Charles McSharry

Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma

Background: Although inhaled corticosteroids have an established role in the treatment of asthma, studies have tended to concentrate on non-smokers and little is known about the possible effect of cigarette smoking on the efficacy of treatment with inhaled steroids in asthma. A study was undertaken to investigate the effect of active cigarette smoking on responses to treatment with inhaled corticosteroids in patients with mild asthma. Methods: The effect of treatment with inhaled fluticasone propionate (1000 μg daily) or placebo for 3 weeks was studied in a double blind, prospective, randomised, placebo controlled study of 38 steroid naïve adult asthmatic patients (21 non-smokers). Efficacy was assessed using morning and evening peak expiratory flow (PEF) readings, spirometric parameters, bronchial hyperreactivity, and sputum eosinophil counts. Comparison was made between responses to treatment in non-smoking and smoking asthmatic patients. Results: There was a significantly greater increase in mean morning PEF in non-smokers than in smokers following inhaled fluticasone (27 l/min v –5 l/min). Non-smokers had a statistically significant increase in mean morning PEF (27 l/min), mean forced expiratory volume in 1 second (0.17 l), and geometric mean PC20 (2.6 doubling doses), and a significant decrease in the proportion of sputum eosinophils (–1.75%) after fluticasone compared with placebo. No significant changes were observed in the smoking asthmatic patients for any of these parameters. Conclusions: Active cigarette smoking impairs the efficacy of short term inhaled corticosteroid treatment in mild asthma. This finding has important implications for the management of patients with mild asthma who smoke.

MicroRNA-155 as a proinflammatory regulator in clinical and experimental arthritis

MicroRNA (miRNA) species (miR) regulate mRNA translation and are implicated as mediators of disease pathology via coordinated regulation of molecular effector pathways. Unraveling miR disease-related activities will facilitate future therapeutic interventions. miR-155 recently has been identified with critical immune regulatory functions. Although detected in articular tissues, the functional role of miR-155 in inflammatory arthritis has not been defined. We report here that miR-155 is up-regulated in synovial membrane and synovial fluid (SF) macrophages from patients with rheumatoid arthritis (RA). The increased expression of miR-155 in SF CD14+ cells was associated with lower expression of the miR-155 target, Src homology 2-containing inositol phosphatase-1 (SHIP-1), an inhibitor of inflammation. Similarly, SHIP-1 expression was decreased in CD68+ cells in the synovial lining layer in RA patients as compared with osteoarthritis patients. Overexpression of miR-155 in PB CD14+ cells led to down-regulation of SHIP-1 and an increase in the production of proinflammatory cytokines. Conversely, inhibition of miR-155 in RA synovial CD14+ cells reduced TNF-α production. Finally, miR-155–deficient mice are resistant to collagen-induced arthritis, with profound suppression of antigen-specific Th17 cell and autoantibody responses and markedly reduced articular inflammation. Our data therefore identify a role of miR-155 in clinical and experimental arthritis and suggest that miR-155 may be an intriguing therapeutic target.

Intergenerational 20 year trends in the prevalence of asthma and hay fever in adults: the Midspan family study surveys of parents and offspring.

Abstract Objective: To estimate trends between 1972–6 and 1996 in the prevalences of asthma and hay fever in adults. Design: Two epidemiological surveys 20 years apart. Identical questions were asked about asthma, hay fever, and respiratory symptoms at each survey. Setting: Renfrew and Paisley, two towns in the west of Scotland. Subjects: 1477 married couples aged 45–64 participated in a general population survey in 1972-6; and 2338 offspring aged 30–59 participated in a 1996 survey. Prevalences were compared in 1708 parents and 1124 offspring aged 45-54. Main outcome measures: Prevalences of asthma, hay fever, and respiratory symptoms. Results: In never smokers, age and sex standardised prevalences of asthma and hay fever were 3.0% and 5.8% respectively in 1972-6, and 8.2% and 19.9% in 1996. In ever smokers, the corresponding values were 1.6% and 5.4% in 1972–6 and 5.3% and 15.5% in 1996. In both generations, the prevalence of asthma was higher in those who reported hay fever (atopic asthma). In never smokers, reports of wheeze not labelled as asthma were about 10 times more common in 1972–6 than in 1996. With a broader definition of asthma (asthma and/or wheeze), to minimise diagnostic bias, the overall prevalence of asthma changed little. However, diagnostic bias mainly affected non-atopic asthma. Atopic asthma increased more than twofold (prevalence ratio 2.52 (95% confidence interval 1.01 to 6.28)) whereas the prevalence of non-atopic asthma did not change (1.00 (0.53 to 1.90)). Conclusion: The prevalence of asthma in adults has increased more than twofold in 20 years, largely in association with trends in atopy, as measured indirectly by the prevalence of hay fever. No evidence was found for an increase in diagnostic awareness being responsible for the trend in atopic asthma, but increased awareness may account for trends in non-atopic asthma.

