Tag: Epithelial

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Decreased Epithelial and Plasma miR-181b-5p Expression Associates with Airway Eosinophilic Inflammation in Asthma.

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Decreased Epithelial and Plasma miR-181b-5p Expression Associates with Airway Eosinophilic Inflammation in Asthma.

Clin Exp Allergy. 2016 May 18;

Authors: Huo X, Zhang K, Yi L, Mo Y, Liang Y, Zhao J, Zhang Z, Xu Y, Zhen G

Abstract
BACKGROUND: Airway eosinophilic inflammation is a pivotal feature of asthma. Epithelial cells play critical roles in airway eosinophilia. We hypothesized that epithelial microRNAs (miRNAs) are involved in airway eosinophilia.
OBJECTIVE: This study investigated the associations between epithelial and plasma miR-181b-5p and airway eosinophilic inflammation, and the possible mechanism by which miR-181b-5p participates in eosinophilic inflammation.
METHODS: Epithelial miRNAs expression was profiled by miRNA array in 8 subjects with asthma and 4 healthy controls. Epithelial miR-181b-5p expression was confirmed by quantitative PCR in the subjects for array experiment and another cohort including 21 subjects with asthma and 10 controls. Plasma miR-181b-5p was determined by quantitative PCR in 72 subjects with asthma and 35 controls. Correlation assays between epithelial or plasma miR-181b-5p expression and airway eosinophilia were performed. The target of miR-181b-5p, SPP1, was predicted by online algorithms and verified in BEAS-2B cells. The role of miR-181b-5p in epithelial proinflammatory cytokine expression was examined in an in vitro system.
RESULTS: Epithelial miR-181b-5p expression was decreased in subjects with asthma. Epithelial miR-181b-5p levels were inversely correlated with sputum and bronchial submucosal eosinophilia. Plasma miR-181b-5p was decreased and correlated with epithelial miR-181b-5p in subjects with asthma. There was a strong inverse correlation between plasma miR-181b-5p and airway eosinophilia in subjects with asthma. Plasma miR-181b-5p was increased after inhaled corticosteroids treatment. We verified that SPP1 is a target of miR-181b-5p. In human bronchial epithelial cells, miR-181b-5p regulated IL-13-induced IL-1? and CCL11 expression by targeting SPP1. Dexamethasone restored IL-13-induced miR-181b-5p downregulation and suppressed IL-13-induced SPP1, IL-1? and CCL11 expression.
CONCLUSIONS AND CLINICAL RELEVANCE: Epithelial and plasma miR-181b-5p are potential biomarkers for airway eosinophilia in asthma. MiR-181b-5p may participate in eosinophilic airway inflammation by regulating proinflammatory cytokines expression via targeting SPP1. This article is protected by copyright. All rights reserved.

PMID: 27192552 [PubMed – as supplied by publisher]

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Rhinovirus-Induced Airway Disease: A Model To Understand the Antiviral and Th2 Epithelial Immune Dysregulation in Childhood Asthma.

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Rhinovirus-Induced Airway Disease: A Model To Understand the Antiviral and Th2 Epithelial Immune Dysregulation in Childhood Asthma.

J Investig Med. 2015 Jun 8;

Authors: Perez GF, Rodriguez-Martinez CE, Nino G

Abstract
Rhinovirus (RV) infections account for most asthma exacerbations among children and adults, yet the fundamental mechanism responsible for why asthmatics are more susceptible to RV than otherwise healthy individuals remains largely unknown. Nonetheless, the use of models to understand the mechanisms of RV-induced airway disease in asthma has dramatically expanded our knowledge about the cellular and molecular pathogenesis of the disease. For instance, ground-breaking studies have recently established that the susceptibility to RV in asthmatic subjects is associated with a dysfunctional airway epithelial inflammatory response generated after innate recognition of viral-related molecules, such as double-stranded RNA. This review summarizes the novel cardinal features of the asthmatic condition identified in the past few years through translational and experimental RV-based approaches. Specifically, we discuss the evidence demonstrating the presence of an abnormal innate antiviral immunity (airway epithelial secretion of types I and III interferons), exaggerated production of the master Th2 molecule thymic stromal lymphopoietin, and altered antimicrobial host defense in the airways of asthmatic individuals with acute RV infection.

PMID: 26057561 [PubMed – as supplied by publisher]

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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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Epithelial regulation of eicosanoid production in asthma.

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Epithelial regulation of eicosanoid production in asthma.

Pulm Pharmacol Ther. 2012 Dec;25(6):432-7

Authors: Hallstrand TS, Lai Y, Henderson WR, Altemeier WA, Gelb MH

Abstract
Alterations in the airway epithelium have been associated with the development of asthma in elite athletes and in subjects that are susceptible to exercise-induced bronchoconstriction (EIB). The syndrome of EIB refers to acute airflow obstruction that is triggered by a period of physical exertion. Asthmatics who are susceptible to EIB have increased levels of cysteinyl leukotrienes (CysLTs, i.e., LTs C?, D?, and E?) in induced sputum and exhaled breath condensate, and greater shedding of epithelial cells into the airway lumen. Exercise challenge in individuals susceptible to this disorder initiates a sustained increase in CysLTs in the airways, and secreted mucin release and smooth muscle constriction, which may be mediated in part through activation of sensory nerves. We have identified a secreted phospholipase A? (sPLA?) with increased levels in the airways of patients with EIB called sPLA? group X(sPLA?-X).We have found that sPLA?-X is strongly expressed in the airway epithelium in asthma. Further,we discovered that transglutaminase 2 (TGM2) is expressed at increased levels in asthma and serves asa regulator of sPLA?-X. Finally, we demonstrated that sPLA?-X acts on target cells such as eosinophils to initiate cellular eicosanoid synthesis. Collectively, these studies identify a novel mechanism linking the airway epithelium to the production of inflammatory eicosanoids by leukocytes.

