Search

Nitric oxide is a gas produced in the airways of asthmatic subjects and related to T2 inflammation. It can be measured as fractional nitric oxide (FeNO) in the exhaled air and used as a non-invasive, easy to evaluate, rapid marker. It is now widely used in many settings to determine airway inflammation. The aim of this narrative review is to report relationship between FeNO and the physiopathologic characteristics of asthmatic patients. Factors affecting FeNO levels have also been analysed as well as the impact of corticosteroid, target therapies and rehabilitation programs. Considering the availability of the test, spreading this method-ology to low income countries has also been considered as a possibility for evaluating airway inflammation and monitoring adherence to inhaled corticosteroid therapy. PubMed data search has been performed restricted to English language papers. Research was limited to studies in adults unless studies in children were the only ones reported for a particular issue. This revision could be useful to summarize the role of FeNO in relation to asthma charac-teristics and help in the use of FeNO in different clinical settings particularly in low income countries. (c) 2020 Sociedade Portuguesa de Pneumologia. Published by Elsevier Espana, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Wheezing is common in childhood. However, current prediction models of pediatric asthma have only modest accuracy. Novel biomarkers and definition of subphenotypes may improve asthma prediction. Interleukin-1-receptor-like-1 (IL1RL1 or ST2) is a well-replicated asthma gene and associates with eosinophilia. We investigated whether serum sST2 predicts asthma and asthma with elevated exhaled NO (FeNO), compared to the commonly used Asthma Prediction Index (API). Using logistic regression modeling, we found that serum sST2 levels in 2-3 years-old wheezers do not predict doctors' diagnosed asthma at age 6 years. Instead, sST2 predicts a subphenotype of asthma characterized by increased levels of FeNO, a marker for eosinophilic airway inflammation. Herein, sST2 improved the predictive value of the API (AUC=0.70, 95% CI 0.56-0.84), but had also significant predictive value on its own (AUC=0.65, 95% CI 0.52-0.79). Our study indicates that sST2 in preschool wheezers has predictive value for the development of eosinophilic airway inflammation in asthmatic children at school age.

Asthma is a chronic respiratory condition, which is highly prevalent worldwide. Although no cure is currently available, it is well recognized that some asthma patients can spontaneously enter remission of the disease later in life. Asthma remission is characterized by absence of symptoms and lack of asthma-medication use. Subjects in asthma remission can be divided into two groups: those in clinical remission and those in complete remission. In clinical asthma remission, subjects still have a degree of lung functional impairment or bronchial hyperresponsiveness, while in complete asthma remission, these features are no longer present. Over longer periods, the latter group is less likely to relapse. This remission group is of great scientific interest due to the higher potential to find biomarkers or biological pathways that elicit or are associated with asthma remission. Despite the fact that the definition of asthma remission varies between studies, some factors are reproducibly observed to be associated with remitted asthma. Among these are lower levels of inflammatory markers, which are lowest in complete remission. Additionally, in both groups some degree of airway remodeling is present. Still, the pathological disease state of asthma remission has been poorly investigated. Future research should focus on at least two aspects: further characterisation of the small airways and airway walls in order to determine histologically true remission, and more thorough biological pathway analyses to explore triggers that elicit this phenomenon. Ultimately, this will result in pharmacological targets that provide the potential to steer the course of asthma towards remission. (C) 2019 Elsevier Inc. All rights reserved.

