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For most patients, asthma is not controlled as defined by guidelines; whether this is achievable has not been prospectively studied. A 1-year, randomized, stratified, double-blind, parallel-group study of 3,421 patients with uncontrolled asthma compared fluticasone propionate and salmeterol/fluticasone in achieving two rigorous, composite, guideline-based measures of control: totally and well-controlled asthma. Treatment was stepped-up until total control was achieved (or maximum 500 microg corticosteroid twice a day). Significantly more patients in each stratum (previously corticosteroid-free, low- and moderate-dose corticosteroid users) achieved control with salmeterol/fluticasone than fluticasone. Total control was achieved across all strata: 520 (31%) versus 326 (19%) patients after dose escalation (p < 0.001) and 690 (41%) versus 468 (28%) at 1 year for salmeterol/fluticasone and fluticasone, respectively. Asthma became well controlled in 1,071 (63%) versus 846 (50%) after dose escalation (p < 0.001) and 1,204 (71%) versus 988 (59%) at 1 year. Control was achieved more rapidly and at a lower corticosteroid dose with salmeterol/fluticasone versus fluticasone. Across all strata, 68% and 76% of the patients receiving salmeterol/fluticasone and fluticasone, respectively, were on the highest dose at the end of treatment. Exacerbation rates (0.07-0.27 per patient per year) and improvement in health status were significantly better with salmeterol/fluticasone. This study confirms that the goal of guideline-derived asthma control was achieved in a majority of the patients. [ABSTRACT FROM AUTHOR]

STUDY OBJECTIVES: Autoadjustable continuous positive airway pressure (CPAP) devices are increasingly used in the treatment of obstructive sleep apnea (OSA). Since different measurements of upper airway obstruction are applied, it is uncertain whether these devices are equally effective in controlling sleep-disordered breathing. Hypothesizing that differences in therapeutic efficacy were to come out, we compared the performance of the AutoSet device (ResMed; Sydney, Australia), which features autoadjustable positive airway pressure (APAP) guided by detection of flow limitation (APAPfl), with the SOMNOsmart device (Weinmann; Hamburg, Germany), which features APAP guided by the forced oscillation technique (APAPfot). DESIGN: A double-blind, randomized, cross-over trial. SETTING: The sleep disorders center and sleep laboratory of a university hospital. PATIENTS AND INTERVENTIONS: An overnight CPAP autotitration procedure was performed in 30 patients with OSA. A split-night protocol allowed that each patient used both devices. MEASUREMENTS AND RESULTS: Using polysomnography, sleep, indexes of sleep-disordered breathing, snoring, and CPAP levels were recorded. No significant differences were found in conventional sleep variables. While the apnea-hypopnea index (AHI) was lower with APAPfl (3.5 +/- 5.6/h) as compared to APAPfot (9.9 +/- 31.0/h), the difference was not statistically significant (mean +/- SD). The snoring index, however, was significantly lower with APAPfl (35.3 +/- 53.7/h vs 111.6 +/- 175.4/h, respectively; p = 0.01). The median and 95th percentile pressure levels rose from wakefulness to sleep in APAPfl, but decreased in APAPfot. Higher pressure variability was present in the latter method. CONCLUSIONS: These findings suggest that the APAPfl is superior to APAPfot in the control of snoring. While a lower AHI was achieved with APAPfl, at the expense of a higher median pressure but less pressure variability, the difference with APAPfot was not statistically significant. [ABSTRACT FROM AUTHOR]

