Regional airflow obstruction after bronchoconstriction and subsequent bronchodilation in subjects without pulmonary disease.

Some subjects with asthma have ventilation defects that are resistant to bronchodilator therapy, and it is thought that these resistant defects may be due to ongoing inflammation or chronic airway remodeling. However, it is unclear whether regional obstruction due to bronchospasm alone persists after bronchodilator therapy. To investigate this, six young, healthy subjects, in whom inflammation and remodeling were assumed to be absent, were bronchoconstricted with a PC20 [the concentration of methacholine that elicits a 20% drop in forced expiratory volume in 1 s (FEV1)] dose of methacholine and subsequently bronchodilated with a standard dose of albuterol on three separate occasions. Specific ventilation imaging, a proton MRI technique, was used to spatially map specific ventilation across 80% of each subject's right lung in each condition. The ratio between regional specific ventilation at baseline and after intervention was used to classify areas that had constricted. After albuterol rescue from methacholine bronchoconstriction, 12% (SD 9) of the lung was classified as constricted. Of the 12% of lung units that were classified as constricted after albuterol, approximately half [7% (SD 7)] had constricted after methacholine and failed to recover, whereas half [6% (SD 4)] had remained open after methacholine but became constricted after albuterol. The incomplete regional recovery was not reflected in the subjects' FEV1 measurements, which did not decrease from baseline (P = 0.97), nor was it detectable as an increase in specific ventilation heterogeneity (P = 0.78).NEW & NOTEWORTHY In normal subjects bronchoconstricted with methacholine and subsequently treated with albuterol, not all regions of the healthy lung returned to their prebronchoconstricted specific ventilation after albuterol, despite full recovery of integrative lung indexes (forced expiratory volume in 1 s and specific ventilation heterogeneity). The regions that remained bronchoconstricted following albuterol were those with the highest specific ventilation at baseline, which suggests that they may have received the highest methacholine dose.

Elevation in lung volume and preventing catastrophic airway closure in asthmatics during bronchoconstriction.

BACKGROUND: Asthma exacerbations cause lung hyperinflation, elevation in load to inspiratory muscles, and decreased breathing capacity that, in severe cases, may lead to inspiratory muscle fatigue and respiratory failure. Hyperinflation has been attributed to a passive mechanical origin; a respiratory system time-constant too long for full exhalation. However, because the increase in volume is also concurrent with activation of inspiratory muscles during exhalation it is unclear whether hyperinflation in broncho-constriction is a passive phenomenon or is actively controlled to avoid airway closure. METHODS: Using CT scanning, we measured the distensibility of individual segmental airways relative to that of their surrounding parenchyma in seven subjects with asthma and nine healthy controls. With this data we tested whether the elevation of lung volume measured after methacholine (MCh) provocation was associated with airway narrowing, or to the volume required to preventing airway closure. We also tested whether the reduction in FVC post-MCh could be attributed to gas trapped behind closed segmental airways. FINDINGS: The changes in lung volume by MCh in subjects with and without asthma were inversely associated with their reduction in average airway lumen. This finding would be inconsistent with hyperinflation by passive elevation of airway resistance. In contrast, the change in volume of each subject was associated with the lung volume estimated to cause the closure of the least stable segmental airway of his/her lungs. In addition, the measured drop in FVC post MCh was associated with the estimated volume of gas trapped behind closed segmental airways at RV. CONCLUSIONS: Our data supports the concept that hyperinflation caused by MCh-induced bronchoconstriction is the result of an actively controlled process where parenchymal distending forces on airways are increased to counteract their closure. To our knowledge, this is the first imaging-based study that associates inter-subject differences in whole lung behavior with the interdependence between individual airways and their surrounding parenchyma.

Bronchial hyper-responsiveness: a technical update.