IS HOMOEOPATHY A PLACEBO RESPONSE? CONTROLLED TRIAL OF HOMOEOPATHIC POTENCY, WITH POLLEN IN HAYFEVER AS MODEL

The hypothesis that homoeopathic potencies are placebos was tested in a randomised, double-blind, placebo-controlled trial. The study model chosen compared the effects of a homoeopathic preparation of mixed grass pollens with placebo in 144 patients with active hayfever. The homoeopathically treated patients showed a significant reduction in patient and doctor assessed symptom scores. The significance of this response was increased when results were corrected for pollen count and the response was associated with a halving of the need for antihistamines. An initial aggravation of symptoms was noted more often in patients receiving the potency and was followed by an improvement in that group. No evidence emerged to support the idea that placebo action fully explains the clinical responses to homoeopathic drugs.

Inhibition of FcεRI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes

Atopic allergy is characterized by an increase in IgE antibodies that signal through the high-affinity Fcε receptor (FcεRI) to induce the release of inflammatory mediators from mast cells. For unknown reasons, the prevalence of allergic diseases has recently increased steeply in the developed world. However, this increase has not been mirrored in developing countries, even though IgE concentrations are often greatly elevated in individuals from these countries, owing to nonspecific IgE induction by universally present parasitic worms. Here we offer one explanation for this paradox based on the properties of ES-62, a molecule secreted by filarial nematodes. We found that highly purified, endotoxin-free ES-62 directly inhibits the FcεRI-induced release of allergy mediators from human mast cells by selectively blocking key signal transduction events, including phospholipase D–coupled, sphingosine kinase–mediated calcium mobilization and nuclear factor-κB activation. ES-62 mediates these effects by forming a complex with Toll-like receptor 4, which results in the sequestration of protein kinase C-α (PKC-α). This causes caveolae/lipid raft–mediated, proteasome-independent degradation of PKC-α, a molecule important for the coupling of FcεRI to phospholipase D and mast cell activation. We also show that ES-62 is able to protect mice from mast cell–dependent hypersensitivity in the skin and lungs, indicating that it has potential as a novel therapeutic for allergy.

Randomised controlled trial of homoeopathy versus placebo in perennial allergic rhinitis with overview of four trial series.

Abstract Objective: To test the hypothesis that homoeopathy is a placebo by examining its effect in patients with allergic rhinitis and so contest the evidence from three previous trials in this series. Design: Randomised, double blind, placebo controlled, parallel group, multicentre study. Setting: Four general practices and a hospital ear, nose, and throat outpatient department. Participants: 51 patients with perennial allergic rhinitis. Intervention: Random assignment to an oral 30c homoeopathic preparation of principal inhalant allergen or to placebo. Main outcome measures: Changes from baseline in nasal inspiratory peak flow and symptom visual analogue scale score over third and fourth weeks after randomisation. Results: Fifty patients completed the study. The homoeopathy group had a significant objective improvement in nasal airflow compared with the placebo group (mean difference 19.8 l/min, 95% confidence interval 10.4 to 29.1, P=0.0001). Both groups reported improvement in symptoms, with patients taking homoeopathy reporting more improvement in all but one of the centres, which had more patients with aggravations. On average no significant difference between the groups was seen on visual analogue scale scores. Initial aggravations of rhinitis symptoms were more common with homoeopathy than placebo (7 (30%) v 2 (7%), P=0.04). Addition of these results to those of three previous trials (n=253) showed a mean symptom reduction on visual analogue scores of 28% (10.9 mm) for homoeopathy compared with 3% (1.1 mm) for placebo (95% confidence interval 4.2 to 15.4, P=0.0007). Conclusion: The objective results reinforce earlier evidence that homoeopathic dilutions differ from placebo.

TLR2 Agonist Ameliorates Established Allergic Airway Inflammation by Promoting Th1 Response and Not via Regulatory T Cells

TLRs are primary sensors of both innate and adaptive immune systems, where they play a pivotal role in the response directed against structurally conserved components of pathogens. Synthetic bacterial lipopeptide Pam3CSK4 is a TLR2 agonist capable of modulating Th1 and Th2 responses. This study examines the therapeutic effect of Pam3CSK4 in established airway inflammation in a murine model of asthma. In mice previously sensitized and challenged with OVA, Pam3CSK4 given i.p. markedly reduced the total inflammatory cell infiltrate and eosinophilia in bronchoalveolar lavage fluid. Pam3CSK4 therapy was associated with a reduction in OVA-induced IL-4 and IL-5 secretion from thoracic lymph node culture, airways inflammation, bronchial hyperresponsiveness, and serum levels of IgE. Pam3CSK4 therapy was also associated with an increase in OVA-induced IFN-γ, IL-12, and IL-10 production. However, the anti-inflammatory effect of Pam3CSK4 was independent of IL-10 or TGF-β, but was critically dependent on IL-12, the production of which by dendritic cells was enhanced by Pam3CSK4 in vitro. Our results provide direct evidence that Pam3CSK4 could represent a novel therapeutic agent in allergic airways disease.