Background: Although inhaled glucocorticosteroids are recommended for persistent asthma, their long-term effect on recent onset, mild, persistent asthma has yet to be established.Methods: We did a randomised, double-blind clinical trial in 7241 patients in 32 countries to assess the effects of budesonide in patients who had had mild persistent asthma for less than 2 years and who had not had previous regular treatment with glucocorticosteroids. Patients aged 5-66 years received either budesonide or placebo once daily for 3 years in addition to their usual asthma medications. The daily budesonide dose was 400 microg, or 200 microg for children younger than 11 years. The primary outcome was time to first severe asthma-related event, and analysis was by intention to treat.Findings: 198 of 3568 patients on placebo and 117 of 3597 on budesonide had at least one severe asthma exacerbation; hazard ratio 0.56 (95% CI 0.45-0.71, p<0.0001). Patients on budesonide had fewer courses of systemic corticosteroids and more symptom-free days than did those on placebo. Compared with placebo, budesonide increased postbronchodilator forced expiratory volume in 1 s (FEV1) from baseline by 1.48% (p<0.0001) after 1 year and by 0.88% (p=0.0005) after 3 years (expressed as percent of the predicted value). The corresponding increase in prebronchodilator FEV1 was 2.24% after 1 year and 1.71% after 3 years (p<0.0001 at both timepoints). The effect of treatment on all outcome variables was independent of the baseline lung function (prebronchodilator or postbronchodilator) or baseline medication. In children younger than 11 years, 3-year growth was reduced in the budesonide group by 1.34 cm. The reduction was greatest in the first year of treatment (0.58 cm) than years 2 and 3 (0.43 cm and 0.33 cm, respectively).Interpretation: Long-term, once-daily treatment with low-dose budesonide decreases the risk of severe exacerbations and improves asthma control in patients with mild persistent asthma of recent onset. [ABSTRACT FROM AUTHOR]

Background: Aclidinium bromide is a novel, long-acting, inhaled muscarinic antagonist bronchodilator currently in Phase III clinical development for the treatment of chronic obstructive pulmonary disease (COPD). This study evaluated the pharmacodynamics, pharmacokinetics, safety and tolerability of ascending doses of aclidinium bromide in patients with COPD., Methods: This double-blind, randomised, placebo-controlled, crossover study was conducted in patients with moderate to severe COPD (forced expiratory volume in 1s [FEV(1)] <65% predicted). Patients were randomly assigned to one of four treatment sequences of aclidinium bromide 100, 300, 900microg and placebo with a washout period between doses. The primary outcome was area under the FEV(1) curve over the 0-24h time interval., Results: Seventeen patients with COPD were studied. Mean FEV(1) over 24h was 1.583L for placebo, and 1.727L, 1.793L and 1.815L for aclidinium bromide 100, 300 and 900microg, respectively (p<0.001 vs. placebo, all doses). Significant changes from baseline in FEV(1) were detected 15min post-dose for aclidinium bromide 300 and 900microg, with a peak effect 2h post-dose (all doses). Aclidinium bromide was undetected in plasma. The majority of adverse events was unrelated to study medication and did not result in discontinuation., Conclusion: Aclidinium bromide 100-900microg produced sustained bronchodilation over 24h in patients with COPD., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Aim: Aclidinium bromide is a muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease (COPD). This phase I trial in healthy subjects investigated the bronchodilator activity of aclidinium and its ability to reduce methacholine-induced bronchoconstriction., Methods: This double-blind, partial-crossover study randomized 12 subjects to treatment with single doses of aclidinium (50, 300 or 600 microg) or placebo. Drug activity was assessed for 24 h after administration by specific airway conductance (sGaw), airways resistance (Raw) and bronchial responsiveness (PC35 sGaw methacholine)., Results: Aclidinium significantly increased sGaw compared with placebo at all assessments and doses (sGaw mean +/- SD AUC (l kPa(-1) h) for placebo 24.4 +/- 4.37, for 50 microg 29.0 +/- 7.08, for 300 microg 31.2 +/- 6.68 and for 600 microg 32.7 +/- 7.95) (P < 0.009), except 50 microg at 1 and 24 h. Significant decreases in Raw were observed with aclidinium 300 and 600 microg compared with placebo at all assessments (Raw mean +/- SD AUC (kPa s(-1) l(-1) h) for placebo 7.7 +/- 3.46, for 300 microg 5.8 +/- 2.33, for 600 microg 6.3 +/- 3.11) (P < 0.04) except 600 microg at 24 h. Differences between aclidinium 300 and 600 microg vs. placebo in PC35 doubling concentration were significant at all assessments (mean +/- SD AUC (mg ml(-1) h) for placebo 100.0 +/- 30.27, for 50 microg 117.2 +/- 33.33, for 300 microg 168.9 +/- 28.66 and for 600 microg 179.1 +/- 15.73 (P < 0.0001). For all endpoints, there was a significant difference between aclidinium 50 microg and the higher doses (P < 0.0001). Aclidinium was not detected in plasma and was well tolerated., Conclusion: Aclidinium produced statistically significant and sustained bronchodilation over 24 h, suggesting long-acting efficacy and providing a rationale for future studies in patients with COPD.