BACKGROUND: Bronchial hyper-responsiveness (BHR) is often regarded as a 'hallmark' of asthma, and bronchoprovocation testing is frequently performed to support a diagnosis of asthma. The European Respiratory Society (ERS) and American Thoracic Society (ATS) have recently updated their technical standards and guidelines for performing methacholine challenge testing (MCT), the most commonly performed clinical test of BHR. AIMS: To review the updated guidelines and discuss the various changes and their potential impact on clinicians. METHODS: We performed a systematic review of references identified using Medline and hand searches of identified articles. RESULTS: The new ERS and ATS guidelines recommend that MCT be performed using tidal breathing, not deep inspirations with breath holding, that results be reported as the PD20 (cumulative dose causing a 20% fall in forced expiratory volume in 1 s [FEV1]), rather than PC20 (concentration causing a 20% fall in FEV1), and that manufacturers of nebulizers and other delivery systems provide performance characteristics to allow calculation of PD20 values. Our preliminary survey found that the new guidelines are only slowly being adopted. CONCLUSIONS: Clinicians should be aware that recommended BHR testing methods, particularly for MCT, have changed. As a result, they should anticipate that test outcomes will increasingly be reported in terms of PD20, which will facilitate longitudinal assessment of their patients. Compliance with the new guidelines will increase the sensitivity of MCT in mild and asymptomatic asthmatics.

Sodium Metabisulfite: Effects on Ionic Currents and Excitotoxicity.

How sodium metabisulfite (SMB; Na2S2O5), a popular food preservative and antioxidant, interacts with excitable membrane and induces excitotoxicity is incompletely understood. In this study, the patch-clamp technique was used to investigate and record the electrophysiological effect of SMB on electrically excitable HL-1 cardiomyocytes and NSC-34 neurons, as well as its relationship to pilocarpine-induced seizures and neuronal excitotoxicity in rats. We used Western blotting, to analyze sodium channel expression on hippocampi after chronic SMB treatment. It was found that voltage-gated Na+ current (I Na) was stimulated, and current inactivation and deactivation were slowed in SMB-treated (30 µM) HL-1 cardiomyocytes. SMB-induced increases of I Na were attenuated in cells treated with ranolazine (10 µM) or eugenol (30 µM). The current-voltage relationship of I Na shifted to slightly more negative potentials in SMB-treated cells, the peak I Na with an EC50 value of 18 µM increased, and the steady-state inactivation curve of I Na shifted to a more positive potential. However, the tail component of the rapidly activating delayed-rectifier K+ current (I Kr) was dose-dependently inhibited. Cell-attached voltage-clamp recordings in SMB-treated cells showed that the frequency of action currents and prolonged action potential were higher. In SMB-treated NSC-34 neurons, the peak I Na was higher; however, neither the time to peak nor the inactivation time constant (I Na) changed. Pilocarpine-induced seizures were exacerbated, and acute neuronal damage and chronic mossy fiber sprouting increased in SMB-treated rats. Western blotting showed higher expression of the sodium channel in cells after chronic SMB treatment. We conclude that SMB contributes to the sodium channel-activating mechanism through which it alters cellular excitability and excitotoxicity in wide-spectrum excitable cells.

Oral administration of Lactobacillus paracasei L9 attenuates PM2.5-induced enhancement of airway hyperresponsiveness and allergic airway response in murine model of asthma.

This study investigated allergy immunotherapy potential of Lactobacillus paracasei L9 to prevent or mitigate the particulate matter 2.5 (PM2.5) enhanced pre-existing asthma in mice. Firstly, we used a mouse model of asthma (a 21-day ovalbumin (OVA) sensitization and challenge model) followed by PM2.5 exposure twice on the same day of the last challenge. PM2.5 was collected from the urban area of Beijing and underwent analysis for metals and polycyclic aromatic hydrocarbon contents. The results showed that PM2.5 exposure enhanced airway hyper-responsiveness (AHR) and lead to a mixed Th2/ IL-17 response in asthmatic mice. Secondly, the PM2.5 exposed asthmatic mice were orally administered with L9 (4×107, 4×109 CFU/mouse, day) from the day of first sensitization to the endpoint, for 20 days, to investigate the potential mitigative effect of L9 on asthma. The results showed that L9 ameliorated PM2.5 exposure enhanced AHR with an approximate 50% decrease in total airway resistance response to methacholine (48 mg/ml). L9 also prevented the exacerbated eosinophil and neutrophil infiltration in bronchoalveolar lavage fluid (BALF), and decreased the serum level of total IgE and OVA-specific IgG1 by 0.44-fold and 0.3-fold, respectively. Additionally, cytokine production showed that L9 significantly decreased T-helper cell type 2 (Th2)-related cytokines (IL-4, -5, -13) and elevated levels of Th1 related IFN-γ in BALF. L9 also reduced the level of IL-17A and increased the level of TGF-ß. Taken together, these results indicate that L9 may exert the anti-allergic benefit, possibly through rebalancing Th1/Th2 immune response and modulating IL-17 pro-inflammatory immune response. Thus, L9 is a promising candidate for preventing PM exposure enhanced pre-existing asthma.

