglycate on Gas Changes, During Bronchial Challenge by UNCDW in Children with Asthma (United States)

    Bavaro, S.; Moramarco, G.; Torio, D.; Falciatore, D.; Ciccarone, G.; Cicciomessere, L.; Rigillo, N.


    Eighteen asthmatic children were challenged with ultrasonically nebulized cold distilled water (UNCDW). Blood gas composition was monitored transcutaneously (tcpO2 and tcpCO2) during and after the challenge. Assuming as basal the response to this UNCDW test, nine children (Group A) were then chosen at random to inhale cromoglycate by aerosol delivery for 8 days. Nine children (Group B), acting as a control, inhaled saline for 8 days. At the end of this therapy, each child repeated the UNCDW test. Statistical analysis with t-test for paired data was used to compare the results of each child to both tests. Mean basal tcpO2 and tcpCO2 were all within the expected normal range. In all children, both mean tcpO2 and tcpCO2 were reduced during and after UNCDW inhalation. Mean tcpCO2 values during the challenge were significantly (p < 0.001) lower than the corresponding steady state 2 rain after the UNCDW challenge, with a mean drop of −7% (2.1 S.D.). Mean tcpO2 values remained significantly decreased (p < 0.001) from the fifth mitt of the UNCDW challenge to the end of the observation period, with a mean drop of −20% (15.5 S.D.). After treatment with cromoglycate (Group A), the mean tcpCO2 values during UNCDW did not change significantly from those ofsteady state conditions: −0.8% (0.5 S.D.); whereas mean tcpO2 values decreased by −4% (4.9 S.D.). The control children treated with saline (Group B) showed mean tcpCO2 and tcpO2 values which were significantly different (p < 0.001) from those of the steady state conditions: mean drop of tcpCO2, −6% (4.2 S.D.); mean drop of tcpO2, −20% (4.7 S.D.). In conclusion, it emerges that: UNCDW induces nonspecific broncho-constriction in asthmatic children with a typical drop of tcpCO2 and tcpO2; the treatment with cromoglycate normalizes the time course of tcpCO2 (hyper-reactivity) and reduces dramatically the drop of tcpO2 time course (hyper-responsivity) during and after the UNCDW test. PMID:18475603

  4. 妊娠期支气管哮喘治疗进展%Achievement of bronchial asthma therapy during pregnancy

    Institute of Scientific and Technical Information of China (English)

    蒋雷服; 殷凯生; 黄茂


    临床研究已证明妊娠期重度及控制不佳的支气管哮喘(简称哮喘)与母亲及胎儿严重并发症相关.对于妊娠期哮喘患者,接受药物治疗比存在哮喘症状和哮喘发作更安全.所有程度的持续妊娠哮喘患者都应当应用吸入糖皮质激素作为控制药物,首选布地奈德.白三烯受体拮抗剂可以缓解支气管痉挛、减轻症状、改善肺功能.长效β2受体激动剂对于正在应用吸入糖皮质激素的患者可作为首选的添加药物.吸入短效β2受体激动剂可以作为缓解药物.对于正在接受维持量或接近维持量治疗,无不良反应、临床疗效好的妊娠哮喘患者可以继续进行变应原免疫治疗.%Clinical studies have confirmed that severe or uncontrolled bronchial asthma (asthma)during pregnancy may result in adverse maternal and fetal outcomes. It is safer for pregnant women with asthma to be treated with asthma medications than for them to have asthma symptoms and exacerbations.Inhaled corticosteroids should be considered the controller medication for all severities of persistent asthma in pregnant women, preferably inhaled budesonide. Leukotrienes receptor antagonists protect against bronchoconstriction,reduce asthma symptoms and improve pulmonary function in patients with asthma.Long-acting β2-adrenergic agonists are the preferred adjunct to inhaled corticosteroids therapy in the pregnant patients with asthma. Inhaled short-acting β2-agonists are the rescue therapy. Continuation of allergen immunotherapy is recommended in patients who are at or near a maintenance dose, not experiencing adverse reactions to the therapy,and apparently deriving clinical benefit.

  5. Breathless. (United States)

    Dominguez, Orlando J


    the patient elderly, and does he/she show pedal edema, JVD, hypoxemia and/or distended neck veins? If yes, CHF may be the cause. [table: see text] There are questions regarding the use of bronchodilators in patients suffering CHF. If a CHF patient is wheezing (bronchospasm), then a beta-2 selective breathing treatment may be appropriate, along with nitrates and diuretics. Oxygenation is the critical problem in CHF, and hypoxemia will continue to worsen cardiac function. Remember, both bronchoconstriction and alveolar sacs filling with fluid will impair oxygenation of the RBCs and ultimately the vital organs. Focused prehospital management of CHF is aggressive in restoring oxygenation. For example, many agencies are now using oxygen, nitrates, ACE inhibitors and CPAP. By better understanding the pathophysiology of respiratory emergencies and their differential diagnosis, we will improve patient outcomes.