Neuroimmune interactions are important in airway diseases such as asthma. We evaluated the role of the tachykinin NK(1) receptor in the contractile response of isolated trachea from tachykinin NK(1) receptor wild type (WT) and knockout (KO) mice, to the antigen ovalbumin and the contractile agonist serotonin (5-hydroxytryptamine). One percent ovalbumin induced contractions of tracheas obtained from ovalbumin-immunized and exposed mice. The tracheas from WT animals showed larger contractions compared to the KO mice. Tracheas from sensitized and ovalbumin-exposed animals released 5-hydroxytyptamine upon addition of ovalbumin. No higher levels of 5-hydroxytryptamine were released from tracheas of WT animals. Tracheas of non-sensitized animals did not release 5-hydroxytryptamine upon ovalbumin challenge. Responses to ovalbumin were abrogated by methysergide, a broad 5-hydroxytryptamine receptor antagonist. Exogenous 5-hydroxytryptamine contracted tracheas but WT tracheas responded significantly more. Atropine and tetrodotoxin (TTX) reduced 5-hydroxytryptamine-induced contractions of the WT tracheas, while they did not affect 5-hydroxytryptamine-induced contractions of KO tracheas. 5-Hydroxytryptamine-induced contractions from atropine- or TTX-treated WT tracheas did not differ significantly from the contractions of the KO tracheas. Single tachykinin NK(1) receptor antagonists SR140,333 and RP67,580 had no effect on 5-hydroxytryptamine-induced contractions. In conclusion, the 5-hydroxytryptamine-induced tracheal contraction includes a cholinergic mechanism that requires the presence of the tachykinin NK(1) receptor.

Objective and Background: Few studies have assessed the effectiveness of inhaled corticosteroid therapy exclusively in Asian patients with asthma. The present analysis compared the efficacy of early intervention with inhaled budesonide in Caucasian and Asian patients over the first 3 years of the inhaled Steroid Treatment As Regular Therapy in early asthma study., Methods: Patients aged 5-66 years with mild persistent asthma of

Chronic obstructive pulmonary disease (COPD) is characterised by a local pulmonary inflammatory response to respiratory pollutants and by systemic inflammation. Tumour necrosis factor (TNF)-alpha has been implicated in systemic effects of COPD and operates by binding the p55 (R1) and p75 (R2) TNF-alpha receptors. To investigate the contribution of each TNF-alpha receptor in the pathogenesis of COPD, the present study examined the effects of chronic air or cigarette smoke (CS) exposure in TNF-alpha R1 knockout (KO) mice, TNF-alpha R2 KO mice and wild type (WT) mice. CS was found to significantly increase the protein levels of soluble TNF-alpha R1 (by four-fold) and TNF-alpha R2 (by 10-fold) in the bronchoalveolar lavage of WT mice. After 3 months, CS induced a prominent pulmonary inflammatory cell influx in WT and TNF-alpha R1 KO mice. In TNF-alpha R2 KO mice, CS-induced pulmonary inflammation was clearly attenuated. After 6 months, no emphysema was observed in CS-exposed TNF-alpha R2 KO mice in contrast to WT and TNF-alpha R1 KO mice. CS-exposed WT and TNF-alpha R1 KO mice failed to gain weight, whereas the body mass of TNF-alpha R2 KO mice was not affected. These current findings suggest that both tumour necrosis factor-alpha receptors contribute to the pathogenesis of chronic obstructive pulmonary disease, but tumour necrosis factor-alpha receptor-2 is the most active receptor in the development of inflammation, emphysema and systemic weight loss in this murine model of chronic obstructive pulmonary disease.

Study Objectives: Asthmatic patients lose lung function faster than normal subjects. The effectiveness of early intervention with inhaled corticosteroids on this decline in lung function is not established in recent-onset disease., Design: The Inhaled Steroid Treatment as Regular Therapy in Early Asthma study was a randomized, double-blind study in 7,165 patients (5 to 66 years old), with persistent asthma for < 2 years to determine whether early intervention with low-dose inhaled budesonide prevents severe asthma-related events and the decline in lung function. Patients received budesonide (200 mug qd for children < 11 years old and 400 mug qd for others) or placebo for 3 years in addition to usual asthma medications., Results: Treatment with budesonide significantly improved prebronchodilator and postbronchodilator FEV(1) percentage of predicted and reduced the mean declines from baseline for postbronchodilator FEV(1) at 1 year and 3 years: - 0.62% and - 1.79% for budesonide and - 2.11% and - 2.68% for placebo, respectively (p < 0.001). The decline was more marked for male patients, active smokers, and patients > 18 years old, and the smallest treatment effects were in adolescents., Conclusions: Long-term, once-daily treatment with low-dose budesonide improved both prebronchodilator and postbronchodilator FEV(1) in patients with recent-onset, persistent asthma, and reduced the loss of lung function over time.