Fluticasone/formoterol association favors long-lasting decrease in bronchial reactivity to methacholine and weekly PEF variability.

Inhaled corticosteroids (ICS)/long-acting beta-agonists (LABA) association offers a better asthma control than a higher steroid dose with short-acting beta-agonists as needed. In this study, we evaluated the effect of the association on bronchial hyperreactivity (BHR) and peak expiratory flow (PEF) variability, as such parameters are positively correlated with increased asthma morbidity and exacerbations. Thirty-six adult patients with mild persistent asthma were enrolled. After a 7-day run-in, they were randomly assigned to three therapy regimens for 6 weeks: Group 1, fluticasone 125 µg + formoterol 5 µg in the same device; Group 2, fluticasone 125 µg + formoterol 12 µg as needed; Group 3, fluticasone 250 µg + formoterol 12 µg as needed. We evaluated changes induced in weekly PEF variability (measured during the entire study and 4 weeks of follow-up) and pre- and post-study PD20 methacholine (MCH). Weekly PEF variability decreased in all groups during treatment with the greatest reduction in Group 1, followed by Group 3, and finally Group 2. During the follow-up, no significant changes were detected in Group 1, whereas a trend towards an increased variability was found in Groups 2 and 3. Post-treatment PD20 MCH was significantly higher versus the pre-treatment. The increase observed in Group 1 was significantly higher compared to Groups 2 and 3 and that observed in Group 3 in respect to Group 2. The study proves that both BHR and PEF variability are influenced by ICS. This effect was greater with fluticasone/formoterol association compared to fluticasone alone with formoterol as needed even at higher steroid dose.

Novel treatment strategies for smooth muscle disorders: Targeting Kv7 potassium channels.

Smooth muscle cells provide crucial contractile functions in visceral, vascular, and lung tissues. The contractile state of smooth muscle is largely determined by their electrical excitability, which is in turn influenced by the activity of potassium channels. The activity of potassium channels sustains smooth muscle cell membrane hyperpolarization, reducing cellular excitability and thereby promoting smooth muscle relaxation. Research over the past decade has indicated an important role for Kv7 (KCNQ) voltage-gated potassium channels in the regulation of the excitability of smooth muscle cells. Expression of multiple Kv7 channel subtypes has been demonstrated in smooth muscle cells from viscera (gastrointestinal, bladder, myometrial), from the systemic and pulmonary vasculature, and from the airways of the lung, from multiple species, including humans. A number of clinically used drugs, some of which were developed to target Kv7 channels in other tissues, have been found to exert robust effects on smooth muscle Kv7 channels. Functional studies have indicated that Kv7 channel activators and inhibitors have the ability to relax and contact smooth muscle preparations, respectively, suggesting a wide range of novel applications for the pharmacological tool set. This review summarizes recent findings regarding the physiological functions of Kv7 channels in smooth muscle, and highlights potential therapeutic applications based on pharmacological targeting of smooth muscle Kv7 channels throughout the body.

Vagotomy reverses established allergen-induced airway hyperreactivity to methacholine in the mouse.

We evaluated the role of vagal reflexes in a mouse model of allergen-induced airway hyperreactivity. Mice were actively sensitized to ovalbumin then exposed to the allergen via inhalation. Prior to ovalbumin inhalation, mice also received intratracheally-instilled particulate matter in order to boost the allergic response. In control mice, methacholine (i.v.) caused a dose-dependent increase in respiratory tract resistance (RT) that only modestly decreased if the vagi were severed bilaterally just prior to the methacholine challenge. Sensitized and challenged mice, however, manifested an airway reactivity increase that was abolished by severing the vagi prior to methacholine challenge. In an innervated ex vivo mouse lung model, methacholine selectively evoked action potential discharge in a subset of distension-sensitive A-fibers. These data support the hypothesis that the major component of the increased airway reactivity in inflamed mice is due to a vagal reflex initiated by activation of afferent fibers, even in response to a direct (i.e., smooth muscle)-acting muscarinic agonist.

Effect of airway smooth muscle tone on airway distensibility measured by the forced oscillation technique in adults with asthma.

