Tag: Bronchial

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Cigarette Smoke Induces uPAR in Vivo and Isoforms Selectively Contribute to Bronchial Epithelial Phenotype.

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Cigarette Smoke Induces uPAR in Vivo and Isoforms Selectively Contribute to Bronchial Epithelial Phenotype.

Am J Respir Cell Mol Biol. 2014 Dec 9;

Authors: Portelli MA, Stewart CE, Hall IP, Brightling CE, Sayers I

Abstract
The urokinase plasminogen activator receptor (uPAR) gene (PLAUR) has been identified as an asthma susceptibility gene, with polymorphisms within that gene being associated with baseline lung function, lung function decline and lung function in a smoking population. Soluble cleaved uPAR (scuPAR), a molecule identified as a marker of increased morbidity and mortality in a number of diseases, has itself been shown to be elevated in the airways of asthma and COPD patients. However, the functionality of soluble receptor isoforms and their relationship with an important initiator for obstructive lung disease, cigarette smoke, remains undefined. In this study, we set out to determine the effect of cigarette smoke on soluble uPAR isoforms, its regulatory pathway and the resultant effect on bronchial epithelial cell function. We identified a positive association between cigarette pack/years and uPAR expression in the airway bronchial epithelium of biopsies from asthma patients (n=27, P=0.0485). In vitro, cigarette smoke promoted cleavage of uPAR from the surface of bronchial epithelial cells (1.5X induction, P<0.0001) and induced the soluble spliced isoform through changes in mRNA expression (~2X change, P<0.001), driven by loss of endogenous 3`UTR suppression. Elevated expression of the soluble isoforms resulted in a pro-remodelling cell phenotype, characterised by increased proliferation and MMP-9 expression in primary bronchial epithelial cells. This suggests that cigarette smoke elevates soluble receptor isoforms in bronchial epithelial cells through direct (cleavage), and indirect (mRNA expression) means. These findings provide further insight into how cigarette smoke may influence changes in the airways of importance to airway remodelling and obstructive lung disease progression.

PMID: 25490122 [PubMed – as supplied by publisher]

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Concomitant inhibition of primary equine bronchial fibroblast proliferation and differentiation by selective ?2-adrenoceptor agonists and dexamethasone.

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Concomitant inhibition of primary equine bronchial fibroblast proliferation and differentiation by selective ?2-adrenoceptor agonists and dexamethasone.

Eur J Pharmacol. 2014 Aug 13;

Authors: Franke J, Abraham G

Abstract
Altered airway cell proliferation plays an important role in the pathogenesis of human bronchial asthma and chronic obstructive pulmonary disease (COPD) as well as the equine recurrent airway obstruction (RAO) with consistent changes, i.e. narrowing the airway wall, explained by proliferation and differentiation of fibroblasts. In permanent cell lines, it has been suggested that ?2-adrenoceptor agonists and glucocorticoids regulate cell proliferation via the ?2-adrenoceptor pathway; indeed, no study was carried out in fresh isolated primary equine bronchial fibroblasts (EBF). We characterized the ?-adrenoceptors in EBF, and compared effects of long-acting (clenbuterol) and short-acting (salbutamol, isoproterenol) ?2-agonists and dexamethasone on proliferation, differentiation and collagen synthesis. High density (Bmax; 5037±494 sites/cell) of ?2-adrenoceptor subtype was expressed in EBF. ?2-agonists inhibited concentration-dependently EBF proliferation with potency of clenbuterol>salbutamol l» isoproterenol which was inhibited by ICI 118.551 and propranolol but not by CGP 20712A. In contrast, dexamethasone alone inhibited less EBF proliferation, but the effect was high when dexamethasone was combined with ?2-agonists. Transforming growth factor-?1 (TGF-?1) increased transformation of fibroblasts into myofibroblasts, and which was inhibited by clenbuterol and dexamethasone alone and drug combination resulted in high inhibition rate. Collagen synthesis in EBF was rather hampered by dexamethasone than by ?-agonists. Collectively, the expression of ?2-adrenoceptor subtype in EBF and the anti-proliferative effect of clenbuterol suggest that ?2-adrenoceptors are growth inhibitory and anti-fibrotic in EBF. These ?2-agonist effects in EBF were synergistically enhanced by dexamethasone, providing the additive effects of glucocorticoids to counteract airway remodelling and morbidity of asthma and RAO.