Background: There is increasing appreciation of gender differences in COPD but scant data whether risk factors for low lung function differ in men and women. We analysed data from 3 years follow-up in 178 women and 464 men with COPD, participants in the Euroscop Study who were smokers unexposed to inhaled corticosteroids., Methods: Explanatory variables of gender, age, starting age and pack-years smoking, respiratory symptoms, FEV(1)%FVC and FEV(1)%IVC (clinically important measures of airway obstruction), body mass index (BMI), and change in smoking were included in multiple linear regression models with baseline and change in post-bronchodilator FEV(1) as dependent variables., Results: Reduced baseline FEV(1) was associated with respiratory symptoms in men only. Annual decline in FEV(1) was not associated with respiratory symptoms in either men or women, and was 55 ml less in obese men (BMI 30 kg/m(2)) than men having normal BMI, an effect not seen in women. It was 32 ml faster in women with FEV(1)%FVC

Background: Several matrix metalloproteinases (MMPs) are involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). In mice, MMP-12 plays a crucial role in the development of cigarette smoke induced emphysema. A study was undertaken to investigate the role of MMP-12 in the development of COPD in human smokers., Methods: Induced sputum samples were collected from patients with stable COPD (n = 28), healthy smokers (n = 14), never smokers (n = 20), and former smokers (n = 14). MMP-12 protein levels in induced sputum were determined by ELISA and compared between the four study groups. MMP-12 enzymatic activity in induced sputum was evaluated by casein zymography and by cleaving of a fluorescence quenched substrate., Results: Median (IQR) MMP-12 levels were significantly higher in COPD patients than in healthy smokers, never smokers, and former smokers (17.5 (7.1-42.1) v 6.7 (3.9-10.4) v 4.2 (2.4-11.3) v 6.1 (4.5-7.6) ng/ml, p = 0.0002). MMP-12 enzymatic activity was significantly higher in patients with COPD than in controls (4.11 (1.4-8.0) v 0.14 (0.1-0.2) microg/microl, p = 0.0002)., Conclusion: MMP-12 is markedly increased in induced sputum from patients with stable COPD compared with controls, suggesting a role for MMP-12 in the development of COPD in smokers.

Guidelines recommend that patients with COPD are stratified arbitrarily by baseline severity (FEV1) to decide when to initiate combination treatment with a long-acting beta2-agonist and an inhaled corticosteroid. Assessment of baseline FEV1 as a continuous variable may provide a more reliable prediction of treatment effects. Patients from a 1-year, parallel-group, randomized controlled trial comparing 50 microg salmeterol (Sal), 500 microg fluticasone propionate (FP), the combination (Sal/FP) and placebo, (bid), were categorized post hoc into FEV1 < 50% and FEV1 > or = 50% predicted subgroups (n = 949/513 respectively). Treatment effects on clinical outcomes-- lung function, exacerbations, health status, diary card symptoms, and adverse events--were investigated. Treatment responses based on a pre-specified analysis explored treatment differences by severity as a continuous variable. Lung function improved with active treatment irrespective of FEV1; Sal/FP had greatest effect. This improvement appeared additive in milder disease; synergistic in severe disease. Active therapy significantly reduced exacerbation rate in patients with FEV1 < 50% predicted, not in milder disease. Health status and breathlessness improved with Sal/FP irrespective of baseline FEV1; adverse events were similar across subgroups. The spirometric response to Sal/FP varied with baseline FEV1, and clinical benefits were not restricted to patients with severe disease. These data have implications for COPD management decisions, suggesting that arbitrary stratifications of baseline severity are not necessarily indicative of treatment efficacy and that the benefits of assessing baseline severity as a continuous variable should be assessed in future trials.