Airway distensibility appears to be unaffected by airway smooth muscle (ASM) tone, despite the influence of ASM tone on the airway diameter-pressure relationship. This discrepancy may be because the greatest effect of ASM tone on airway diameter-pressure behavior occurs at low transpulmonary pressures, i.e., low lung volumes, which has not been investigated. Our study aimed to determine the contribution of ASM tone to airway distensibility, as assessed via the forced oscillation technique (FOT), across all lung volumes with a specific focus on low lung volumes. We also investigated the accompanying influence of ASM tone on peripheral airway closure and heterogeneity inferred from the reactance versus lung volume relationship. Respiratory system conductance and reactance were measured using FOT across the entire lung volume range in 22 asthma subjects and 19 healthy controls before and after bronchodilator. Airway distensibility (slope of conductance vs. lung volume) was calculated at residual volume (RV), functional residual capacity (FRC), and total lung capacity. At baseline, airway distensibility was significantly lower in subjects with asthma at all lung volumes. After bronchodilator, distensibility significantly increased at RV (64.8%, P < 0.001) and at FRC (61.8%, P < 0.01) in subjects with asthma but not in control subjects. The increased distensibility at RV and FRC in asthma were not associated with the accompanying changes in the reactance versus lung volume relationship. Our findings demonstrate that, at low lung volumes, ASM tone reduces airway distensibility in adults with asthma, independent of changes in airway closure and heterogeneity.

Leukotriene receptors are differently expressed in fibroblast from peripheral versus central airways in asthmatics and healthy controls.

Leukotrienes are involved in airway inflammation, and are believed to stimulate airway remodeling in asthma. The aim of the project was to investigate the expression of leukotriene receptors in peripheral and central airway fibroblasts. Peripheral and central airway fibroblasts, from asthmatics and healthy controls, were investigated for the amount of cysteinyl-leukotriene receptors (CysLT(1) and CysLT(2)), leukotriene B(4) receptors (BLT(1) and BLT(2)), IL-13 receptor-α(1) (IL-13Rα(1)) and the IL-4 receptor (IL-4R). The mRNA expression of CysLT(1) in fibroblasts from peripheral airways was higher compared to central airways. There was no difference in CysLT(2) between peripheral and central airways. On the contrary, BLT(1) and BLT(2) were lower in fibroblasts from peripheral airways compared to central. The expression of CysLT(1) was higher than CysLT(2) in fibroblasts from peripheral airways, and the expression of BLT(1) was higher than BLT(2) in both peripheral and central airways. Both BLT(1) and BLT(2) were higher in asthmatics compared to healthy controls, while CysLT(1) and CysLT(2) did not differ. The expression of IL-13Rα(1) was higher in asthmatics compared to controls, and correlated to the BLTs. All fibroblasts stained for the different receptor proteins. Leukotriene receptors are differently expressed in fibroblasts from peripheral compared to central airways, which may explain a suggested cysteinyl-leukotriene driven remodeling mainly in the peripheral airways.

Airway responsiveness and bronchoalveolar lavage fluid profiling in individual rats: effects of different ovalbumin exposures.

We studied repeatedly the development of bronchial hyperreactivity (BHR) and bronchoalveolar lavage fluid (BALF) in rats undergoing different modes of ovalbumin exposures. Treatment was two intraperitoneal injections of ovalbumin in Groups 1-3, followed by one ovalbumin aerosolization in Groups 2 and 3, while rats in Group 4 received repeated ovalbumin aerosols after one single intraperitoneal injection. BHR was assessed longitudinally on day 0 (before treatment) and on day 14 (Groups 1 and 2) or 20 (Groups 3 and 4) and cellular influx was estimated from BALF. No BHR or change in BALF cellular profile was detected in Groups 1-3. However, the infiltration of inflammatory cells, associated with BHR (PC(100) 8.9+/-1.3 microg/kg vs. 4.2+/-1.1 microg/kg), was observed in Group 4. The BHR was always associated with increased number of eosinophils in the BALF. The substantial interindividual variability confirmed the need for a technique that permits follow-up of lung responsiveness and BALF profile. This approach evidenced strong associations between the severity of BHR and the eosinophilia.