Severe asthma is a debilitating and treatment refractory disease. As many as half of these patients have complex neutrophil-predominant lung inflammation that is distinct from milder asthma with type 2 eosinophilic inflammation. New insights into severe asthma pathogenesis are needed. Concomitant exposure of mice to an aeroallergen and endotoxin during sensitization resulted in complex neutrophilic immune responses to allergen alone during later airway challenge. Unlike allergen alone, sensitization with allergen and endotoxin led to NETosis. In addition to neutrophil extracellular traps (NETs), enucleated neutrophil cytoplasts were evident in the lungs. Surprisingly, allergen-driven airway neutrophilia was decreased in peptidyl arginine deiminase 4-deficient mice with defective NETosis but not by deoxyribonuclease treatment, implicating the cytoplasts for the non-type 2 immune responses to allergen. Neutrophil cytoplasts were also present in mediastinal lymph nodes, and the cytoplasts activated lung dendritic cells in vitro to trigger antigen-specific interleukin-17 (IL-17) production from naïve CD4+ T cells. Bronchoalveolar lavage fluid from patients with severe asthma and high neutrophil counts had detectable NETs and cytoplasts that were positively correlated with IL-17 levels. Together, these translational findings have identified neutrophil cytoplast formation in asthmatic lung inflammation and linked the cytoplasts to T helper 17-mediated neutrophilic inflammation in severe asthma. ispartof: SCIENCE IMMUNOLOGY vol:3 issue:26 ispartof: location:United States status: published

The biological responses of airway smooth muscle (ASM) are diverse, in part due to ASM phenotype plasticity. ASM phenotype plasticity refers to the ability of ASM cells to change the degree of a variety of functions, including contractility, proliferation, migration and secretion of inflammatory mediators. This plasticity occurs due to intrinsic or acquired abnormalities in ASM cells, and these abnormalities or predisposition of the ASM cell may alter the ASM response and in some cases recapitulate disease hallmarks of asthma.These phenotypic changes are ultimately determined by multiple stimuli and occur due to alterations in the intricate balance or reversible state that maintains ASM cells in either a contractile or synthetic state, through processes termed maturation or modulation, respectively. To elucidate the role of ASM phenotype in disease states, numerous in vitro studies have suggested a phenotypic switch in ASM primary cell cultures as an explanation for the plethora of responses mediated by ASM cells. Moreover, there is overwhelming evidence suggesting that the immunomodulatory response of ASM is due to the acquisition of a synthetic phenotype; however, whether this degree of plasticity is present in vivo as opposed to cell culture-based models remains speculative. Nonetheless, this review will give an overall scope of ASM phenotypic markers, triggers of ASM phenotype modulation and novel therapeutic approaches to control ASM phenotype plasticity. (C) 2012 Elsevier Ltd. All rights reserved.

Mouse models of allergic asthma are characterized by airway hyperreactivity (AHR), Th2-driven eosinophilic airway inflammation, high allergen-specific IgE (anti-OVA IgE) levels in serum, and airway remodeling. Because asthma susceptibility has a strong genetic component, we aimed to identify new asthma susceptibility genes in the mouse by analyzing the asthma phenotypes of the Leishmania major resistant (lmr) recombinant congenic (RC) strains. The lmr RC strains are derived from C57BL/6 and BALB/c intercrosses and carry congenic loci on chromosome 17 (lmr1) and 9 (lmr2) in both backgrounds. Whereas the lmr2 locus on chromosome 9 contributes to a small background-specific effect on anti-OVA IgE and AHR, the lmr1 locus on chromosome 17 mediates a strong effect on Th2-driven eosinophilic airway inflammation and background-specific effects on anti-OVA IgE and AHR. The lmr1 locus contains almost 600 polymorphic genes. To narrow down this number of candidate genes, we performed genome-wide transcriptional profiling on lung tissue from C. lmr1 RC mice and BALB/c control mice. We identified a small number of differentially expressed genes located within the congenic fragment, including a number of Mhc genes, polymorphic between BALB/c and C57Bl/6. The analysis of asthma phenotypes in the C.B10-H2b RC strain, carrying the C57Bl/6 haplotype of the Mhc locus in a BALB/c genetic background, reveals a strikingly similar asthma phenotype compared with C. lmr1, indicating that the differentially expressed genes located within the C.B10-H2b congenic fragment are the most likely candidate genes to contribute to the reduced asthma phenotypes associated with the C57Bl/6 allele of lmr1.

