Omar S. Usmani

Regulation of Th2 Cytokine Genes by p38 MAPK-Mediated Phosphorylation of GATA-3

GATA-3 plays a critical role in allergic diseases by regulating the release of cytokines from Th2 lymphocytes. However, the molecular mechanisms involved in the regulation of GATA-3 in human T lymphocytes are not yet understood. Using small interfering RNA to knock down GATA-3, we have demonstrated its critical role in regulating IL-4, IL-5, and IL-13 release from a human T cell line. Specific stimulation of T lymphocytes by costimulation of CD3 and CD28 to mimic activation by APCs induces translocation of GATA-3 from the cytoplasm to the nucleus, with binding to the promoter region of Th2 cytokine genes, as determined by chromatin immunoprecipitation. GATA-3 nuclear translocation is dependent on its phosphorylation on serine residues by p38 MAPK, which facilitates interaction with the nuclear transporter protein importin-α. This provides a means whereby allergen exposure leads to the expression of Th2 cytokines, and this novel mechanism may provide new approaches to treating allergic diseases.

Reduced pH and chloride levels in exhaled breath condensate of patients with chronic cough

Background: Increased hydrogen and reduced chloride ionic environments of the airways are conducive to the stimulation of cough. However, the constituents of the local milieu of the airways of patients with chronic cough are unknown. Methods: The pH and chloride levels in exhaled breath condensate and capsaicin cough threshold (C5) were measured in 50 patients with chronic cough and in 16 healthy controls. pH and chloride measurements were repeated after capsaicin challenge in those with cough. The cause of cough was asthma (n = 13), postnasal drip/rhinitis (n = 7), gastro-oesophageal reflux (n = 5), bronchiectasis (n = 5), but remained unidentified in 20. Results: Compared with controls, patients with chronic cough had lower pH (mean 7.9 v 8.3, 95% CI of difference −0.5 to −0.2, p<0.0001), chloride levels (median 4 v 6 mmol/l, 95% CI −3.1 to −0.2, p = 0.007), and C5 (median 3.9 v 125 μM, 95% CI −270.0 to −17.6, p = 0.002). The pH levels were different in the six subgroups including controls, and were reduced in all diagnostic subgroups of patients with cough compared with controls but did not differ between them. Chloride levels were significantly different in the six subgroups but were lower than controls in only the gastro-oesophageal reflux subgroup. There was a weak but significant correlation between chloride levels and C5 when all participants were analysed together, but not between pH and C5 or chloride levels. pH and chloride levels did not change after capsaicin challenge. Conclusions: The epithelial lining fluid of patients with chronic cough has a reduced pH and reduced chloride levels which could contribute to the enhanced cough reflex.

Theobromine inhibits sensory nerve activation and cough

Cough is a common and protective reflex, but persistent coughing is debilitating and impairs quality of life. Antitussive treatment using opioids is limited by unacceptable side effects, and there is a great need for more effective remedies. The present study demonstrates that theobromine, a methylxanthine derivative present in cocoa, effectively inhibits citric acid‐induced cough in guinea‐pigs in vivo. Furthermore, in a randomized, double‐blind, placebo‐controlled study in man, theobromine suppresses capsaicin‐induced cough with no adverse effects. We also demonstrate that theobromine directly inhibits capsaicin‐induced sensory nerve depolarization of guinea‐pig and human vagus nerve suggestive of an inhibitory effect on afferent nerve activation. These data indicate the actions of theobromine appear to be peripherally mediated. We conclude theobromine is a novel and promising treatment, which may form the basis for a new class of antitussive drugs.