Percepción de la disnea y cumplimiento terapéutico en pacientes con asma / Perception of dyspnea and treatment adherence in asthmatic patients

OBJETIVO: El cumplimiento terapéutico en una enfermedad crónica como el asma no supera el 50% en la mayoría de las series. Aunque las razones sean de muy diversa índole, es evidente que el incumplimiento es un factor determinante en el mal control de la enfermedad. Por otra parte, la falta de percepción de la disnea se ha asociado con el asma de control difícil y con la aparición de crisis de asma fatal o casi fatal. Así pues, el objetivo del presente estudio ha sido intentar demostrar que una de las razones por las cuales los asmáticos no toman su medicación es que no tienen percepción de disnea cuando sus bronquios se obstruyen. PACIENTES Y MÉTODOS: Hemos estudiado a 2 grupos de pacientes con asma persistente y moderada, a quienes se había prescrito el mismo tratamiento de forma continuada (una dosis de medicación inhalada en polvo seco cada 12 h). El primero estaba formado por 24 pacientes (16 mujeres y 8 varones; edad media ± desviación estándar: 44 ± 15 años) que tomaban casi todos los días la medicación, y el segundo, por otros 24 pacientes (16 mujeres y 8 varones; edad media: 48 ± 14 años) que no tomaban la medicación o lo hacían sólo de vez en cuando. No había diferencias significativas entre los grupos en cuanto a edad, sexo, porcentaje de fumadores, niveles económico y educativo, ansiedad, depresión y parámetros espirométricos. A todos ellos se les realizó una prueba de broncoprovocación con histamina, y se midió la disnea experimentada tras cada dosis del fármaco en una escala modificada de Borg. Se determinaron la dosis de histamina con la que se alcanzó una caída del 20% en el volumen espiratorio forzado en el primer segundo (FEV1), la percepción de disnea con una caída del FEV1 del 20% (PS20) y el cambio de disnea en la escala de Borg desde la situación inicial hasta la caída del 20% de FEV1 (cambio en Borg). Además, se clasificó a los pacientes como hipoperceptores de disnea cuando su cambio en Borg fue igual o inferior a 0. RESULTADOS: El grupo de incumplidores tenía menor PS20 (2,27 ± 1,9 frente a 3,51 ± 1,8 en el grupo de cumplidores; p = 0,030) y cambio en Borg (1,64 ± 1,9 frente a 2,7 ± 1,84; p = 0,057), y eran con mayor frecuencia hipoperceptores de disnea (el 50% frente al 21%; p = 0,034). CONCLUSIONES: Existe relación entre el cumplimiento del tratamiento y la percepción de disnea, de forma que uno de los motivos del incumplimiento terapéutico en los pacientes con asma es la hipopercepción de disnea

OBJECTIVE: The majority of studies show that treatment adherence in chronic diseases such as asthma does not exceed 50%. Although the reasons may vary, it is clear that lack of treatment adherence is a determining factor in poor disease control. An association has also been observed between lack of perception of dyspnea and difficult-to-control asthma and with the occurrence of fatal or near-fatal asthma attacks. In this study we therefore attempted to demonstrate that one of the reasons that asthmatic patients do not adhere to treatment is a failure to perceive dyspnea associated with bronchial obstruction. PATIENTS AND METHODS: We analyzed 2 groups of patients with moderate persistent asthma who had all been prescribed the same chronic treatment (a dose of inhaled drug administered with a dry powder inhaler every 12 hours). The first group comprised 24 patients (16 women and 8 men; mean [SD] age, 44 [15] years) who took the medication almost every day. The second group contained 24 patients (16 women and 8 men; mean [SD] age, 48 [14] years) who did not use the medication or only took it occasionally. There were no significant differences between the groups in terms of age, sex, percentage of smokers, socioeconomic and educational level, anxiety, depression, or spirometry variables. A histamine challenge test was carried out in all patients and the dyspnea perceived after each dose of the drug was measured on a modified Borg scale. The dose of histamine leading to a 20% reduction in forced expiratory volume in 1 second (FEV1), perception of dyspnea associated with a 20% reduction in FEV1 (PS20), and the change in dyspnea measured on the Borg scale between baseline and 20% reduction in FEV1 were analyzed. Patients were also classified as poor perceivers of dyspnea if the change in perception of dyspnea on the modified Borg scale was less than or equal to zero. RESULTS: The group of patients with poor treatment compliance had a lower PS20 (2.27 [1.9] vs 3.51 [1.8], P=.03) and change in Borg score (1.64 [1.9] vs 2.7 [1.84], P=.057), and they were more often poor perceivers of dyspnea (50% vs 21%, P=.034). CONCLUSIONS: There is a relationship between treatment adherence and dyspnea perception, such that poor perception is among the reasons for poor treatment adherence in patients with asthma