Allergic asthma is a genetically complex disease characterized by allergen-specific immunoglobulin (Ig)E, eosinophilic inflammation of the lungs and airway hyper-responsiveness to bronchospasmogenic stimuli. In this study, we compared 13 recombinant congenic ( RC) mouse strains in an ovalbumin model of allergic asthma. Different intensities and types of responses are observed throughout the RC strains. Intensities range from resistance to asthma in CcS05, to a very severe bronchoconstrictive reaction upon methacholine challenge for the parental STS strain. All strains show a 'modified' Th2 response except CcS14, which shows a 'true' Th2 response. When data from all strains are pooled, airway reactivity shows significant correlations with the serum Ig levels and the levels of interleukin (IL)-4, IL-5 and IL-13 in the broncho-alveolar lavage (BAL), at low dosage of methacholine (below 25 mg/ml), whereas at high dosage airway reactivity only correlates with BAL neutrophil levels. This indicates that at least two different mechanisms are involved in the airway reactivity to methacholine. None of these correlations can be found in every individual strain, which demonstrates that the asthma traits in this mouse model are genetically dissociated and that the loci can be genetically mapped.

Background The long-acting anticholinergic tiotropium has recently been registered for the treatment of asthma, and its use is associated with a reduction in exacerbation frequency. Anti-inflammatory and anti-remodeling effects of tiotropium have been demonstrated in in vitro and in vivo models. Because tiotropium treatment is used in combination with inhaled corticosteroids, potential additive effects between the two would be clinically relevant. Therefore, the aim of this study was to investigate additive effects between tiotropium and ciclesonide on airway inflammation and remodeling in guinea pig models of asthma. Methods Guinea pigs (n = 3–8/group) were sensitized and challenged with ovalbumin in an acute (single challenge) and a chronic model (12 weekly challenges) of allergic asthma. Animals were treated with vehicle, nebulized tiotropium (0.01–0.3 mM) and/or intranasally instilled ciclesonide (0.001–1 mg/kg) before each challenge. Bronchoalveolar lavage fluid and lungs were collected for analysis of airway inflammation and remodeling. Results Tiotropium and ciclesonide treatment, alone or in combination, did not inhibit airway inflammation in the acute asthma model. In a dose-finding study, low doses of tiotropium and ciclesonide inhibited airway eosinophilia and airway smooth muscle thickening in the chronic asthma model. Threshold doses of 0.01 mM tiotropium (nebulizer concentration) and 0.01 mg/kg ciclesonide were selected to investigate potential additive effects between both drugs. At these doses, tiotropium and ciclesonide did not inhibit airway eosinophilia or airway smooth muscle thickening when administered alone, but significantly inhibited these allergen-induced responses when administered in combination. Conclusions Combined treatment with low doses of tiotropium and ciclesonide inhibits airway inflammation and remodeling in a guinea pig model of chronic asthma, suggesting that combined treatment with anticholinergics and corticosteroids may have anti-inflammatory and anti-remodeling activity in allergic airway diseases. Since tiotropium is registered as a therapy for asthma added on to corticosteroid treatment, these beneficial effects of the combination therapy may be clinically relevant. Electronic supplementary material The online version of this article (doi:10.1186/s12931-016-0327-6) contains supplementary material, which is available to authorized users.