Background: Chronic obstructive pulmonary disease (COPD) is associated with an abnormal inflammatory response of the lungs to noxious particles or gases. We investigated whether Toll-like receptor 4 (TLR4) is implicated in cigarette smoke (CS)-induced pulmonary inflammation in a murine model of COPD., Methods: C3H/HeOuJ (Tlr4(WT)) and C3H/HeJ (Tlr4(defective)) mice were exposed to air or CS for 5 weeks (subacute) and 26 weeks (chronic), and pulmonary inflammation was evaluated., Results: In Tlr4(WT) mice, subacute and chronic CS exposure induced a substantial pulmonary infiltration of macrophages, neutrophils, lymphocytes and dendritic cells (DCs), that was absent in air-exposed mice. CS exposure increased the costimulatory marker expression on DCs, the levels of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha) in bronchoalveolar lavage (BAL) fluid and induced the pulmonary expression of matrix metalloproteinase-12 (MMP-12), TLR4 and TLR2. In contrast, after subacute CS exposure, Tlr4(defective) mice showed a limited (5-fold lower) increase of DCs and lymphocytes in BAL fluid, lower costimulatory marker expression on DCs and lower MCP-1 and TNF-alpha levels in BAL fluid compared to Tlr4(WT) animals. After chronic CS exposure, however, the difference in pulmonary inflammation between Tlr4(WT) and Tlr4(defective) mice was less pronounced and both strains showed similar MCP-1 and TNF-alpha levels in BAL and similar pulmonary MMP-12, TLR4 and TLR2 expression., Conclusions: We demonstrated that the TLR4 mutation in C3H/HeJ mice is protective against CS-induced pulmonary influx of neutrophils, DCs and lymphocytes upon subacute CS exposure. However, TLR4 is only of minor importance in chronic CS-induced inflammation in mice.

Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation, that is not fully reversible, and that is associated with an abnormal inflammatory response of the airways and lungs to noxious particles and gases. The airflow limitation is caused by increased resistance of the small conducting airways and by decreased elastic recoil forces of the lung due to emphysematous destruction of the lung parenchyma. In vivo animal models can help to unravel the molecular and cellular mechanisms underlying the pathogenesis of COPD. Mice represent the most favored animal species with regard to the study of (both innate and adaptive) immune mechanisms, since they offer the opportunity to manipulate gene expression. Several experimental approaches are applied in order to mimic the different traits of COPD in these murine models. Firstly, the tracheal instillation of tissue-degrading enzymes induces emphysema-like lesions in the lung parenchyma, adding further proof to the protease-antiprotease imbalance hypothesis. Secondly, the inhalation of noxious stimuli, including tobacco smoke, sulfur dioxide, nitrogen dioxide, or oxidants such as ozone, may also lead to COPD-like lesions in mice, depending on concentration, duration of exposure and strainspecific genetic susceptibility. Thirdly, in transgenic mice, a specific gene is either overexpressed (non-specific or organ-specific) or selectively depleted (constitutively or conditionally). The study of these transgenic mice, either per se or in combination with the above mentioned experimental approaches (e.g. the inhalation of tobacco smoke), can offer valuable information on both the physiological function of the gene of interest as well as the pathophysiological mechanisms of diseases with complex traits such as COPD.

Background: Budesonide is the only inhaled corticosteroid to be given a category B pregnancy rating by the US Food and Drug Administration, based on observational data from the Swedish Medical Birth Registry. However, data from large randomized controlled trials are lacking., Objective: To compare pregnancy outcomes among patients with recent-onset mild-to-moderate persistent asthma receiving low-dose budesonide vs placebo., Methods: In a randomized, double-blind, placebo-controlled trial, 7241 patients aged 5 to 66 years with mild-to-moderate persistent asthma for less than 2 years and no previous regular corticosteroid therapy received once-daily budesonide or placebo via dry powder inhaler in addition to their usual asthma medication for 3 years. This trial was followed by a 2-year open-label treatment period. The daily dose of budesonide was 400 microg for adults. The study included 2473 females aged 15 to 50 years at randomization. Pregnancy was not an exclusion criterion (except for U.S. patients)., Results: Of 319 pregnancies reported, 313 were analyzed. Healthy children were delivered in 81% and 77% of all pregnancies in the budesonide and placebo groups, respectively. Of the 196 pregnancies reported by participants taking budesonide, 38 (19%) had adverse outcomes: 23 (12%) had miscarriages, 3 (2%) had congenital malformations, and 12 (6%) had other outcomes. Of the 117 pregnancies reported in the placebo group, 27 (23%) had adverse outcomes: 11 (9%) had miscarriages, 4 (3%) had congenital malformations, and 12 (10%) had other outcomes., Conclusions: Treatment with low-dose inhaled budesonide in females with mild-to-moderate persistent asthma does not seem to affect the outcome of pregnancy.

