Interleukin-33 Drives Activation of Alveolar Macrophages and Airway Inflammation in a Mouse Model of Acute Exacerbation of Chronic Asthma

BioMed Research International
Volume 2013 (2013), Article ID 250938, 10 pages
http://dx.doi.org/10.1155/2013/250938

Research Article

Interleukin-33 Drives Activation of Alveolar Macrophages and Airway Inflammation in a Mouse Model of Acute Exacerbation of Chronic Asthma

Melissa M. Bunting, Alexander M. Shadie, Rylie P. Flesher, Valentina Nikiforova, Linda Garthwaite, Nicodemus Tedla, Cristan Herbert, and Rakesh K. Kumar

Department of Pathology, Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia

Received 8 February 2013; Revised 23 April 2013; Accepted 29 April 2013

Academic Editor: Carlo Jose Freire de Oliveira

Copyright © 2013 Melissa M. Bunting et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

We investigated the role of interleukin-33 (IL-33) in airway inflammation in an experimental model of an acute exacerbation of chronic asthma, which reproduces many of the features of the human disease. Systemically sensitized female BALB/c mice were challenged with a low mass concentration of aerosolized ovalbumin for 4 weeks to induce chronic asthmatic inflammation and then received a single moderate-level challenge to trigger acute airway inflammation simulating an asthmatic exacerbation. The inflammatory response and expression of cytokines and activation markers by alveolar macrophages (AM) were assessed, as was the effect of pretreatment with a neutralizing antibody to IL-33. Compared to chronically challenged mice, AM from an acute exacerbation exhibited significantly enhanced expression of markers of alternative activation, together with enhanced expression of proinflammatory cytokines and of cell surface proteins associated with antigen presentation. In parallel, there was markedly increased expression of both mRNA and immunoreactivity for IL-33 in the airways. Neutralization of IL-33 significantly decreased both airway inflammation and the expression of proinflammatory cytokines by AM. Collectively, these data indicate that in this model of an acute exacerbation of chronic asthma, IL-33 drives activation of AM and has an important role in the pathogenesis of airway inflammation.

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• PLoS One
• v.8(7); 2013
• PMC3720563

PLoS One. 2013; 8(7): e69670.

Published online 2013 July 23. doi:  10.1371/journal.pone.0069670

PMCID: PMC3720563

Roflumilast Inhibits Respiratory Syncytial Virus Infection in Human Differentiated Bronchial Epithelial Cells

Manuel Mata,1,2,3,* Isidoro Martinez,4,6 Jose A. Melero,5,6 Herman Tenor,7 and Julio Cortijo1,2,3

Steven M. Varga, Editor

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Abstract

Respiratory syncytial virus (RSV) causes acute exacerbations in COPD and asthma. RSV infects bronchial epithelial cells (HBE) that trigger RSV associated lung pathology. This study explores whether the phosphodiesterase 4 (PDE4) inhibitor Roflumilast N-oxide (RNO), alters RSV infection of well-differentiated HBE (WD-HBE) in vitro. WD-HBE were RSV infected in the presence or absence of RNO (0.1-100 nM). Viral infection (staining of F and G proteins, nucleoprotein RNA level), mRNA of ICAM-1, ciliated cell markers (digital high speed videomicroscopy, β-tubulin immunofluorescence, Foxj1 and Dnai2 mRNA), Goblet cells (PAS), mRNA of MUC5AC and CLCA1, mRNA and protein level of IL-13, IL-6, IL-8, TNFα, formation of H2O2 and the anti-oxidative armamentarium (mRNA of Nrf2, HO-1, GPx; total antioxidant capacity (TAC) were measured at day 10 or 15 post infection. RNO inhibited RSV infection of WD-HBE, prevented the loss of ciliated cells and markers, reduced the increase of MUC5AC and CLCA1 and inhibited the increase of IL-13, IL-6, IL-8, TNFα and ICAM-1. Additionally RNO reversed the reduction of Nrf2, HO-1 and GPx mRNA levels and consequently restored the TAC and reduced the H2O2 formation. RNO inhibits RSV infection of WD-HBE cultures and mitigates the cytopathological changes associated to this virus.