Background Inflammation and oxidative stress play critical roles in patients with chronic obstructive pulmonary disease (COPD). Mitochondrial oxidative stress might be involved in driving the oxidative stress–induced pathology. Objective We sought to determine the effects of oxidative stress on mitochondrial function in the pathophysiology of airway inflammation in ozone-exposed mice and human airway smooth muscle (ASM) cells. Methods Mice were exposed to ozone, and lung inflammation, airway hyperresponsiveness (AHR), and mitochondrial function were determined. Human ASM cells were isolated from bronchial biopsy specimens from healthy subjects, smokers, and patients with COPD. Inflammation and mitochondrial function in mice and human ASM cells were measured with and without the presence of the mitochondria-targeted antioxidant MitoQ. Results Mice exposed to ozone, a source of oxidative stress, had lung inflammation and AHR associated with mitochondrial dysfunction and reflected by decreased mitochondrial membrane potential (ΔΨm), increased mitochondrial oxidative stress, and reduced mitochondrial complex I, III, and V expression. Reversal of mitochondrial dysfunction by the mitochondria-targeted antioxidant MitoQ reduced inflammation and AHR. ASM cells from patients with COPD have reduced ΔΨm, adenosine triphosphate content, complex expression, basal and maximum respiration levels, and respiratory reserve capacity compared with those from healthy control subjects, whereas mitochondrial reactive oxygen species (ROS) levels were increased. Healthy smokers were intermediate between healthy nonsmokers and patients with COPD. Hydrogen peroxide induced mitochondrial dysfunction in ASM cells from healthy subjects. MitoQ and Tiron inhibited TGF-β–induced ASM cell proliferation and CXCL8 release. Conclusions Mitochondrial dysfunction in patients with COPD is associated with excessive mitochondrial ROS levels, which contribute to enhanced inflammation and cell hyperproliferation. Targeting mitochondrial ROS represents a promising therapeutic approach in patients with COPD.

Airway inflammation and remodeling are major features of chronic obstructive pulmonary disease (COPD), whereas pulmonary hypertension is a common comorbidity associated with a poor disease prognosis. Recent studies in animal models have indicated that increased arginase activity contributes to features of asthma, including allergen-induced airway eosinophilia and mucus hypersecretion. Although cigarette smoke and lipopolysaccharide (LPS), major risk factors for COPD, may increase arginase expression, the role of arginase in COPD is unknown. This study aimed to investigate the role of arginase in pulmonary inflammation and remodeling using an animal model of COPD. Guinea pigs were instilled intranasally with LPS or saline twice weekly for 12 weeks and pretreated by inhalation of the arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) or vehicle. Repeated LPS exposure increased lung arginase activity, resulting in increased L-ornithine/L-arginine and L-ornithine/L-citrulline ratios. Both ratios were reversed by ABH. ABH inhibited the LPS-induced increases in pulmonary IL-8, neutrophils, and goblet cells as well as airway fibrosis. Remarkably, LPS-induced right ventricular hypertrophy, indicative of pulmonary hypertension, was prevented by ABH. Strong correlations were found between arginase activity and inflammation, airway remodeling, and right ventricular hypertrophy. Increased arginase activity contributes to pulmonary inflammation, airway remodeling, and right ventricular hypertrophy in a guinea pig model of COPD, indicating therapeutic potential for arginase inhibitors in this disease.

Nocturnal symptoms of asthma such as coughing, wheezing, dyspnoea and dyspnoea on awakening are common in children with asthma. This is an important issue since nocturnal symptoms may have a negative influence on the child's life, affecting, for example, school performance or quality of life. Only a minority of the patients report their nocturnal symptoms spontaneously. Doctors should therefore specifically ask if a child is experiencing such symptoms. Nocturnal airflow limitation, induced by an increase in inflammatory activity, is thought to be responsible for these symptoms. Several other factors, both endogenous and exogenous, contribute to this fall in lung function. Therapeutic regimens aim to reduce inflammation and the subsequent constriction of the smooth muscle cell. Environmental measures, like smoke avoidance or house dust mite reduction, can reduce the exposure to exogenous triggers, while inhaled medication acts specifically on the inflammation or smooth muscle cell constriction. Treatment with inhaled corticosteroids; has a positive influence on lung function and the degree of bronchial hyperresponsiveness. Since short-acting bronchodilators provide dilation for only 4 to 6 hours, their role in the treatment of nocturnal symptoms is less important, especially in children. Long-acting bronchodilators, such as sustained release theophylline, have been shown to improve nocturnal symptoms and (nocturnal) lung function. However, the small therapeutic range of those agents with respect to plasma concentration is a complicating factor for treatment of children with asthma. Long-acting beta(2) agonists have a positive influence on nightly awakenings and lung function. Some studies indicate, however, that the combination of a long-acting beta(2) agonist with an inhaled corticosteroid is superior to long-acting beta(2) agonists alone.

