Role of non-coding RNAs in maintaining primary airway smooth muscle cells

BACKGROUND: The airway smooth muscle (ASM) cell maintains its own proliferative rate and contributes to the inflammatory response in the airways, effects that are inhibited by corticosteroids, used in the treatment of airways diseases. OBJECTIVE: We determined the differential expression of mRNAs, microRNAs (miRNAs) and long noncoding RNA species (lncRNAs) in primary ASM cells following treatment with a corticosteroid, dexamethasone, and fetal calf serum (FCS). METHODS: mRNA, miRNA and lncRNA expression was measured by microarray and quantitative real-time PCR. RESULTS: A small number of miRNAs (including miR-150, −371-5p, −718, −940, −1181, −1207-5p, −1915, and −3663-3p) were decreased following exposure to dexamethasone and FCS. The mRNA targets of these miRNAs were increased in expression. The changes in mRNA expression were associated with regulation of ASM actin cytoskeleton. We also observed changes in expression of lncRNAs, including natural antisense, pseudogenes, intronic lncRNAs, and intergenic lncRNAs following dexamethasone and FCS. We confirmed the change in expression of three of these, LINC00882, LINC00883, PVT1, and its transcriptional activator, c-MYC. We propose that four of these lincRNAs (RP11-46A10.4, LINC00883, BCYRN1, and LINC00882) act as miRNA ‘sponges’ for 4 miRNAs (miR-150, −371-5p, −940, −1207-5p). CONCLUSION: This in-vitro model of primary ASM cell phenotype was associated with the regulation of several ncRNAs. Their identification allows for in-vitro functional experimentation to establish causality with the primary ASM phenotype, and in airway diseases such as asthma and chronic obstructive pulmonary disease (COPD)

Degree of control of physician-diagnosed asthma and COPD in Italy.

Background. It is important for the Italian National Health Service to obtain data on the degree of control of asthma and chronic obstructive pulmonary disease (COPD) in the general population in Italy in order for balanced planning of future investments in these diseases to be made. Currently, precise estimates of these parameters are not available in literature. Objectives. In collaboration with the Italian Academy of General Practitioners (SIMG; www.simg.it) we have investigated the degree of control of physician-diagnosed asthma and COPD in Italy. Methods. A standardised questionnaire on asthma and COPD has been self-administered to a sample of 1937 Italian family physicians (representing around 5% of all the Italian doctors involved in general practice) chosen to cover all the Italian counties. Results. We have collected questionnaire data from 19,917 patients with asthma and COPD followed in their practice and 12,438 (62.4%) were correctly filled in enabling evaluation. We selected the number of emergency room visits, hospitalisations and intensive care unit admissions for asthma and COPD in the last 12 months as objective measures of the degree of asthma and COPD morbidity in these patients. The figures were respectively 12.4% (emergency room visits), 17.3% (hospitalisations) and 1.2% (intensive care unit admissions) of all patients with physician-diagnosed asthma and COPD. Conclusions. This data suggests that in Italy the morbidity of asthma and COPD remains high; representing a significant burden for the Italian National Health Service. There is a clear necessity for further studies to investigate the causes of this incomplete control

Susceptibility to mycobacterial disease due to mutations in IL-12R beta 1 in three Iranian patients

Immunogenetics and cellular immunology of bacterial infectious disease

Treatable traits in the European U-BIOPRED adult asthma cohorts

No abstract availabl

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

Clinical definition of COPD exacerbations and classification of their severity

A standardized definition of chronic obstructive pulmonary disease (COPD) exacerbation still represents an unmet need in respiratory medicine; definitions currently rely oil clinical empiricism with little evidence-based scientific support. Exacerbations of COPD are certainly clear events in the mind of practicing physicians. However, when one tries to provide simple concepts such as their definition and classification of severity, one realizes how little we know. Current symptom- and event-based definitions of a COPD exacerbation, as well as the classifications of the severity of COPD exacerbations, all have their own limitations. Efforts to assess the efficacy of new therapies in the treatment and prevention of COPD exacerbations have been hampered by the lack of a widely agreed upon and consistently used definition. There is a need for greater investment in research oil COPD exacerbations in order to promote a better understanding of COPD exacerbation

TRANSCRIPTION FACTORS Overview

The term ‘transcription factor’ refers to a large family of proteins, which exert transcriptional control via specific interactions with regulatory gene sequences. Here, we provide a summary of the different classes of the transcription factor divided according to their DNA-binding motifs. The modular structure of transcription factors and the presence of distinct interacting domains determine the ability of these factors to associate with each other and with coactivating/repressing proteins. By recruiting transcriptional coactivators, transcription factors can induce changes in chromatin structure enabling gene expression to occur. We use the activation of the Rel transcription factor NF-κB and the nuclear receptor GR as examples to indicate some of the intricacies and subtleties of DNA binding, chromatin remodeling, and transcription factor cross-talk. Finally, we review the evidence for the involvement of select transcription factors in allergic and inflammatory diseases of the lung, and how changes in the expression and/or activity of these factors may vary in disease and provide important targets for future drug development

Inhaled corticosteroids in airways disease

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Strategies for improving the efficacy and therapeutic ratio of glucocorticoids

Although glucocorticoids are very effective in suppressing inflammation there is a clear clinical unmet need for new or improved glucocorticoids in patients with severe asthma and COPD. Recent developments include the targeted deposition of ultrafine glucocorticoid particles to treat small airways and the potential of novel agents that have a reduced side effect profile. Understanding the drivers of relative glucocorticoid resistance in these patients may lead to the development of newer drugs aimed at subsets of patients, for example asthmatics with high periostin levels. Alternatively, inhibitors of kinase pathways that are associated with inflammatory responses may be able to modulate glucocorticoid function and combinations of these inhibitors along with novel glucocorticoids may provide the combination therapy of the future

Chronic obstructive pulmonary disease and lung cancer: new molecular insights

Both chronic obstructive pulmonary disease (COPD) and lung cancer are major causes of death worldwide. In most cases this reflects cigarette smoke exposure which is able to induce an inflammatory response in the airways of smokers. Indeed, COPD is characterized by lower airway inflammation, and importantly, the presence of COPD is by far the greatest risk factor for lung cancer amongst smokers. Cigarette smoke induces the release of many inflammatory mediators and growth factors including TGF-β, EGFR, IL-1, IL-8 and G-CSF through oxidative stress pathways and this inflammation may persist for decades after smoking cessation. Mucus production is also increased by these inflammatory mediators, further linking airway inflammation to an important mechanism of lung cancer. A greater understanding of the molecular and cellular pathobiology that distinguishes smokers with lung cancer from smokers with and without COPD is needed to unravel the complex molecular interactions between COPD and lung cancer. By understanding the common signalling pathways involved in COPD and lung cancer the hope is that treatments will be developed that not only treat the underlying disease process in COPD, but also reduce the currently high risk of developing lung cancer in these patients