Comparison of inspiratory and expiratory resistance and reactance in patients with asthma and chronic obstructive pulmonary disease

Background The usual analysis of forced oscillometry measures respiratory resistance (Rrs) and reactance (Xrs) averaged over several tidal breaths (whole-breath analysis). Recent within-breath analyses have separated Rrs and Xrs into their mean inspiratory and mean expiratory components (inspiratory–expiratory breath analysis) but these have not been used to compare patients with asthma and those with chronic obstructive pulmonary disease (COPD). Large inspiratory–expiratory variations in Xrs at 5 Hz (ΔX5) in an individual have been used as a surrogate marker of expiratory flow limitation. Methods Whole-breath and inspiratory–expiratory impulse oscillometry was assessed in 34 patients with asthma (49±3 years; 15 male, forced expiratory volume in 1 s (FEV1) 69±4% predicted), 48 patients with COPD (64±2 years; 32 male, FEV1 59±3% predicted) and 18 normal subjects (37±2 years; 8 male). Results Whole-breath analysis failed to discriminate between patients with asthma and patients with COPD either for all patients or for patients with FEV1 <60% predicted. Inspiratory–expiratory analysis in patients with FEV1 <60% predicted showed that in the COPD group mean expiratory X5 (−0.44±0.04 kPa/l/s) was greater than inspiratory X5 (−0.23±0.02 kPa/l/s, p<0.001) whereas patients with asthma did not show such changes (−0.36±0.07 kPa/l/s vs −0.26±0.03 kPa/l/s, p=0.23). Even though ΔX5 was larger in patients with COPD (0.21±0.03 kPa/l/s) than in patients with asthma (0.10±0.07 kPa/l/s), this was not significant (p=0.15). Conclusions Whole-breath impulse oscillation system analysis failed to discriminate between patients with asthma and those with COPD. Inspiratory–expiratory X5 analysis differentiated patients with asthma from those with COPD presumably reflecting enhanced dynamic airway narrowing on expiration in COPD. Further studies are needed to confirm these differences and investigate their cause.

Current evidence and future research needs for FeNO measurement in respiratory diseases

Although not yet widely implemented, fraction of exhaled nitric oxide (FeNO) has emerged in recent years as a potentially useful biomarker for the assessment of airway inflammation both in undiagnosed patients with non-specific respiratory symptoms and in those with established airway disease. Research to date essentially suggests that FeNO measurement facilitates the identification of patients exhibiting T-helper cell type 2 (Th2)-mediated airway inflammation, and effectively those in whom anti-inflammatory therapy, particularly inhaled corticosteroids (ICS), is beneficial. In some studies, FeNO-guided management of patients with established airway disease is associated with lower exacerbation rates, improvements in adherence to anti-inflammatory therapy, and the ability to predict risk of future exacerbations or decline in lung function. Despite these data, concerns regarding the applicability and utility of FeNO in clinical practice still remain. This article reviews the current evidence, both supportive and critical of FeNO measurement, in the diagnosis and management of asthma and other inflammatory airway diseases. It additionally provides suggestions regarding the practical application of FeNO measurement: how it could be integrated into routine clinical practice, how its utility could be assessed and its true value to both clinicians and patients could be established. Although some unanswered questions remain, current evidence suggests that FeNO is potentially a valuable tool for improving the personalised management of inflammatory airway diseases.

Ventilation heterogeneity in the acinar and conductive zones of the normal ageing lung

Rationale Small airways function studies in lung disease have used three promising multiple breath washout (MBW) derived indices: indices of ventilation heterogeneity in the acinar (Sacin) and conductive (Scond) lung zones, and the lung clearance index (LCI). Since peripheral lung structure is known to change with age, ventilation heterogeneity is expected to be affected too. However, the age dependence of the MBW indices of ventilation heterogeneity in the normal lung is unknown. Objectives The authors systematically investigated Sacin, Scond or LCI as a function of age, testing also the robustness of these relationships across two laboratories. Methods MBW tests were performed by never-smokers (50% men) in the age range 25–65 years, with data gathered across two laboratories (n=120 and n=60). For comparison with the literature, the phase III slopes from classical single breath washout tests were also acquired in one group (n=120). Measurements and main results All three MBW indices consistently increased with age, representing a steady worsening of ventilation heterogeneity in the age range 25–65. Age explained 7–16% of the variability in Sacin and Scond and 36% of the variability in LCI. There was a small but significant gender difference only for Sacin. Classical single breath washout phase III slopes also showed age dependencies, with gender effects depending on the normalisation method used. Conclusions With respect to the clinical response, age is a small but consistent effect that needs to be factored in when using the MBW indices for the detection of small airways abnormality in disease.