In asthma, the airway smooth muscle (ASM) cell plays a central role in disease pathogenesis through cellular changes which may impact on its microenvironment and alter ASM response and function. The answer to the long debated question of what makes a 'healthy' ASM cell become 'asthmatic' still remains speculative. What is known of an 'asthmatic' ASM cell, is its ability to contribute to the hallmarks of asthma such as bronchoconstriction (contractile phenotype), inflammation (synthetic phenotype) and ASM hyperplasia (proliferative phenotype).The phenotype of healthy or diseased ASM cells or tissue for the most part is determined by expression of key phenotypic markers. ASM is commonly accepted to have different phenotypes: the contractile (differentiated) state versus the synthetic (dedifferentiated) state (with the capacity to synthesize mediators, proliferate and migrate). There is now accumulating evidence that the synthetic functions of ASM in culture derived from asthmatic and non-asthmatic donors differ. Some of these differences include an altered profile and increased production of extracellular matrix proteins, pro-inflammatory mediators and adhesion receptors, collectively suggesting that ASM cells from asthmatic subjects have the capacity to alter their environment, actively participate in repair processes and functionally respond to changes in their microenvironment. (C) 2012 Elsevier Ltd. All rights reserved.

Background: Local IgE production may play a role in asthma pathogenesis. The aim of the study was to assess sputum total IgE and cytokines in asthmatics according to sputum cellular phenotype. Methods: We studied 122 subjects including 22 non atopic healthy subjects, 41 eosinophilic (sputum eosinophils < 3%), 16 neutrophilic (sputum neutrophils = 0.1 kU/l) when compared to "IgE low'' asthmatics (IgE < 0.1 kU/l). Conclusion: The eosinophilic asthma phenotype was associated with raised sputum IgE and a Th2 cytokine profile. Raised sputum IgE was associated with a heterogeneous cytokine overproduction.

RATIONALE: Bronchial thermoplasty (BT) is a bronchoscopic procedure in which controlled thermal energy is applied to the airway wall to decrease smooth muscle. OBJECTIVES: To evaluate the effectiveness and safety of BT versus a sham procedure in subjects with severe asthma who remain symptomatic despite treatment with high-dose inhaled corticosteroids and long-acting beta(2)-agonists. METHODS: A total of 288 adult subjects (Intent-to-Treat [ITT]) randomized to BT or sham control underwent three bronchoscopy procedures. Primary outcome was the difference in Asthma Quality of Life Questionnaire (AQLQ) scores from baseline to average of 6, 9, and 12 months (integrated AQLQ). Adverse events and health care use were collected to assess safety. Statistical design and analysis of the primary endpoint was Bayesian. Target posterior probability of superiority (PPS) of BT over sham was 95%, except for the primary endpoint (96.4%). MEASUREMENTS AND MAIN RESULTS: The improvement from baseline in the integrated AQLQ score was superior in the BT group compared with sham (BT, 1.35 +/- 1.10; sham, 1.16 +/- 1.23 [PPS, 96.0% ITT and 97.9% per protocol]). Seventy-nine percent of BT and 64% of sham subjects achieved changes in AQLQ of 0.5 or greater (PPS, 99.6%). Six percent more BT subjects were hospitalized in the treatment period (up to 6 wk after BT). In the posttreatment period (6-52 wk after BT), the BT group experienced fewer severe exacerbations, emergency department (ED) visits, and days missed from work/school compared with the sham group (PPS, 95.5, 99.9, and 99.3%, respectively). CONCLUSIONS: BT in subjects with severe asthma improves asthma-specific quality of life with a reduction in severe exacerbations and healthcare use in the posttreatment period. Clinical trial registered with www.clinialtrials.gov (NCT00231114).