PMID: 25128704 [PubMed – as supplied by publisher]

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Cytokine profile of bronchoalveolar lavage fluid from a mouse model of bronchial asthma during seasonal H1N1 infection.

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Cytokine profile of bronchoalveolar lavage fluid from a mouse model of bronchial asthma during seasonal H1N1 infection.

Cytokine. 2014 Jul 3;69(2):206-210

Authors: Hasegawa S, Wakiguchi H, Okada S, Gui Kang Y, Fujii N, Hasegawa M, Hasegawa H, Ainai A, Atsuta R, Shirabe K, Toda S, Wakabayashi-Takahara M, Morishima T, Ichiyama T

Abstract
BACKGROUND: Several studies support the role of viral infections in the pathogenesis of asthma exacerbation. However, several pediatricians believe that influenza virus infection does not exacerbate bronchial asthma, except for influenza A H1N1 2009 pandemic [A(H1N1)pdm09] virus infection. We previously reported that A(H1N1)pdm09 infection possibly induces severe pulmonary inflammation or severe asthmatic attack in a mouse model of bronchial asthma and in asthmatic children. However, the ability of seasonal H1N1 influenza (H1N1) infection to exacerbate asthmatic attacks in bronchial asthma patients has not been previously reported, and the differences in the pathogenicity profiles, such as cytokine profiles, remains unclear in bronchial asthma patients after A(H1N1)pdm09 and H1N1 infections.
METHODS: The cytokine levels and viral titers in the bronchoalveolar lavage (BAL) fluid from mice with and without asthma after H1N1 infection (A/Yamagata and A/Puerto Rico strains) were compared.
RESULTS: The interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-?, IL-5, interferon (IFN)-?, IFN-?, and IFN-? levels were significantly higher in the BAL fluids from the control/H1N1 mice than from the asthmatic/H1N1 mice. The viral titers in the BAL fluid were also significantly higher in the control/H1N1mice than in the asthmatic/H1N1 mice infected with either A/Yamagata or A/Puerto Rico.
CONCLUSIONS: A(H1N1)pdm09 infection, but not H1N1 infection, can induce severe pulmonary inflammation through elevated cytokine levels in a mouse model of asthma.

PMID: 24998935 [PubMed – as supplied by publisher]

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Registry of Bronchial Thermoplasty (BT) Procedures EMEA BT Registry.

Condition:   Asthma
Intervention:   Device: Alair System (Bronchial Thermoplasty)
Sponsors:   Boston Scientific Corporation;   Steering Committee member: Robert Niven, MD;   Steering Committee member: Alfons Torrego, MD;   Steering Committee member: Felix Herth, MD;   Steering Committee member: Narinder Shargill, PhD
Recruiting – verified January 2014

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[Severe bronchial asthma].

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[Severe bronchial asthma].

Ned Tijdschr Geneeskd. 2013;157(33):A6117

Authors: Toutenhoofd P, van der Zee JS

Abstract
– The term ‘difficult-to-treat asthma’ indicates that the asthma is not sufficiently controlled despite prescription of high doses of asthma medication.- The term ‘severe asthma’ is used when the asthma is still insufficiently controlled after exclusion or treatment of any complicating factors; an important complicating factor is poor compliance.- Recent studies have focused on the heterogeneous character of asthma and on the definition of specific phenotypes, with the aim of developing phenotype-specific treatments.- Treatment options for severe asthma are only partly evidence based.- The decision to implement additional therapy for severe asthma depends on the individual patient, the asthma phenotype, and the adverse-event profile of the treatment.- Many of the additional therapies should be given as a trial treatment under strict control, especially when efficacy has not been convincingly scientifically proven.

PMID: 23945432 [PubMed – in process]

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