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

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) test, a field-based exercise test (FBT), a laboratory-based exercise test (LBT), and a methacholine challenge. The criteria suggested by the IOC-MC were used to define a positive response to the challenges (EVH, field test, and laboratory test: minimum 10% decrease in FEV1; methacholine: PD20 < or = 2 micromol). RESULTS: Eight swimmers (50%) had at least one positive test to hyperpnea. Five were identified with the EVH test, four with FBT, and four with LBT. None were identified using methacholine. Three swimmers with airway hyperresponsiveness to exercise would have been identified using a higher cutoff for methacholine (PD20 < or = 8 micromol). CONCLUSIONS: The EVH test is the test that diagnoses most swimmers with an abnormal response to hyperpnea, but not all cases of EIB are identified with the EVH test. Performing a methacholine test using IOC-MC's cutoff value does not improve the chances 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.

Comparison and optimal use of fixed combinations in the management of COPD.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Indications for the use of long-acting beta-agonists (LABAs) and inhaled corticosteroids (ICS) in patients with COPD are described in the various international guidelines, but no special recommendations are made concerning the use of combination inhalers containing a LABA as well as an ICS. To determine the place of combination inhalers in the treatment of COPD we reviewed recent literature concerning this subject. On molecular level ICS/LABA combination therapy has anti-inflammatory properties which cannot be attributed to ICS alone. All clinical studies indicate that the two available combinations (salmeterol/fluticasone and formoterol/budesonide) significantly reduce exacerbation rate of moderate/severe exacerbations when compared with placebo. Some studies also showed a significant reduction in exacerbation rate compared with LABA monotherapy, but not compared with ICS monotherapy. From the patient's perspective, ICS/LABA combination inhalers are the first choice when both need to be prescribed, possibly improving patient compliance for ICS. Currently little evidence is available to predict if flexible treatment with LABA/ICS combination inhalers will improve disease control in COPD. Further studies are needed to elucidate the clinical benefit of combination inhalers versus the individual components in different inhalers, and to investigate the clinical benefit of flexible dosing of combination inhalers in patients with COPD.

Estudio de la función pulmonar en el paciente colaborador. Parte II / Respiratory function assessment in cooperative patients. Part II

El análisis de la hiperrespuesta bronquial mediante pruebas de provocación bronquial es uno de los pilares fundamentales para el diagnóstico de asma, así como un instrumento válido para la monitorización de la enfermedad, valoración de su gravedad, su evolución y la respuesta al tratamiento. Revisamos las pruebas de provocación bronquial inespecíficas tanto por estímulos físicos (ejercicio físico, soluciones hiperosmolares, y la hiperventilación con aire frío) como por fármacos (metacolina y adenosina). Aunque hay una cierta correlación entre las respuestas a diferentes tipos de prueba, hay niños que responden de forma diferente. La elección de la prueba que hay que utilizar dependerá de los fines diagnósticos o epidemiológicos que persigamos, de la experiencia de su utilización, dándonos frecuentemente información complementaria. Las pruebas de provocación indirectas como los estímulos físicos y la adenosina son más específicas del asma

Analysis of bronchial hyperresponsiveness using bronchial provocation tests are a key feature in the diagnosis of asthma, as well as a valid tool for monitoring disease severity, clinical course, and treatment response. We review non-specific bronchial challenge tests, including pharmacological stimuli (methacholine, adenosine) and physical stimuli (exercise, hypertonic saline, cold air hyperventilation). Although there is some correlation among responses to the distinct tests, individual responses are also observed. The indication for a single test will depend on whether the procedure will be used for diagnostic or epidemiologic purposes, and on experience of its use. Frequently, complementary information will be obtained. Indirect airway challenges tests such as physical stimuli and adenosine are more specific for asthma diagnosis

The i.v. infusion of mannitol decreases airway responsiveness to methacholine in asthma.

Bronchial asthma and chronic obstructive pulmonary disease (COPD) are characterized by airway inflammation and oedema. The oedema of the airway wall may contribute to airway narrowing and hyperresponsiveness by increasing airway wall thickness, by altering airway compliance, or by impairing the transmission of the lung elastic recoil to the airway smooth muscle (ASM). We hypothesized that the i.v. infusion of mannitol, an osmotic diuretic, would reduce the water content of the airway wall in asthma and COPD, thus decreasing airway responsiveness to methacholine (MCh). In eight asthmatic and in six COPD patients, airway responsiveness to MCh, lung volumes and lung mechanics were measured before and after infusion of mannitol. In the asthmatics, mannitol decreased airway responsiveness to MCh and lung elastic recoil. In the COPD patients, no differences were recorded after mannitol infusion. These data suggest that the airway wall oedema, in asthma, has an impact on airway responsiveness to MCh. The differential effect of mannitol in asthma versus COPD, may relate to the specific pathologic features of the diseases.