Peroxynitrite has been shown to be crucially involved in airway hyperresponsiveness (AHR) after the late asthmatic reaction (LAR). Peroxynitrite production may result from simultaneous synthesis of nitric oxide (NO) and superoxide by inducible NO-synthase (iNOS) at low L-arginine concentrations. L-Arginine availability to iNOS is regulated by Its cellular uptake, which can be inhibited by eosinophil-derived polycations and by arginase, which competes with iNOS for the common substrate.Using a guinea pig model of allergic asthma, we investigated whether aberrant L-arginine homeostasis could underlie peroxynitrite-mediated AHR after the LAR.After the LAR, arginase activity in the airways and eosinophil peroxidase release from bronchoalveolar lavage cells were increased. These changes were associated with a 2.0-fold AHR to methacholine as measured in isolated perfused tracheal preparations. AHR was reduced by exogenous L-arginine administration. Moreover, both the arginase inhibitor N(omega)-hydroxy-nor-L-arginine (nor-NOHA) and the polycation antagonist heparin normalised airway responsiveness. These effects were reversed by the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME), indicating that both agents reduced AHR by restoring bronchodilating NO production.In conclusion, in allergen-challenged guinea pigs, the AHR after the LAR is caused by arginase- and polycation-induced attenuation Of L-arginine availability to iNOS, which may switch the enzyme to simultaneous production of superoxide and NO, and, consequently, peroxynitrite.

The effects of treatment with budesonide (200-mu-g twice daily) and terbutaline (500-mu-g four times daily) has been compared with the effects of placebo and terbutaline in 27 children with mild asthma, aged 7-14 years, in a double blind, randomised placebo controlled study over eight weeks. Bronchial responsiveness (PC20 histamine), lung function, the amplitude of diurnal variation in peak expiratory flow (PEF), and symptom scores were measured. Baseline FEV1 was over 70% predicted and PC20 histamine less than 8 mg/ml. Twelve children were treated with budesonide and terbutaline and 15 with placebo and terbutaline. After four and eight weeks of treatment the change in PC20 was significantly greater after terbutaline alone by 2.1 (95% CI 0.5-3.8) and 1.3 (95% CI 0.1-2.5) doubling doses respectively. Mean FEV1 did not change in either group. The change in afternoon and nocturnal PEF was significantly greater after budesonide and terbutaline than after terbutaline alone. The amplitude of diurnal variation in PEF did not change significantly in either group. Peak flow reversibility decreased in the budesonide group. There were no differences between treatments for cough and dyspnoea, but wheeze improved in the budesonide group. The children with mild asthma treated with budesonide and terbutaline showed improvement in bronchial responsiveness, afternoon and nocturnal PEF, and symptoms of wheeze and a fall in peak flow reversibility by comparison with those who received terbutaline alone.

Allergic asthma is a genetically complex disease characterized by allergen-specific immunoglobulin (Ig)E, eosinophilic inflammation of the lungs and airway hyper-responsiveness to bronchospasmogenic stimuli. In this study, we compared 13 recombinant congenic ( RC) mouse strains in an ovalbumin model of allergic asthma. Different intensities and types of responses are observed throughout the RC strains. Intensities range from resistance to asthma in CcS05, to a very severe bronchoconstrictive reaction upon methacholine challenge for the parental STS strain. All strains show a 'modified' Th2 response except CcS14, which shows a 'true' Th2 response. When data from all strains are pooled, airway reactivity shows significant correlations with the serum Ig levels and the levels of interleukin (IL)-4, IL-5 and IL-13 in the broncho-alveolar lavage (BAL), at low dosage of methacholine (below 25 mg/ml), whereas at high dosage airway reactivity only correlates with BAL neutrophil levels. This indicates that at least two different mechanisms are involved in the airway reactivity to methacholine. None of these correlations can be found in every individual strain, which demonstrates that the asthma traits in this mouse model are genetically dissociated and that the loci can be genetically mapped.

