Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation

Background: Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear. Objective: We sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients. Methods: An IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS-specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens. Results: Activation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS-high asthma with increased epithelial expression of IL-6TS-inducible genes in the absence of systemic inflammation. The IL-6TS-high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1 beta, IL-8, and IL-1 beta. Conclusions: Local lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.Peer reviewe

[The treatment of asthma: indications for a change in approach],[The treatment of asthma : indications for a change in approach]

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[The treatment of asthma: indications for a change in approach]

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Lifestyle intervention for non-alcoholic fatty liver disease: prospective cohort study of its efficacy and factors related to improvement.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has a high prevalence in obese children. Lifestyle intervention is the primary treatment for NAFLD. However, limited data are available regarding the efficacy of lifestyle interventions. OBJECTIVES: To prospectively determine the efficacy of a lifestyle intervention programme on NAFLD in severely obese children and identify the clinical parameters related to improvement in NAFLD. METHODS: Children admitted to a lifestyle intervention programme were screened for NAFLD. Steatosis was defined as increased echogenicity of the liver on ultrasonography. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were used as surrogate markers for steatohepatitis. The lifestyle intervention programme consisted of physical exercise, dietary counselling and behavioural counselling for a period of 6 months. RESULTS: 144 children were included with a mean age of 14.1 (±2.3) years, BMI z-score of 3.35 (±0.40) kg/m(2). Lifestyle intervention significantly reduced the prevalence of steatosis (31.2-11.9%, p<0.001) and the prevalence of elevated serum ALT (25.7-11.1%, p<0.001) and serum AST (13.3-4.3%, p<0.002). In multivariate regression analysis, improvement in the degree of steatosis and decrease in ALT and AST were all significantly related to improvement in insulin resistance. Improvement in insulin resistance only explained a small part of the observed changes in transaminases. CONCLUSIONS: A lifestyle intervention of 6 months is moderately effective in improving NAFLD in severely obese children. Improvement in insulin resistance is the clinical parameter most strongly associated with improvement in NAFLD. Other factors related to the successful treatment of NAFLD need to be identified so that these can be a focus for new lifestyle and drug interventions. (aut.ref.

Asthma-Related Outcomes in Patients Initiating Extrafine Ciclesonide or Fine-Particle Inhaled Corticosteroids

Contains fulltext : 189792.pdf (Publisher’s version ) (Open Access

Gain in lung function after weight reduction in severely obese children

AIM: The primary objective of this prospective cohort study was to determine the effect of weight loss on pulmonary function values in extremely obese children. METHODS: Obese children participated in a 26-week in-hospital or outpatient multidisciplinary treatment programme. Waist circumference was measured and pulmonary function tests were performed at enrolment and after 6 months. RESULTS: The data of 112 children were analysed. The children had a mean age of 14.4 (range 8.5-18.9) years and 62.5% were girls. The mean SD score-body mass index (SDS-BMI) was +3.38 at baseline and +2.91 after the intervention. Lung function improved significantly: functional vital capacity increased by 3.08% (95% CI 1.16% to 5.00%) of the predicted value, forced expiratory volume in 1 s (FEV(1)) by 2.91% (95% CI 1.11% to 4.71%) of the predicted value, total lung capacity by 2.27% (95% CI 1.16% to 5.00%) of the predicted value, and expiratory reserve volume (ERV) by 14.8% (95% CI 8.66% to 20.88%) of the predicted value. The increase in ERV correlated with the reduction in SDS-BMI and with the reduction in waist circumference. FEV(1) did not correlate with the reduction in either SDS-BMI or waist circumference. CONCLUSIONS: Weight loss in severely obese children correlated with an improvement in lung function, especially ERV. The improvement in ERV correlated with the decrease in SDS-BMI and waist circumference