  6. Pantoea agglomerans: a marvelous bacterium of evil and good.Part I. Deleterious effects: Dust-borne endotoxins and allergens – focus on cotton dust

    Directory of Open Access Journals (Sweden)

    Jacek Dutkiewicz


    that cause accumulation of platelets in pulmonary capillaries initiating an acute and chronic inflammation resulting in endothelial cell damage and extravasation of cells and fluids into the lung interstitium. These changes cause bronchoconstriction, the decrement of lung function expressed as reduction of forced expiratory volume in one second (FEV1 and/or diffusion capacity, increase in the airway hyperreactivity and subjective symptoms such as fever, airway irritation and chest tightness. The conclusions from these experiments, performed mostly 2-3 decades ago, did not loose their actuality until recently as so far no other cotton dust component was identified as a more important work-related hazard than bacterial endotoxin. Though also other microbial and plant constituents are considered as potential causative agents of byssinosis, the endotoxin produced by Pantoea agglomerans and other Gram-negative bacteria present in cotton dust is still regarded as a major cause of this mysterious disease.

  7. Preclinical evaluation of an inhibitor of cytosolic phospholipase A2α for the treatment of asthma. (United States)

    Hewson, Christopher A; Patel, Sheena; Calzetta, Luigino; Campwala, Hinnah; Havard, Suzanne; Luscombe, Emma; Clarke, Philip A; Peachell, Peter T; Matera, Maria G; Cazzola, Mario; Page, Clive; Abraham, William M; Williams, Cara M; Clark, James D; Liu, Wai L; Clarke, Nicholas P; Yeadon, Michael


    Asthma is a chronic inflammatory lung disease with considerable unmet medical needs for new and effective therapies. Cytosolic phospholipase A(2)α (cPLA(2)α) is the rate-limiting enzyme that is ultimately responsible for the production of eicosanoids implicated in the pathogenesis of asthma. We investigated a novel cPLA(2)α inhibitor, PF-5212372, to establish the potential of this drug as a treatment for asthma. PF-5212372 was a potent inhibitor of cPLA(2)α (7 nM) and was able to inhibit prostaglandin (PG)D(2) and cysteinyl leukotriene release from anti-IgE-stimulated human lung mast cells (0.29 and 0.45 nM, respectively). In a mixed human lung cell population, PF-5212372 was able to inhibit ionomycin-stimulated release of leukotriene B(4), thromboxane A(2), and PGD(2) (2.6, 2.6, and 4.0 nM, respectively) but was significantly less effective against PGE(2) release (>301 nM; p < 0.05). In an in vitro cell retention assay, PF-5212372 retained its potency up to 24 h after being washed off. In a sheep model of allergic inflammation, inhalation of PF-5212372 significantly inhibited late-phase bronchoconstriction (78% inhibition; p < 0.001) and airway hyper-responsiveness (94% inhibition; p < 0.001), and isolated sheep lung mast cell assays confirmed species translation via effective inhibition of PGD(2) release (0.78 nM). Finally, PF-5212372 was assessed for its ability to inhibit the contraction of human bronchi induced by AMP. PF5212372 significantly inhibited AMP-induced contraction of human bronchi (81% inhibition; p < 0.001); this finding, together with the ability of this drug to be effective in a wide range of preclinical asthma models, suggests that inhibition of cPLA(2)α with PF-5212372 may represent a new therapeutic option for the treatment of asthma.

  8. House dust mite major allergens Der p 1 and Der p 5 activate human airway-derived epithelial cells by protease-dependent and protease-independent mechanisms

    Directory of Open Access Journals (Sweden)