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Review

A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy

Dora Liu, Alexandra Ahmet, Leanne Ward, Preetha Krishnamoorthy, Efrem D Mandelcorn, Richard Leigh, Jacques P Brown, Albert Cohen and Harold Kim

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Allergy, Asthma & Clinical Immunology 2013, 9:30 doi:10.1186/1710-1492-9-30

Published: 15 August 2013

Abstract (provisional)

Systemic corticosteroids play an integral role in the management of many inflammatory and immunologic conditions, but these agents are also associated with serious risks. Osteoporosis, adrenal suppression, hyperglycemia, dyslipidemia, cardiovascular disease, Cushing's syndrome, psychiatric disturbances and immunosuppression are among the more serious side effects noted with systemic corticosteroid therapy, particularly when used at high doses for prolonged periods. This comprehensive article reviews these adverse events and provides practical recommendations for their prevention and management based on both current literature and the clinical experience of the authors.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

Practice characteristics influence spirometry use

Research article

General practice variation in spirometry testing among patients receiving first-time prescriptions for medication targeting obstructive lung disease in Denmark: a population-based observational study

Mette M Koefoed^*, Jens Søndergaard, René dePont Christensen and Dorte E Jarbøl

• *Corresponding author: Mette M Koefoed mkoefoed@health.sdu.dk

Author Affiliations

Research Unit of General Practice, Institute of Public Health, University of Southern Denmark, J.B. Winsløws Vej 9A, 1, DK-5000, Odense C, Denmark

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BMC Family Practice 2013, 14:113 doi:10.1186/1471-2296-14-113

The electronic version of this article is the complete one and can be found online at:http://www.biomedcentral.com/1471-2296/14/113

Received:	7 December 2012
Accepted:	8 July 2013
Published:	7 August 2013

© 2013 Koefoed et al.; licensee BioMed Central Ltd. 

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

Spirometry testing is essential to confirm an obstructive lung disease, but studies have reported that a large proportion of patients diagnosed with COPD or asthma have no history of spirometry testing. Also, it has been shown that many patients are prescribed medication for obstructive lung disease without a relevant diagnosis or spirometry test registered. General practice characteristics have been reported to influence diagnosis and management of several chronic diseases. However, these findings are inconsistent, and it is uncertain whether practice characteristics influence spirometry testing among patients receiving medication for obstructive lung disease. The aim of this study was therefore to examine if practice characteristics are associated with spirometry testing among patients receiving first-time prescriptions for medication targeting obstructive lung disease.

Methods

A national register-based cohort study was performed. All patients over 18 years receiving first-time prescriptions for medication targeting obstructive lung disease in 2008 were identified and detailed patient-specific data on sociodemographic status and spirometry tests were extracted. Information on practice characteristics like number of doctors, number of patients per doctor, training practice status, as well as age and gender of the general practitioners was linked to each medication user.

Results

Partnership practices had a higher odds ratio (OR) of performing spirometry compared with single-handed practices (OR 1.24, CI 1.09-1.40). We found a significant association between increasing general practitioner age and decreasing spirometry testing. This tendency was most pronounced among partnership practices, where doctors over 65 years had the lowest odds of spirometry testing (OR 0.25, CI 0.10-0.61). Training practice status was significantly associated with spirometry testing among single-handed practices (OR 1.40, CI 1.10-1.79).

Conclusion

Some of the variation in spirometry testing among patients receiving first-time prescriptions for medication targeting obstructive lung disease was associated with practice characteristics. This variation in performance may indicate a potential for quality improvement.