Non-invasive markers of airway inflammation as predictors of oral steroid responsiveness in asthma

BACKGROUND Sputum eosinophil counts and exhaled nitric oxide (NO) levels are increased in asthma and both measurements fall in response to corticosteroids. METHODS Exhaled NO levels and sputum eosinophil counts were assessed as non-invasive markers of the response to an oral steroid in 37 patients (19 women) with stable chronic asthma (mean (SD) age 48.6 (12.2) years, asthma duration 25.9 (17.3) years, and baseline forced expiratory volume in one second (FEV1) 76.3 (21.9)% predicted). Spirometric tests, with reversibility to a β agonist (2.5 mg nebulised salbutamol), and induced sputum (using nebulised 3% saline) were performed at recruitment and following treatment with 30 mg prednisolone/day for 14 days. RESULTS Baseline NO levels correlated with the percentage improvement in FEV1from baseline to the post-steroid, post-bronchodilator value (r s = 0.47, p = 0.003), with an NO level of >10 ppb at baseline having a positive predictive value of 83% for an improvement in FEV1 of ⩾15% (sensitivity 59%, specificity 90%). Sputum eosinophilia (⩾4%) had a positive predictive value of 68% (sensitivity 54%, specificity 76%) for an increase in FEV1 of ⩾15%. A combination of sputum eosinophilia and increased NO levels resulted in a positive predictive value of 72% and a negative predictive value of 79% (sensitivity 76%, specificity 75%). CONCLUSION Exhaled NO levels and sputum eosinophilia may be useful in predicting the response to a trial of oral steroid in asthma.

IL-33 promotes ST2-dependent lung fibrosis by the induction of alternatively activated macrophages and innate lymphoid cells in mice

Background The initiation and regulation of pulmonary fibrosis are not well understood. IL-33, an important cytokine for respiratory diseases, is overexpressed in the lungs of patients with idiopathic pulmonary fibrosis. Objectives We aimed to determine the effects and mechanism of IL-33 on the development and severity of pulmonary fibrosis in murine bleomycin-induced fibrosis. Methods Lung fibrosis was induced by bleomycin in wild-type or Il33r (St2)−/− C57BL/6 mice treated with the recombinant mature form of IL-33 or anti–IL-33 antibody or transferred with type 2 innate lymphoid cells (ILC2s). The development and severity of fibrosis was evaluated based on lung histology, collagen levels, and lavage cytology. Cytokine and chemokine levels were quantified by using quantitative PCR, ELISA, and cytometry. Results IL-33 is constitutively expressed in lung epithelial cells but is induced in macrophages by bleomycin. Bleomycin enhanced the production of the mature but reduced full-length form of IL-33 in lung tissue. ST2 deficiency, anti–IL-33 antibody treatment, or alveolar macrophage depletion attenuated and exogenous IL-33 or adoptive transfer of ILC2s enhanced bleomycin-induced lung inflammation and fibrosis. These pathologic changes were accompanied, respectively, by reduced or increased IL-33, IL-13, TGF-β1, and inflammatory chemokine production in the lung. Furthermore, IL-33 polarized M2 macrophages to produce IL-13 and TGF-β1 and induced the expansion of ILC2s to produce IL-13 in vitro and in vivo. Conclusions IL-33 is a novel profibrogenic cytokine that signals through ST2 to promote the initiation and progression of pulmonary fibrosis by recruiting and directing inflammatory cell function and enhancing profibrogenic cytokine production in an ST2- and macrophage-dependent manner.

Association of forced expiratory volume with disease duration and sputum neutrophils in chronic asthma

Some patients with chronic asthma develop irreversible airflow obstruction. Our aim was to assess whether reported duration of asthma and induced sputum cell counts were associated with pulmonary function in patients with asthma who did not smoke. Maximal forced expiratory volume in the first second (FEV(1)) was determined following a steroid trial (oral prednisolone, 30 mg/d [n = 92 patients]; or inhaled fluticasone, 2000 microg/d [n = 5]; for 2 weeks) and 2.5 mg of nebulized albuterol. Asthma history was recorded with duration from first diagnosis. All subjects were nonsmokers, or were to have stopped smoking > or =5 years previously and smoked < or =5 pack-years (n = 12). Induced sputum was obtained from 59 subjects for analysis of airway cell counts. Maximal FEV(1) was inversely associated with asthma duration (r = -0.47, P <0.0001), age (r = -0.40, P <0.0001), and the proportion of sputum neutrophils (r(s) = -0.50, P = 0.00004). After adjusting for age, both duration of disease and sputum neutrophils were independently associated with maximal FEV(1). Neutrophil activation, as measured by sputum myeloperoxidase levels, was positively associated with the proportion of sputum neutrophils (r(s) = 0.45, P = 0.0004) and inversely associated with maximal FEV(1) (r(s) = -0.59, P <0.0001). Long disease duration may be a predisposing factor for the development of irreversible airflow obstruction in patients with chronic asthma. The negative associations of sputum neutrophil count and activation with maximal FEV(1) suggest that neutrophils may be involved in the pathophysiology of irreversible airflow obstruction in asthma.