Current Issue : January - March Volume : 2014 Issue Number : 1 Articles : 5 Articles
Background: Preclinical studies suggest that interleukin-9 may be a central mediator in the development and\r\nmaintenance of airway inflammation in asthma. The aim of this study was therefore to evaluate the effects of MEDI-528,\r\nan anti-interleukin-9 monoclonal antibody, in adults with confirmed uncontrolled moderate-to-severe asthma.\r\nMethods: In this prospective double-blind, multicenter, parallel-group study, 329 subjects were randomized\r\n(1:1:1:1) to subcutaneous placebo or MEDI-528 (30, 100, 300 mg) every 2 weeks for 24 weeks, in addition to their\r\nusual asthma medications. The primary endpoint was change in mean Asthma Control Questionnaire-6 (ACQ-6)\r\nscore at week 13. Secondary endpoints included weighted asthma exacerbation rates and pre-bronchodilator\r\nforced expiratory volume in 1 second (FEV1) at weeks 13 and 25, as well as Asthma Quality of Life Questionnaire\r\nscores at weeks 12 and 25 and the safety of MEDI-528 throughout the study period. The primary endpoint was\r\nanalyzed using analysis of covariance.\r\nResults: The study population (n = 327) was predominantly female (69%) with a mean age of 43 years (range 18ââ?¬â??65).\r\nThe mean (SD) baseline ACQ-6 score for placebo (n = 82) and combined MEDI-528 (n = 245) was 2.8 (0.7) and 2.8 (0.8);\r\nFEV1 % predicted was 70.7% (15.9) and 71.5% (16.7). Mean (SD) change from baseline to week 13 in ACQ-6 scores for\r\nplacebo vs combined MEDI-528 groups was -1.2 (1.0) vs -1.2 (1.1) (p = 0.86). Asthma exacerbation rates (95% CI) at\r\nweek 25 for placebo vs MEDI-528 were 0.58 (0.36ââ?¬â??0.88) vs 0.49 (0.37ââ?¬â??0.64) exacerbations/subject/year (p = 0.52). No\r\nsignificant improvements in FEV1 % predicted were observed between the placebo and MEDI-528 groups. Adverse\r\nevents were comparable for placebo (82.9%) and MEDI-528 groups (30 mg, 76.5%; 100 mg, 81.9%; 300 mg, 85.2%).\r\nThe most frequent were asthma (placebo vs MEDI-528, 30.5% vs 33.5%), upper respiratory tract infection (14.6% vs\r\n17.1%), and headache (9.8% vs 9.8%).\r\nConclusions: The addition of MEDI-528 to existing asthma controller medications was not associated with any\r\nimprovement in ACQ-6 scores, asthma exacerbation rates, or FEV1 values, nor was it associated with any major\r\nsafety concerns....
Background: Human rhinovirus (HRV) triggers exacerbations of asthma and chronic obstructive pulmonary disease\r\n(COPD). Cigarette smoking is the leading risk factor for the development of COPD and 25% of asthmatics smoke.\r\nSmoking asthmatics have worse symptoms and more frequent hospitalizations compared to non-smoking\r\nasthmatics. The degree of neutrophil recruitment to the airways correlates with disease severity in COPD and\r\nduring viral exacerbations of asthma. We have previously shown that HRV and cigarette smoke, in the form of\r\ncigarette smoke extract (CSE), each induce expression of the neutrophil chemoattractant and activator, CXCL8, in\r\nhuman airway epithelial cells. Additionally, we demonstrated that the combination of HRV and CSE induces\r\nexpression of levels of CXCL8 that are at least additive relative to induction by each stimulus alone, and that\r\nenhancement of CXCL8 expression by HRV+CSE is regulated, at least in part, via mRNA stabilization. Here we further\r\ninvestigate the mechanisms by which HRV+CSE enhances CXCL8 expression.\r\nMethods: Primary human bronchial epithelial cells were cultured and treated with CSE alone, HRV alone or the\r\ncombination of the two stimuli. Stabilizing/destabilizing proteins adenine/uridine-rich factor-1 (AUF-1), KH-type\r\nsplicing regulatory protein (KHSRP) and human antigen R (HuR) were measured in cell lysates to determine\r\nexpression levels following treatment. siRNA knockdown of each protein was used to assess their contribution to\r\nthe induction of CXCL8 expression following treatment of cells with HRV and CSE.\r\nResults: We show that total expression of stabilizing/de-stabilizing proteins linked to CXCL8 regulation, including\r\nAUF-1, KHSRP and HuR, are not altered by CSE, HRV or the combination of the two stimuli. Importantly, however,\r\nsiRNA-mediated knock-down of HuR, but not AUF-1 or KHSRP, abolishes the enhancement of CXCL8 by HRV+CSE.\r\nData were analyzed using one-way ANOVA with student Newman-Keuls post hoc analysis and values of p= 0.05\r\nwere considered significant.\r\nConclusions: Induction of CXCL8 by the combination of HRV and CSE is regulated by mRNA stabilization\r\ninvolving HuR. Thus, targeting the HuR pathway may be an effective method of dampening CXCL8 production\r\nduring HRV-induced exacerbations of lower airway disease, particularly in COPD patients and asthmatic patients\r\nwho smoke....