Background: Clinical studies suggest that inhaled corticosteroids reduce exacerbations and improve health status in chronic obstructive pulmonary disease (COPD). However, their effect on mortality is unknown., Methods: A pooled analysis, based on intention to treat, of individual patient data from seven randomised trials (involving 5085 patients) was performed in which the effects of inhaled corticosteroids and placebo were compared over at least 12 months in patients with stable COPD. The end point was all-cause mortality., Results: Overall, 4% of the participants died during a mean follow up period of 26 months. Inhaled corticosteroids reduced all-cause mortality by about 25% relative to placebo. Stratification by individual trials and adjustments for age, sex, baseline post-bronchodilator percentage predicted forced expiratory volume in 1 second, smoking status, and body mass index did not materially change the results (adjusted hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.55 to 0.96). Although there was considerable overlap between subgroups in terms of effect sizes, the beneficial effect was especially noticeable in women (adjusted HR 0.46; 95% CI 0.24 to 0.91) and former smokers (adjusted HR 0.60; 95% CI 0.39 to 0.93)., Conclusions: Inhaled corticosteroids reduce all-cause mortality in COPD. Further studies are required to determine whether the survival benefits persist beyond 2-3 years.

An imbalance between proteinases and their inhibitors is believed to play an essential role in the development of chronic obstructive pulmonary disease (COPD) and pulmonary emphysema. COPD is mainly caused by cigarette smoking, and is characterized by an increase in inflammatory cells in small airways and lung parenchyma. We examined the mRNA expression of several proteinases in lungs of mice exposed to cigarette smoke or control air. After 1, 3 and 6 months' smoke exposure there was a significant increase of matrix metalloproteinase (MMP)-12 and Cathepsin D mRNA, compared to air-exposed mice. To determine the cellular origin of MMP-12 and Cathepsin D, we isolated dendritic cells (DCs) and macrophages from the lungs of mice. There was an increase in MMP-12 mRNA after smoke exposure in both macrophage and DC populations, whereas Cathepsin D was predominantly expressed in macrophages. Immunohistochemistry clearly revealed the expression of Cathepsin D protein in alveolar macrophages of cigarette smoke-exposed mice, in contrast to air-exposed littermates. Western blots on lung tissue demonstrated an increase of MMP-12 protein in cigarette smoke-exposed animals. These results indicate that cigarette smoke increases the expression of MMP-12 and Cathepsin D in the lungs of mice, and that not only macrophages but also DCs produce MMP-12., ((c) 2005 S. Karger AG, Basel.)

Asthma and allergic rhinitis are both characterized by airway inflammation, and glucocorticosteroids form the cornerstone of their pharmacologic treatment. All patients with asthma should be prescribed rapid-acting inhaled beta2-agonists as needed to use as rescue therapy in case of symptoms. As soon as patients experience symptoms at least once a week, controller medications should be started on a daily basis to achieve and maintain control of their asthma. Intranasal corticosteroids are given as first-line therapy for moderate to severe persistent rhinitis. Depending on the dominant symptom, H1-antihistamines, decongestants, or ipratropium can be added after re-evaluation.

Inflammation of the airways and lung parenchyma plays a major role in the pathogenesis of chronic obstructive pulmonary disease. In the present study a murine model of tobacco smoke-induced emphysema was used to investigate the time course of airway and pulmonary inflammatory response, with a special emphasis on pulmonary dendritic cell (DC) populations. Groups of mice were exposed to either cigarette smoke or to control air for up to 24 weeks. In response to cigarette smoke, inflammatory cells (i.e. neutrophils, macrophages and lymphocytes) progressively accumulated both in the airways and lung parenchyma of mice. Furthermore, a clear infiltration of DCs was observed in airways (10-fold increase) and lung parenchyma (1.5-fold increase) of cigarette-exposed mice at 24 weeks. Flow cytometric analysis of bronchoalveolar lavage (BAL) DCs of smoke-exposed mice showed upregulation of major histocompatability complex II molecules and costimulatory molecules CD40 and CD86, compared with BAL DCs of air-exposed mice. Morphometric analysis of lung histology demonstrated a significant increase in mean linear intercept and alveolar wall destruction after 24 weeks of smoke exposure. In conclusion, the time course of the changes in inflammatory and dendritic cells in both bronchoalveolar lavage and the pulmonary compartment of cigarette smoke-exposed mice was carefully characterised.