Background: Five to twenty percent of healthy, nonasthmatic individuals exhibit airway hyperreactivity. Because cytokines are important intermediates in airway responses, we investigated the relationship between serum cytokines and airway responsiveness in a well-characterized population of pregnant women. Methods: We analyzed serum levels of interleukin-4 (IL-4), IL-5, IL-6, interferon-γ (IFN-γ), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in frozen sera from 240 pregnant nonasthmatic subjects from a previous study of airway responsiveness and preterm labor for their relationship to methacholine challenge test results. Results: Serum IFN-γ and GM-CSF levels were significantly related to levels of methacholine airway responsiveness among nonasthmatics in this population. Nonasthmatics with PD20 20 ≤ 50 µmol had intermediate levels, and those with PD20 >50 µmol had the lowest levels. Both serum IFN-γ and GM-CSF levels were also significantly related to the log dose-response slope for methacholine responsiveness. These relationships were confirmed in a multiple linear regression analysis controlling for age, ethnic background, and cigarette smoking. Current smoking was uniformly associated with decreased cytokine levels. Conclusion: IFN-γ, GM-CSF, and other cytokines may be useful serum markers in population studies of airway responsiveness.

Nocturnal symptoms of asthma such as coughing, wheezing, dyspnoea and dyspnoea on awakening are common in children with asthma. This is an important issue since nocturnal symptoms may have a negative influence on the child's life, affecting, for example, school performance or quality of life. Only a minority of the patients report their nocturnal symptoms spontaneously. Doctors should therefore specifically ask if a child is experiencing such symptoms. Nocturnal airflow limitation, induced by an increase in inflammatory activity, is thought to be responsible for these symptoms. Several other factors, both endogenous and exogenous, contribute to this fall in lung function. Therapeutic regimens aim to reduce inflammation and the subsequent constriction of the smooth muscle cell. Environmental measures, like smoke avoidance or house dust mite reduction, can reduce the exposure to exogenous triggers, while inhaled medication acts specifically on the inflammation or smooth muscle cell constriction. Treatment with inhaled corticosteroids; has a positive influence on lung function and the degree of bronchial hyperresponsiveness. Since short-acting bronchodilators provide dilation for only 4 to 6 hours, their role in the treatment of nocturnal symptoms is less important, especially in children. Long-acting bronchodilators, such as sustained release theophylline, have been shown to improve nocturnal symptoms and (nocturnal) lung function. However, the small therapeutic range of those agents with respect to plasma concentration is a complicating factor for treatment of children with asthma. Long-acting beta(2) agonists have a positive influence on nightly awakenings and lung function. Some studies indicate, however, that the combination of a long-acting beta(2) agonist with an inhaled corticosteroid is superior to long-acting beta(2) agonists alone.

The effects of treatment with budesonide (200-mu-g twice daily) and terbutaline (500-mu-g four times daily) has been compared with the effects of placebo and terbutaline in 27 children with mild asthma, aged 7-14 years, in a double blind, randomised placebo controlled study over eight weeks. Bronchial responsiveness (PC20 histamine), lung function, the amplitude of diurnal variation in peak expiratory flow (PEF), and symptom scores were measured. Baseline FEV1 was over 70% predicted and PC20 histamine less than 8 mg/ml. Twelve children were treated with budesonide and terbutaline and 15 with placebo and terbutaline. After four and eight weeks of treatment the change in PC20 was significantly greater after terbutaline alone by 2.1 (95% CI 0.5-3.8) and 1.3 (95% CI 0.1-2.5) doubling doses respectively. Mean FEV1 did not change in either group. The change in afternoon and nocturnal PEF was significantly greater after budesonide and terbutaline than after terbutaline alone. The amplitude of diurnal variation in PEF did not change significantly in either group. Peak flow reversibility decreased in the budesonide group. There were no differences between treatments for cough and dyspnoea, but wheeze improved in the budesonide group. The children with mild asthma treated with budesonide and terbutaline showed improvement in bronchial responsiveness, afternoon and nocturnal PEF, and symptoms of wheeze and a fall in peak flow reversibility by comparison with those who received terbutaline alone.