    Timmerman J André B


    Full Text Available Abstract House dust mite allergens (HDM cause bronchoconstriction in asthma patients and induce an inflammatory response in the lungs due to the release of cytokines, chemokines and additional mediators. The mechanism how HDM components achieve this is largely unknown. The objective of this study was to assess whether HDM components of Dermatophagoides pteronissinus with protease activity (Der p 1 and unknown enzymatic activity (Der p 2, Der p 5 induce biological responses in a human airway-derived epithelial cell line (A549, and if so, to elucidate the underlying mechanism(s of action. A549 cells were incubated with HDM extract, Der p 1, recombinant Der p 2 and recombinant Der p 5. Cell desquamation was assessed by microscopy. The proinflammatory cytokines, IL-6 and IL-8, were measured by ELISA. Intracellular Ca2+ levels were assessed in A549 cells and in mouse fibroblasts expressing the human protease activated receptor (PAR1, PAR2 or PAR4. HDM extract, Der p 1 and Der p 5 dose-dependently increased the production of IL-6 and IL-8. Added simultaneously, Der p 1 and Der p 5 further increased the production of IL-6 and IL-8. The action of Der p 1 was blocked by cysteine-protease inhibitors, while that of Der p 5 couldn't be blocked by either serine- or cysteine protease inhibitors. Der p 5 only induced cell shrinking, whereas HDM extract and Der p1 also induced cell desquamation. Der p 2 had no effect on A549 cells. Der p 1's protease activity causes desquamation and induced the release of IL6 and IL-8 by a mechanism independent of Ca2+ mobilisation and PAR activation. Der p 5 exerts a protease-independent activation of A549 that involves Ca2+ mobilisation and also leads to the production of these cytokines. Together, our data indicate that allergens present in HDM extracts can trigger protease-dependent and protease-independent signalling pathways in A549 cells.

  9. The in vitro and in vivo profile of aclidinium bromide in comparison with glycopyrronium bromide. (United States)

    Gavaldà, Amadeu; Ramos, Israel; Carcasona, Carla; Calama, Elena; Otal, Raquel; Montero, José Luis; Sentellas, Sonia; Aparici, Monica; Vilella, Dolors; Alberti, Joan; Beleta, Jorge; Miralpeix, Montserrat


    This study characterised the in vitro and in vivo profiles of two novel long-acting muscarinic antagonists, aclidinium bromide and glycopyrronium bromide, using tiotropium bromide and ipratropium bromide as comparators. All four antagonists had high affinity for the five muscarinic receptor sub-types (M1-M5); aclidinium had comparable affinity to tiotropium but higher affinity than glycopyrronium and ipratropium for all receptors. Glycopyrronium dissociated faster from recombinant M3 receptors than aclidinium and tiotropium but more slowly than ipratropium; all four compounds dissociated more rapidly from M2 receptors than from M3 receptors. In vitro, aclidinium, glycopyrronium and tiotropium had a long duration of action at native M3 receptors (>8 h versus 42 min for ipratropium). In vivo, all compounds were equi-potent at reversing acetylcholine-induced bronchoconstriction. Aclidinium, glycopyrronium and ipratropium had a faster onset of bronchodilator action than tiotropium. Aclidinium had a longer duration of action than glycopyronnium (time to 50% recovery of effect [t½ offset] = 29 h and 13 h, respectively); these compare with a t½ offset of 64 h and 8 h for tiotropium and ipratropium, respectively. Aclidinium was less potent than glycopyrronium and tiotropium at inhibiting salivation in conscious rats (dose required to produce half-maximal effect [ED50] = 38, 0.74 and 0.88 μg/kg, respectively) and was more rapidly hydrolysed in rat, guinea pig and human plasma compared with glycopyrronium or tiotropium. These results indicate that while aclidinium and glycopyrronium are both potent antagonists at muscarinic receptors with similar kinetic selectivity for M3 receptors versus M2, aclidinium has a longer dissociation half-life at M3 receptors and a longer duration of bronchodilator action in vivo than glycopyrronium. The rapid plasma hydrolysis of aclidinium, coupled to its kinetic selectivity, may confer a reduced propensity for systemic

  10. Subcutaneous and Sublingual Immunotherapy in a Mouse Model of Allergic Asthma. (United States)

    Hesse, Laura; Nawijn, Martijn C


    Allergic asthma, caused by inhaled allergens such as house dust mite or grass pollen, is characterized by reversible airway obstruction, associated with an eosinophilic inflammation of the airways, as well as airway hyper responsiveness and remodeling. The inhaled allergens trigger a type-2 inflammatory response with involvement of innate lymphoid cells (ILC2) and Th2 cells, resulting in high production of immunoglobulin E (IgE) antibodies. Consequently, renewed allergen exposure results in a classic allergic response with a distinct early and late phase, both resulting in bronchoconstriction and shortness of breath. Allergen specific immunotherapy (AIT) is the only treatment that is capable of modifying the immunological process underlying allergic responses including allergic asthma and both subcutaneous AIT (SCIT) as well as sublingual AIT (SLIT) have proven clinical efficacy in long term suppression of the allergic response. Although these treatments are very successful for rhinitis, application of AIT in asthma is hampered by variable efficacy, long duration of treatment, and the risk of severe side-effects. A more profound understanding of the mechanisms by which AIT achieves tolerance to allergens in sensitized individuals is needed to improve its efficacy. Mouse models have been very valuable as a preclinical model to characterize the mechanisms of desensitization in AIT and to evaluate novel approaches for improved efficacy. Here, we present a rapid and reproducible mouse model for allergen-specific immunotherapy. In this model, mice are sensitized with two injections of allergen absorbed to aluminum hydroxide to induce allergic sensitization, followed by subcutaneous injections (SCIT) or sublingual administrations (SLIT) of the allergen as immunotherapy treatment. Finally, mice are challenged by three intranasal allergen administrations. We will describe the protocols as well as the most important read-out parameters including measurement of invasive lung