Significant linkage to airway responsiveness on chromosome 12q24 in families of children with asthma in Costa Rica.

Although asthma is a major public health problem in certain Hispanic subgroups in the United States and Latin America, only one genome scan for asthma has included Hispanic individuals. Because of small sample size, that study had limited statistical power to detect linkage to asthma and its intermediate phenotypes in Hispanic participants. To identify genomic regions that contain susceptibility genes for asthma and airway responsiveness in an isolated Hispanic population living in the Central Valley of Costa Rica, we conducted a genome-wide linkage analysis of asthma (n = 638) and airway responsiveness (n = 488) in members of eight large pedigrees of Costa Rican children with asthma. Nonparametric multipoint linkage analysis of asthma was conducted by the NPL-PAIR allele-sharing statistic, and variance component models were used for the multipoint linkage analysis of airway responsiveness as a quantitative phenotype. All linkage analyses were repeated after exclusion of the phenotypic data of former and current smokers. Chromosome 12q showed some evidence of linkage to asthma, particularly in nonsmokers (P < 0.01). Among nonsmokers, there was suggestive evidence of linkage to airway responsiveness on chromosome 12q24.31 (LOD = 2.33 at 146 cM). After genotyping 18 additional short-tandem repeat markers on chromosome 12q, there was significant evidence of linkage to airway responsiveness on chromosome 12q24.31 (LOD = 3.79 at 144 cM), with a relatively narrow 1.5-LOD unit support interval for the observed linkage peak (142-147 cM). Our results suggest that chromosome 12q24.31 contains a locus (or loci) that influence a critical intermediate phenotype of asthma (airway responsiveness) in Costa Ricans.

Comparative effects of a high-intensity interval warm-up and salbutamol on the bronchoconstrictor response to exercise in asthmatic athletes.

Approximately half of all asthmatics become refractory to exercise-induced bronchoconstriction (EIB) with repeated challenges. Exercise refractoriness has been utilized by asthmatic athletes to reduce the bronchoconstrictor response to exercise prior to competition, and this has led to the observation that some asthmatic athletes can "run through" their asthma. The main aim of this study was to investigate the efficacy of short high-intensity, repeated warm-ups compared with salbutamol (a commonly used inhaled beta (2)-agonist) on the severity of EIB. Eight moderately trained (.VO(2peak), 51.9 +/- 2.3 ml . kg (-1) . min (-1)) recreational asthmatic athletes with documented EIB were tested under 4 experimental conditions: 1) control (CON) condition; 2) an interval warm-up (WU) consisting of 8 x 30-sec runs at peak treadmill speed, with 45-sec recovery between each sprint; 3) inhaling 200 microg of salbutamol (Ventolin, GlaxoSmithKline, Uxbridge, Middlesex, U.K.) (IH); and 4) combining both the WU and IH session. All 4 experimental sessions were followed by an exercise challenge test (85-90 % predicted maximum heart rate for 8 min). Pulmonary function was measured pre-exercise and at 1, 5, 10, 15 min postexercise. The mean maximum percent fall in pre- to postexercise forced expiratory volume in 1-sec (FEV (1)) for all 8 asthmatic subjects during the EIB screening test (CON session) was - 18.25 +/- 4.01 %. The mean maximum percent decrease in postexercise FEV (1) significantly decreased (p < 0.05) to only - 9.1 +/- 0.6 % following the WU condition, which is below the EIB diagnostic threshold of a 10 % fall in postexercise FEV (1). The IH and WU + IH condition resulted in a substantial postexercise bronchodilation as shown by a significant increase (p < 0.05) in the mean maximum percent change in postexercise FEV (1) following the IH (+ 8.9 +/- 6.1 %) and WU + IH (+ 15.2 +/- 4.6 %) condition. Similar changes as a result of experimental condition were observed for FEF (25-75 %). These data indicate that repeated high-intensity warm-ups can lessen the bronchoconstrictor response to exercise. In addition, combining the interval warm-up with salbutamol prior to exercise resulted in substantial bronchodilation and conferred a greater protective effect against developing EIB than either intervention alone.