Background The link between eosinophils and the development of airway hyperresponsiveness (AHR) in asthma is still controversial. This question was assessed in a murine model of asthma in which we performed a dose ranging study to establish whether the dose of steroid needed to inhibit the eosinophil infiltration correlated with that needed to block AHR. Methods The sensitised BALB/c mice were dosed with vehicle or dexamethasone (0.01–3 mg/kg) 2 hours before and 6 hours after each challenge (once daily for 6 days) and 2 hours before AHR determination by whole-body plethysmography. At 30 minutes after the AHR to aerosolised methacholine the mice were lavaged and differential white cell counts were determined. Challenging with antigen caused a significant increase in eosinophils in the bronchoalveolar lavage (BAL) fluid and lung tissue, and increased AHR. Results Dexamethasone reduced BAL and lung tissue eosinophilia (ED50 values of 0.06 and 0.08 mg/kg, respectively), whereas a higher dose was needed to block AHR (ED50 of 0.32 mg/kg at 3 mg/ml methacholine. Dissociation was observed between the dose of steroid needed to affect AHR in comparison with eosinophilia and suggests that AHR is not a direct consequence of eosinophilia. Conclusion This novel pharmacological approach has revealed a clear dissociation between eosinophilia and AHR by using steroids that are the mainstay of asthma therapy. These data suggest that eosinophilia is not associated with AHR and questions the rationale that many pharmaceutical companies are adopting in developing low-molecular-mass compounds that target eosinophil activation/recruitment for the treatment of asthma.

Asthma affects more than 300 million people worldwide and poses a large socioeconomic burden, particularly in the 5% to 10% of severe asthmatics. So far, each entry of new biologics in clinical trials has led to high expectations for treating all severe asthma forms, but the outcome has only been successful if the biologic, as add-on treatment, targeted specific patient subgroups. Indeed, we now realize that asthma is a heterogeneous disease with multiple phenotypes, based on distinct pathophysiological mechanisms, called endotypes. Thus, asthma therapy is gradually moving to a personalized medicine approach, tailored to individual's asthma endotypes identified through biomarkers. Here, we review the clinical efficacy of antibody-related therapeutics undergoing clinical trials, or those already approved, for the treatment of severe type 2 asthma. Biologics targeting type 2 cytokines have shown consistent efficacy, especially in patients with evidence of type 2 inflammation, suggesting that the future of asthma biologics is promising.

Asthma is a complex, heterogeneous and chronic airway inflammatory disease with different clinical phenotypes caused by diverse triggers and pathophysi ological mechanisms. Asthma heritability has been established in many genetic studies but it is evident that only genetic elements are not responsible for the development of asthma. Increasing rate of asthma incidence during past decades has implicated the role of epigenetics in development of asthma. Environmental factors perform as initiator signals through epigenetic mechanisms. Three epigenetic mechanisms have been identified, including DNA methylation, histone modifications, and small noncoding RNAs. These mechanisms regulate the immune responses and inflammatory genes expression in asthma and allergy. This review explains the role of epigenetic modifications in controlling Th2 response and IgE production in asthma and also briefly overviews the role o f environmental factors such as pollutions, allergens, prenatal exposures and diet in developing asthma. Recognizing environmental risk factors and their effects on epigenetic mechanisms would be of great interest for prognostic and preventive aspect in t reatment of asthma.