Tag: Induces

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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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Why influenza induces asthma attacks? – Times of India

Why influenza induces asthma attacks?
Times of India
A study has found a previously unknown biological pathway that helps explain why influenza induces asthma attacks in children with the disease. Researchers at Children's Hospital Boston studied a mouse model and found that influenza activates a newly …
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Allergen-Induced Coexpression of bFGF and TGF-?1 by Macrophages in a Mouse Model of Airway Remodeling: bFGF Induces Macrophage TGF-?1 Expression in vitro.

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Allergen-Induced Coexpression of bFGF and TGF-?1 by Macrophages in a Mouse Model of Airway Remodeling: bFGF Induces Macrophage TGF-?1 Expression in vitro.

Int Arch Allergy Immunol. 2010 Nov 25;155(1):12-22

Authors: Yum HY, Cho JY, Miller M, Broide DH

Background: Basic fibroblast growth factor (bFGF) is a cytokine that is mitogenic for fibroblasts and smooth muscle and may play a role in airway remodeling in asthma. We have used a mouse model of chronic ovalbumin (OVA) allergen-induced airway remodeling to determine whether bFGF and fibroblast growth factor receptor-1 are expressed and regulated by corticosteroids in the airway, as well as to determine whether bFGF mediates expression of another proremodeling cytokine, transforming growth factor (TGF)-?1. Methods: The airway levels and localization of bFGF, FGF receptor-1 and TGF-?1 were determined by ELISA, immunohistology and image analysis in the remodeled airways of chronic OVA-challenged mice treated with either corticosteroids or diluent. In vitro cultures of bone narrow-derived macrophages were used to determine whether bFGF induced TGF-?1 expression. Results: Mice chronically challenged with OVA developed significant airway remodeling that was associated with significantly increased levels of bFGF and TGF-?1. Immunohistochemistry demonstrated significantly increased bFGF and FGF receptor-1 expression by peri- bronchial F4/80+ cells. Double-label immunofluorescence microscopy studies demonstrated that peribronchial macrophages coexpressed bFGF and TGF-?1. In vitro studies demonstrated that incubation of bone marrow-derived macrophages with bFGF induced expression of TGF-?1. Mice treated with corticosteroids and subjected to chronic OVA challenge had significantly reduced levels of bFGF, FGF receptor-1, peribronchial TGF-?1+ cells and airway remodeling. Conclusions: Overall, this study demonstrates that allergen challenge stimulates peribronchial macrophages to coexpress bFGF and TGF-?1 and that bFGF may potentiate macrophage release of TGF-?1 through autocrine and/or paracrine pathways.

PMID: 21109744 [PubMed – as supplied by publisher]

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Flagellin Induces the Expression of Thymic Stromal Lymphopoietin in Human Keratinocytes via Toll-Like Receptor 5.

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Flagellin Induces the Expression of Thymic Stromal Lymphopoietin in Human Keratinocytes via Toll-Like Receptor 5.

Int Arch Allergy Immunol. 2010 Nov 25;155(1):31-37

Authors: Le TA, Takai T, Vu AT, Kinoshita H, Chen X, Ikeda S, Ogawa H, Okumura K

Background: Thymic stromal lymphopoietin (TSLP), highly expressed by keratinocytes in skin lesions of atopic dermatitis patients and bronchial epithelial cells in asthma, plays a key role in allergic diseases. Information on triggers for the release of TSLP in keratinocytes is still limited. Keratinocytes express Toll-like receptor (TLR) 5, the ligand for which is flagellin, the major structural protein of the flagella of Gram-negative bacteria. IL-4, IL-13 and TNF-? (Th2/TNF) are associated with allergic diseases. TGF-?, one of the ligands for the epidermal growth factor receptor, is overexpressed in keratinocytes in atopic dermatitis. We investigated the induction of TSLP expression in keratinocytes stimulated with flagellin and its modulation by the Th2/TNF cytokines and TGF-?. Methods: Primary human keratinocytes were stimulated with flagellin with or without cytokines. The TSLP released was measured by ELISA. Gene expression was analyzed by quantitative real-time PCR. Results: Stimulation of keratinocytes with flagellin induced the release of TSLP protein and upregulation of the gene expression of TSLP and other pro-inflammatory molecules. The flagellin-induced release of TSLP was enhanced by the Th2/TNF cytokines or TGF-?. Small interfering RNA-mediated knockdown of TLR5 expression suppressed the flagellin-induced TSLP gene expression. Conclusions: Flagellin induces TSLP expression in keratinocytes via TLR5 and the expression can be upregulated by a cytokine milieu with Th2/TNF or TGF-?, suggesting that exposure of barrier-defective skin to Gram-negative bacteria or environmental flagellin contributes to the initiation and/or amplification of Th2-type skin inflammation including atopic dermatitis through the induction of TSLP expression in keratinocytes.

PMID: 21109746 [PubMed – as supplied by publisher]

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