Suppression of GATA-3 Nuclear Import and Phosphorylation: A Novel Mechanism of Corticosteroid Action in Allergic Disease

Peter Barnes and colleagues show that corticosteroids have a potent inhibitory effect on GATA-3 via two interacting mechanisms that suppress Th2 cytokine expression. This novel mechanism of corticosteroid action may help explain the efficacy of corticosteroids in allergic diseases.

Restoration of Corticosteroid Sensitivity by p38 Mitogen Activated Protein Kinase Inhibition in Peripheral Blood Mononuclear Cells from Severe Asthma

Background Severe asthma accounts for a small number of asthmatics but represents a disproportionate cost to health care systems. The underlying mechanism in severe asthma remains unknown but several mechanisms are likely to be involved because of a very heterogeneous profile. We investigated the effects of a p38MAPK inhibitor in corticosteroid sensitivity in peripheral blood mononuclear cells (PBMCs) from severe asthmatics and the profile of its responders. Methodology/Principal Findings Corticosteroid sensitivity was determined by measuring dexamethasone inhibition of CD3/28 and TNF-α induced IL-8 production in PBMCs by using ELISA. PBMCs from severe asthmatics were relatively less sensitive to dexamethasone (Dex) as compared to those of non-severe asthmatics and healthy volunteers. The IC50 values of Dex negatively correlated with decreased glucocorticoid receptor (GR) nuclear translocation assessed using immunocytochemistry (r = −0.65; p<0.0005) and with decreased FEV1 (% predicted) (r = 0.6; p<0.0005). A p38α/β inhibitor (SB203580) restored Dex-sensitivity in a subpopulation of severe asthma that was characterized by a defective GR nuclear translocation, clinically by lower FEV1 and higher use of oral prednisolone. We also found that SB203580 partially inhibited GR phosphorylation at serine 226, resulting in increased GR nuclear translocation in IL-2/IL-4 treated corticosteroid insensitive U937s. Conclusions/Significance p38MAPKα/β is involved in defective GR nuclear translocation due to phosphorylation at Ser226 and this will be a useful biomarker to identify responders to p38MAPKα/β inhibitor in the future.

Assessing and treating small airways disease in asthma and chronic obstructive pulmonary disease

Abstract Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory disorders of the respiratory tract that are characterized by airflow limitation. They are distinct conditions with different causes, structural changes, and immunopathology. The pathophysiology in asthma and COPD involves not only the proximal large airways, but also the distal small airways, and thus the small airways are an important therapeutic target in the treatment of both diseases. The assessment of diseased distal small airways is challenging. Extensive disease can be present in the small airways with little abnormality in conventional pulmonary function tests. Recent advances in imaging technologies have led to better spatial resolution to assess small airways morphology non-invasively. New physiological tests have been developed to detect disease and response to therapy in regional airways. Improving the efficiency of existing aerosolized therapy to direct drug to the appropriate lung regions may improve clinical efficacy. Approaches to target distal lung regions include developing new drug formulations with smaller aerosol particle size or using inhaler devices that emit aerosolized drug at slow inhalation flows. Large studies are needed to determine whether better distal lung deposition leads to improvements in small airways function that are translated into clinically significant patient outcomes.

New Inhaler Devices - The Good, the Bad and the Ugly

Drug delivery to the lungs is an effective way of targeting inhaled therapeutic aerosols and treating obstructive airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD). In the past 10 years, several new drugs for the management of asthma and COPD have been marketed and more are under development. These new therapeutic respiratory drugs have been furthered by innovations in all categories of pulmonary drug delivery systems to ensure optimal aerosolisation performance, consistency in efficacy and satisfactory patient adherence. In this review, we discuss the technological advances and innovations in recent inhaler devices and the evolving roles of pressurised metered-dose inhalers, dry powder inhalers and nebulisers, as well as their impact on patient adherence to treatment.