Rationale: Epidemiologic studies suggest that tobacco smoke contributes to the prevalence and occurrence of exacerbations in asthma. The effect of active smoking in adolescents with atopy is poorly understood., Objectives: We developed an experimental model to investigate the influence of smoking on antigen-induced airway inflammation and airway responsiveness in mice that were previously sensitized., Methods: Ovalbumin (OVA)-sensitized BALB/c mice were exposed to air or mainstream smoke (5 days/week) and to phosphate-buffered saline (PBS) or OVA aerosol (3 times/week) for 2 weeks (n = 8 for each group)., Results: Airway responsiveness to intravenously injected carbachol was increased (p < 0.05) in smoke- and OVA-exposed mice compared with all other groups. There was an additive effect of smoke and OVA exposure on total cell numbers, macrophages, and dendritic cells in bronchoalveolar lavage fluid and on CD4+ and CD8+ T lymphocytes and dendritic cells in lung tissue (p < 0.05 compared with mice exposed to smoke and PBS and to mice exposed to air and OVA). Concurrent smoke and OVA exposure augmented OVA-specific IgE in serum compared with air and OVA exposure. In lavage fluid supernatant, eotaxin was increased in air- and OVA-exposed mice. The further increase observed in the group exposed to both OVA and cigarette smoke came close to formal significance (p = 0.06). Thymus- and activation-regulated chemokine was augmented in mice exposed to either smoke or OVA, without additional effect., Conclusions: Our data indicate that acute concurrent exposure to allergen and mainstream cigarette smoke enhances airway inflammation and airway responsiveness in previously sensitized mice.

Asthma and chronic obstructive pulmonary disease (COPD) are both highly prevalent, chronic inflammatory lung diseases that lead to significant morbidity and mortality. Matrix metalloproteinases (MMPs) are extracellular matrix degrading enzymes that play a critical role in normal development and physiological tissue remodeling and repair. In addition, they play an important role in the regulation of the kinetics and function of inflammatory cells. There is increasing evidence that MMPs are involved in the pathogenesis of both asthma and COPD, and several MMPs are possible therapeutic targets in these common chronic airway diseases.

Dendritic cells (DC) are specialized antigen-presenting cells, linking innate and adaptive immune responses, and thus play an important role in immunologically mediated diseases, including pulmonary diseases such as asthma and respiratory viral infections. Although much is known about the characteristics of lung DC in animal models, very few data concerning human lung DC are available. The goal of our study was to identify and characterize dendritic cells in human lung by preparing single-cell suspensions from surgical resection specimens and subsequent labeling with the recently developed blood dendritic cell antigen (BDCA) markers. A straightforward isolation procedure was developed to avoid phenotypical and functional changes induced by extensive purification methods. In this way, human lung DC were directly identified without the need for an additional adherence step for further purification. For the first time, we demonstrate the presence of three previously unidentified DC subsets in human lung digests: myeloid DC type 1 (BDCA1+/HLA-DR+), myeloid DC type 2 (BDCA3+/HLA-DR+), and plasmacytoid DC (BDCA2+/CD123+). The presence of CD1a+ DC in the human lung was confirmed. The identification and characterization of different human pulmonary DC subtypes is of great importance for the future development of DC-based immunotherapies.

Inhaled corticosteroids have a key role in the treatment of asthma and chronic obstructive pulmonary disease. In recent times, beclometasone dipropionate has been reformulated in pressurised metered dose inhalers (pMDIs), using hydrofluoroalkanes (HFAs) as a propellant. Extensive toxicological testing has shown that HFA-propellants are well tolerated. Among the reformulated beclometasone dipropionate-containing pMDIs, only the characteristics of the two Qvar formulations have been thoroughly explored. Compared to the reference beclometasone dipropionate formulation, the mass median aerodynamic diameter of the Qvar formulations are substantially smaller (1.1 vs 4.0 microm), whereas that of Modulite averages 2.6 microm. Scintigraphic and pharmacokinetic studies indicate a higher lung deposition for both the Qvar and the Beclazone formulations, compared with reference beclometasone dipropionate formulation. Since the 2- to 3-fold increase in pulmonary deposition results in a 2.6- to 3-fold difference in relative efficacy for Qvar, half the dose of the reference beclometasone dipropionate formulation has been currently recommended in adult patients with asthma, a recommendation that is supported by a large number of clinical trials. Conversely, the design of the studies conducted to compare the efficacy of Qvar with fluticasone propionate and budesonide does not allow establishing their equivalence on a milligram per milligram basis. Good studies on the bioequivalence between the reference beclometasone dipropionate formulation and the Modulite or Beclazone formulations are not available.