PMID: 23323271 [PubMed – in process]

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IL-13 exposure enhances vitamin D-mediated expression of the human cathelicidin antimicrobial peptide-hCAP18/LL-37 in bronchial epithelial cells.

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IL-13 exposure enhances vitamin D-mediated expression of the human cathelicidin antimicrobial peptide-hCAP18/LL-37 in bronchial epithelial cells.

Infect Immun. 2012 Oct 8;

Authors: Schrumpf JA, van Sterkenburg MA, Verhoosel RM, Zuyderduyn S, Hiemstra PS

Abstract
Vitamin D is an important regulator of the expression of antimicrobial peptides, and vitamin D deficiency is associated with respiratory infections. Regulating expression of antimicrobial peptides such as the human cathelicidin antimicrobial peptide (hCAP)18/LL-37 by vitamin D in bronchial epithelial cells requires local conversion of 25(OH)vitaminD(3) (25D(3)) into its bioactive metabolite 1,25(OH)(2)vitaminD(3) (1,25D(3)) by CYP27B1. Low circulating vitamin D-levels in childhood asthma are associated with more severe exacerbations, which are often associated with infections. Atopic asthma is accompanied by Th2 driven inflammation mediated by cytokines such as IL-4 and IL-13, and the effect of these cytokines on vitamin D metabolism and hCAP-18/LL-37 expression is unknown. Therefore we investigated this in well-differentiated bronchial epithelial cells. To this end, cells were treated with IL-13 with and without 25D(3) and expression of hCAP18/LL-37, CYP27B1, the 1,25D(3) inactivating enzyme CYP24A1, and vitamin D receptor was assessed by quantitative PCR. We show that IL-13 enhances the ability of 25D(3) to increase expression of hCAP18/LL-37 and CYP24A1. In addition, exposure to IL-13 resulted in increased CYP27B1 expression, whereas VDR expression was not significantly affected. The enhancing effect of IL-13 on 25D(3)-mediated expression of hCAP18/LL-37 was further confirmed using SDS-PAGE Western Blot and immunofluorescence staining. In conclusion, we demonstrate that IL-13 induces vitamin D(-)dependent hCAP18/LL-37 expression, most likely by increasing CYP27B1. These data suggest that Th2 cytokines regulate the vitamin D metabolic pathway in bronchial epithelial cells.

PMID: 23045480 [PubMed – as supplied by publisher]

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Epithelial eotaxin-2 and eotaxin-3 expression: relation to asthma severity, luminal eosinophilia and age at onset.

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Epithelial eotaxin-2 and eotaxin-3 expression: relation to asthma severity, luminal eosinophilia and age at onset.

Thorax. 2012 Sep 26;

Authors: Coleman JM, Naik C, Holguin F, Ray A, Ray P, Trudeau JB, Wenzel SE

Abstract
BACKGROUND: Eosinophilic inflammation is implicated in asthma. Eotaxin 1-3 regulate eosinophil trafficking into the airways along with other chemotactic factors. However, the epithelial and bronchoalveolar lavage (BAL) cell expression of these chemokines in relation to asthma severity and eosinophilic phenotypes has not been addressed. OBJECTIVE: To measure the expression of the three eotaxin isoforms in bronchoscopically obtained samples and compare them with clinically relevant parameters between normal subjects and patients with asthma. METHODS: Normal subjects and patients with asthma of varying severity recruited through the Severe Asthma Research Program underwent clinical assessment and bronchoscopy with airway brushing and BAL. Eotaxin 1-3 mRNA/protein were measured in epithelial and BAL cells and compared with asthma severity, control and eosinophilic inflammation. RESULTS: Eotaxin-2 and eotaxin-3 mRNA and eotaxin-2 protein were increased in airway epithelial brushings from patients with asthma and were highest in cases of severe asthma (p values 0.0155, 0.0033 and 0.0006, respectively), with eotaxin-2 protein increased with age at onset. BAL cells normally expressed high levels of eotaxin-2 mRNA/protein but BAL fluid levels of eotaxin-2 were lowest in severe asthma. Epithelial eotaxin-2 and eotaxin-3 mRNA/protein was associated with sputum eosinophilia, lower forced expiratory volume in 1 s and more asthma exacerbations. Airway epithelial cell eotaxin-2 protein differed by asthma severity only in those with late onset disease, and tended to be highest in those with late onset eosinophilic asthma. CONCLUSIONS: Epithelial eotaxin-2 and 3 are increased in asthma and severe asthma. Their expression may contribute to luminal migration of eosinophils, especially in later onset disease, asthma control and severity.

PMID: 23015684 [PubMed – as supplied by publisher]

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