  11. Dichrostachys cinerea (L. Wight et Arn (Mimosaceae hydro-alcoholic extract action on the contractility of tracheal smooth muscle isolated from guinea-pig

    Directory of Open Access Journals (Sweden)

    Datté Jacques Y


    Full Text Available Abstract Background Dichrostachys cinerea (L. Wight et Arn. (Mimosaceae is largely used in ethno-medically across Africa, and mainly employed for the treatment of asthma in Ivory Coast and Gabon. The paper analyses the relaxation induced by the methanolic extract of D. cinerea (Edici in the guinea-pig trachea preparations (GPTPs. Purpose: This study aimed to bring out the scientific basis to the use of this plant leading to the validation of this phytomedicine. Method The aorta obtained from guinea-pigs was immediately placed in a Mac Ewen solution. Experiments were performed in preparations suspended between two L-shaped stainless steel hooks in a 10 ml organ bath containing Mac Ewen solution. The isometric contractile force of the aorta strips of guinea-pig were recorded by using a strain gauge. The different drugs were directly administered into the organ bath and the magnitude of GPTPs was evaluated. Results Phytochemical analysis of the methanolic extract of Dichrostachys cinerea (Edici using chemical methods revealed the presence of flavenoids, tannins, sterols, triterpenes and polyphenols. Pharmacological studies performed in GPTPs show that of Dichrostachys cinerea (0.1 mg/ml - 2 mg/ml evoked a broncho-constriction in GPTPs. Whereas, at concentration up to 2 mg/ml, Edici induced a significant dose-dependent relaxation in the GPTPs. KCl-, ACh- or histamine-evoked contractions of isolated trachea was significantly inhibited by increasing concentrations of Edici (3.5-10 mg/ml. Edici (10 mg/ml as well as promethazine (0.25 mg/ml significantly inhibited contractions induced by increasing concentrations of histamine (1×10-7-1×10-4mg/ml. In the presence of atropine at a concentration of 10-6mg/ml, contractile response curve (CRC evoked by ACh (1×10-5-1×10-2 mg/ml was significantly abolished in concentration-dependent manner. Edici did not significantly reduced ACh evoked contraction (10-5-10-2mg/ml. Conclusion These observations suggest

  12. The efficacy of a comprehensive lifestyle modification programme based on yoga in the management of bronchial asthma: a randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Bijlani Ramesh


    Full Text Available Abstract Background There is a substantial body of evidence on the efficacy of yoga in the management of bronchial asthma. Many studies have reported, as the effects of yoga on bronchial asthma, significant improvements in pulmonary functions, quality of life and reduction in airway hyper-reactivity, frequency of attacks and medication use. In addition, a few studies have attempted to understand the effects of yoga on exercise-induced bronchoconstriction (EIB or exercise tolerance capacity. However, none of these studies has investigated any immunological mechanisms by which yoga improves these variables in bronchial asthma. Methods The present randomized controlled trial (RCT was conducted on 57 adult subjects with mild or moderate bronchial asthma who were allocated randomly to either the yoga (intervention group (n = 29 or the wait-listed control group (n = 28. The control group received only conventional care and the yoga group received an intervention based on yoga, in addition to the conventional care. The intervention consisted of 2-wk supervised training in lifestyle modification and stress management based on yoga followed by closely monitored continuation of the practices at home for 6-wk. The outcome measures were assessed in both the groups at 0 wk (baseline, 2, 4 and 8 wk by using Generalized Linear Model (GLM repeated measures followed by post-hoc analysis. Results In the yoga group, there was a steady and progressive improvement in pulmonary function, the change being statistically significant in case of the first second of forced expiratory volume (FEV1 at 8 wk, and peak expiratory flow rate (PEFR at 2, 4 and 8 wk as compared to the corresponding baseline values. There was a significant reduction in EIB in the yoga group. However, there was no corresponding reduction in the urinary prostaglandin D2 metabolite (11β prostaglandin F2α levels in response to the exercise challenge. There was also no significant change in serum