This study aimed to evaluate the cost-effectiveness of formoterol (Oxis) Turbuhaler 4.5 microg and salbutamol 200 microg as reliever medications in Sweden and Spain. The study used data on effectiveness (exacerbations and symptom-free days) and resource utilisation from an open, 6-month, parallel-group, multicentre randomised trial with 18,124 asthma patients in 24 countries. Country-specific unit costs for Sweden and for Spain were used to transform resource utilisation data into costs. Total healthcare costs were not significantly different between formoterol and salbutamol dry powder inhalers in Sweden, whereas in Spain, the healthcare costs were 20% higher for formoterol vs. salbutamol pressurised metered dose inhalers. Total healthcare costs increased with disease severity, defined according to the Global Initiative for Asthma guidelines. Compared with salbutamol, formoterol produced statistically significant improvements in effectiveness, less reliever and maintenance medication usage, reduced healthcare resource utilisation, with no increase or a limited increase in healthcare cost.

Background: Tachykinins are present in sensory nerves and in nonneuronal cells like macrophages. Human data suggest a role for these peptides in asthma, but the exact role of tachykinins and their receptors in allergic airway inflammation is still a matter of debate., Objective: The aim of this study was to determine the role of the tachykinin NK1 receptor in allergic airway responses in a mouse model., Methods: Tachykinin NK1 receptor wild-type and knockout animals were sensitized intraperitoneally to ovalbumin and subsequently exposed from days 14 to 21 to aerosolized ovalbumin (1% ). On day 22, the immunologic and histologic changes were evaluated, and lung function measurements were performed., Results: Mice lacking the tachykinin NK1 receptor and their wild-type litter mates developed inflammatory cell infiltrates in the airways and ovalbumin-specific IgE on sensitization and exposure to ovalbumin compared with saline-exposed controls. No differences were detected between wild-type and knockout mice. The substance P content of alveolar macrophages was not influenced by ovalbumin or by the lack of the NK1 receptor. Ovalbumin-induced hyperresponsiveness was not observed, but at baseline, the knockout mice were more reactive despite similar morphology. Ovalbumin induced more goblet cell hyperplasia in wild-type animals compared with knockout animals. No differences in airway wall thickness were observed., Conclusion: These data suggest that tachykinin NK1 receptors do not affect allergic airway inflammation or endogenous substance P content of alveolar macrophages but influence baseline responsiveness and promote features of remodeling such as goblet cell hyperplasia.

Inhalation of neurokinin A (NKA) causes bronchoconstriction in patients with asthma. In vitro both tachykinin NK1 and NK2 receptors can mediate airway contraction. In this study the authors examined the effects of a single dose of the dual tachykinin NK1/NK2 receptor antagonist, DNK333, on NKA-induced bronchoconstriction in asthma. A total of 19 male adults with mild asthma completed a randomised, double-blind, placebo-controlled crossover trial. Increasing concentrations of NKA (3.3x10(-9) to 1.0x10(-6) mol x mLP(-1)) were inhaled at 1 and 10 h intervals after a single oral dosing with either DNK333 (100 mg) or a placebo. It was observed that DNK333 did not affect baseline lung function but did protect against NKA-induced bronchoconstriction in those patients. The mean log10 provocative concentration causing a 20% fall in forced expiratory volume in one second for NKA was -5.6 log10 mol x mL(-1) at 1 h after DNK333 treatment and -6.8 log10 mol x mL(-1) after placebo. This was equivalent to a difference of 4.08 doubling doses, which decreased to a difference of 0.90 doubling doses 10 h after treatment. The results shown in this report indicate that DNK333 blocks neurokinin A-induced bronchoconstriction in patients with asthma.