Background: Patients with chronic obstructive pulmonary disease (COPD) can be categorized as having frequent\r\n(FE) or infrequent (IE) exacerbations depending on whether they respectively experience two or more, or one or\r\nzero exacerbations per year. Although most patients do not change category from year to year, some will, and the\r\nfactors associated with this behaviour have not been examined.\r\nMethods: 1832 patients completing two year follow-up in the Evaluation of COPD Longitudinally to Identify\r\nPredictive Surrogate End-points (ECLIPSE) study were examined at baseline and then yearly. Exacerbations were\r\ndefined by health care utilisation. Patient characteristics compared between those patients who did or did not\r\nchange exacerbation category from year 1 to year 2.\r\nFindings: Between years 1 and 2, 221 patients (17%) changed from IE to FE and 210 patients (39%) from FE to IE.\r\nMore severe disease was associated with changing from IE to FE and less severe disease from FE to IE. Over the\r\npreceding year, small falls in FEV1 and 6-minute walking distance were associated with changing from IE to FE, and\r\nsmall falls in platelet count associated with changing from FE to IE.\r\nConclusion: No parameter clearly predicts an imminent change in exacerbation frequency category....
Background: Interstitial lung disease is a major cause of morbidity and mortality in systemic sclerosis (SSc), with\r\ninsufficiently effective treatment options. Progression of pulmonary fibrosis involves expanding populations of\r\nfibroblasts, and the accumulation of extracellular matrix proteins. Characterisation of SSc lung fibroblast gene\r\nexpression profiles underlying the fibrotic cell phenotype could enable a better understanding of the processes\r\nleading to the progressive build-up of scar tissue in the lungs. In this study we evaluate the transcriptomes of\r\nfibroblasts isolated from SSc lung biopsies at the time of diagnosis, compared with those from control lungs.\r\nMethods: We used Affymetrix oligonucleotide microarrays to compare the gene expression profile of pulmonary\r\nfibroblasts cultured from 8 patients with pulmonary fibrosis associated with SSc (SSc-ILD), with those from control\r\nlung tissue peripheral to resected cancer (n=10). Fibroblast cultures from 3 patients with idiopathic pulmonary\r\nfibrosis (IPF) were included as a further comparison. Genes differentially expressed were identified using two\r\nseparate analysis programs following a set of pre-determined criteria: only genes significant in both analyses were\r\nconsidered. Microarray expression data was verified by qRT-PCR and/or western blot analysis.\r\nResults: A total of 843 genes were identified as differentially expressed in pulmonary fibroblasts from SSc-ILD and/\r\nor IPF compared to control lung, with a large overlap in the expression profiles of both diseases. We observed\r\nincreased expression of a TGF-�Ÿ response signature including fibrosis associated genes and myofibroblast markers,\r\nwith marked heterogeneity across samples. Strongly suppressed expression of interferon stimulated genes,\r\nincluding antiviral, chemokine, and MHC class 1 genes, was uniformly observed in fibrotic fibroblasts. This\r\nexpression profile includes key regulators and mediators of the interferon response, such as STAT1, and CXCL10, and\r\nwas also independent of disease group.\r\nConclusions: This study identified a strongly suppressed interferon-stimulated gene program in fibroblasts from\r\nfibrotic lung. The data suggests that the repressed expression of interferon-stimulated genes may underpin critical\r\naspects of the profibrotic fibroblast phenotype, identifying an area in pulmonary fibrosis that requires further\r\ninvestigation....
Background: The excess and persistent accumulation of fibroblasts due to aberrant tissue repair results in fibrotic\r\ndiseases such as idiopathic pulmonary fibrosis. Recent reports have revealed significant changes in microRNAs\r\nduring idiopathic pulmonary fibrosis and evidence in support of a role for microRNAs in myofibroblast\r\ndifferentiation and the epithelial-mesenchymal transition in the context of fibrosis. It has been reported that\r\nmicroRNA-21 is up-regulated in myofibroblasts during fibrosis and promotes transforming growth factor-beta\r\nsignaling by inhibiting Smad7. However, expression changes in microRNA-21 and the role of microRNA-21 in\r\nepithelial-mesenchymal transition during lung fibrosis have not yet been defined.\r\nMethods: Lungs from saline- or bleomycin-treated C57BL/6 J mice and lung specimens from patients with\r\nidiopathic pulmonary fibrosis were analyzed. Enzymatic digestions were performed to isolate single lung cells. Lung\r\nepithelial cells were isolated by flow cytometric cell sorting. The expression of microRNA-21 was analyzed using\r\nboth quantitative PCR and in situ hybridization. To induce epithelial-mesenchymal transition in culture, isolated\r\nmouse lung alveolar type II cells were cultured on fibronectin-coated chamber slides in the presence of\r\ntransforming growth factor-�Ÿ, thus generating conditions that enhance epithelial-mesenchymal transition. To\r\ninvestigate the role of microRNA-21 in epithelial-mesenchymal transition, we transfected cells with a microRNA-21\r\ninhibitor. Total RNA was isolated from the freshly isolated and cultured cells. MicroRNA-21, as well as mRNAs\r\nof genes that are markers of alveolar epithelial or mesenchymal cell differentiation, were quantified using\r\nquantitative PCR.\r\nResults: The lung epithelial cells isolated from the bleomycin-induced lung fibrosis model system had decreased\r\nexpression of epithelial marker genes, whereas the expression of mesenchymal marker genes was increased.\r\nMicroRNA-21 was significantly upregulated in isolated lung epithelial cells during bleomycin-induced lung fibrosis\r\nand human idiopathic pulmonary fibrosis. MicroRNA-21 was also upregulated in the cultured alveolar epithelial cells\r\nunder the conditions that enhance epithelial-mesenchymal transition. Exogenous administration of a microRNA-21\r\ninhibitor prevented the increased expression of vimentin and alpha-smooth muscle actin in cultured primary\r\nmouse alveolar type II cells under culture conditions that induce epithelial-mesenchymal transition.\r\nConclusions: Our experiments demonstrate that microRNA-21 is increased in lung epithelial cells during lung\r\nfibrosis and that it promotes epithelial-mesenchymal transition....
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