  13. O volume expiratório forçado no primeiro segundo não é suficiente para avaliar resposta broncodilatadora em doença pulmonar obstrutiva crônica Measuring forced expiratory volume in one second alone is not an accurate method of assessing response to bronchodilators in chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Felícia de Moraes Branco Tavares


    , residual volume, airway resistance and specific airway conductance. METHODS: A total of 64 patients with chronic obstructive pulmonary disease were submitted to whole body plethysmography, and reversibility of bronchoconstriction after the administration 400 µg of fenoterol was quantified. RESULTS: A response in forced expiratory volume in one second was observed in 31% of the patients. Excluding patients presenting a response in forced expiratory volume in one second, 5% presented responses in 5 of the other 6 parameters, 10% presented responses in 4 parameters, 17.5% in 3 parameters, 27.5% in 2 parameters, and 25% in only 1 parameter. CONCLUSION: When included in the evaluation of bronchodilator response together with forced expiratory volume in one second, static lung volumes, airway resistance and airway conductance allowed a broader evaluation of those patients presenting a functional pharmacodynamic response. These results are in accordance with the observation that bronchodilator use provides clinical improvement and relief of dyspnea to many patients with chronic obstructive pulmonary disease, even to those in whom such treatment leads to no improvement in forced expiratory volume in one second.

  14. ¿Son las cenizas volcánicas un riesgo para la salud respiratoria?: Revisión a propósito de la erupción del cordón del Caulle en junio de 2011 Are volcanic ashes a risk for the respiratory health?: A review apropos of volcanic eruption of cord of Caulle, Chile in June 2011

    Directory of Open Access Journals (Sweden)

    Edgardo Grob B


    others. The impact of a volcanic eruption on human health depends on the type of eruption at which inhabitants have been exposed, the duration of this exposure and the previous health conditions of the exposed people. Some of these effects on human health are well known, such as burns, trauma, and respiratory disorders. In acute as well as in long term exposure, some of the respiratory health effects are still a matter of controversy and research on the mechanisms involved. Among the main adverse effects described in the respiratory tract are bronchoconstriction, amplification of the inflammatory response, complement disorders, silicosis and carcinogenesis. Considering the recent volcano eruptions of mount Chaitén (2008 and the cord of Caulle (2011 located in the south of Chile, we reviewed the deleterious effects of volcanic eruptions on human health and specifically on the respiratory system. Throughout this review we enclosed a number of recommendations, hopefully they will be useful in facing new volcanic eruptions in our country and everywhere.

  15. Respiratory medicine and research at McGill University: A historical perspective (United States)

    Martin, James G; Schwartzman, Kevin


    pioneered the study of the physiological consequences of small airway pathology. Dr Joseph Milic-Emili succeeded Dr Macklem as director of the Meakins-Christie Laboratories in 1979. Milic-Emili was renowned for his work on ventilation distribution and the assessment of pleural pressure. He led the development of convenient tools for the assessment of respiratory drive. He clarified the physiological basis for carbon dioxide retention in patients with COPD placed on high inspired oxygen concentrations. Another area that captured many investigators’ attention in the 1980s was the notion of respiratory failure as a consequence of respiratory muscle fatigue. Dr Charalambos (‘Charis’) Roussos made seminal contributions in this field. These studies triggered a long-lasting interest in respiratory muscle training, in rehabilitation, and in noninvasive mechanical ventilation for acute and chronic respiratory failure. Dr Ludwig Engel obtained his PhD under the supervision of Peter Macklem and established himself in the area of ventilation distribution in health and in bronchoconstriction and the mechanics of breathing in asthma; he trained many investigators including one of the authors, Dr Jim Martin, who succeeded Milic-Emili as director of the Meakins Christie Laboratories from 1993 to 2008. Dr Martin developed small animal models of allergic asthma, and adopted a recruitment strategy that diversified the research programs at the Meakins Christie Laboratories. Dr Manuel Cosio built on earlier work with Macklem and Hogg in his development of key structure-function studies of COPD. He was instrumental in recruiting a new generation of young investigators with interests in sleep medicine and neuromuscular diseases. The 1970s and 1980s also witnessed the emergence of a topnotch respiratory division at the Montreal General Hospital, in large part reflecting the leadership of Dr Neil Colman, later a lead author of the revised Fraser and Paré textbook. At the Montreal General