Keywords: 

Obstructive lung disease; Spirometry; Practice characteristics

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Lower Respiratory Tract Infections Associated with Rhinovirus during Infancy and Increased Risk of Wheezing during Childhood

Abstract

Background and Objectives

Although association between respiratory syncytial virus infection and later asthma development has been established, little is known about the role of other respiratory viruses. Rhinovirus was considered a mild pathogen of the upper respiratory tract but current evidence suggests that rhinovirus is highly prevalent among children with lower respiratory tract infections (LRTI). The aim of the study was to evaluate whether LRTI hospitalization associated with rhinovirus during infancy was associated with an increased risk of wheezing – a proxy measure of asthma – during childhood.

Methods

During a 12 months period, all infants - 1 year admitted to Manhiça District Hospital with symptoms of LRTI who survived the LRTI episode, were enrolled in the study cohort. Nasopharyngeal aspirates were collected on admission for viral determination and study infants were classified according to presence or not of rhinovirus. The study cohort was passively followed-up at the Manhiça District Hospital for up to 4 years and 9 months to evaluate the association between LRTI associated with rhinovirus in infancy and wheezing during childhood.

Findings and Conclusions

A total of 220 infants entered the cohort; 25% of them had rhinovirus detected during the LRTI episode as opposed to 75% who tested negative for rhinovirus. After adjusting for sex and age and HIV infection at recruitment, infants hospitalized with LRTI associated with rhinovirus had higher incidence of subsequent visits with wheezing within the year following hospitalization [Rate ratio=1.68, (95% confidence interval=1.02-2.75); Wald test p-value = 0.039]. No evidence of increased incidence rate of visits with wheezing was observed for the remaining follow-up period. Our data suggest a short term increased risk of wheezing after an initial episode of LRTI with RV.

Citation: O’Callaghan-Gordo C, Bassat Q, Díez-Padrisa N, Morais L, Machevo S, et al. (2013) Lower Respiratory Tract Infections Associated with Rhinovirus during Infancy and Increased Risk of Wheezing during Childhood. A Cohort Study. PLoS ONE 8(7): e69370. doi:10.1371/journal.pone.0069370

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Editor: Helene F. Rosenberg, NIAID, United States of America

Received: February 4, 2013; Accepted: June 9, 2013; Published: July 31, 2013

Copyright: © 2013 O'Callaghan-Gordo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: The study was supported by a grant from the Health Research Found of the Spanish Ministry of Science and Innovation (FIS: PS09/01843). The Centro de Investigação em Saúde da Manhiça receives major core funding from the Spanish Agency of International Cooperation (http://www.micinn.es/portal/site/MICINN/). QB and AR were supported during the time of the study implementation by grants from the Spanish Ministry of Science and Innovation (FIS: CM05/00134 and Ramón y Cajal: RYC-2008-02777, respectively;http://www.micinn.es/portal/site/MICINN/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Lung Macrophages Contribute to House Dust Mite Driven Airway Remodeling via HIF-1α

OPEN ACCESS PEER-REVIEWED

Abstract

HIF-1α is a transcription factor that is activated during hypoxia and inflammation and is a key regulator of angiogenesis in vivo. During the development of asthma, peribronchial angiogenesis is induced in response to aeroallergens and is thought to be an important feature of sustained chronic allergic inflammation. Recently, elevated HIF-1α levels have been demonstrated in both the lung tissue and bronchoalveolar lavage of allergic patients, respectively. Therefore, we investigated the role of HIF-1α on the development of angiogenesis and inflammation following acute and chronic allergen exposure. Our data shows that intranasal exposure to house dust mite (HDM) increases the expression of HIF-1α in the lung, whilst reducing the expression of the HIF-1α negative regulators, PHD1 and PHD3. Blockade of HIF-1α in vivo, significantly decreased allergic inflammation and eosinophilia induced by allergen, due to a reduction in the levels of IL-5 and Eotaxin-2. Importantly, HIF-1α blockade significantly decreased levels of VEGF-A and CXCL1 in the lungs, which in turn led to a profound decrease in the recruitment of endothelial progenitor cells and a reduction of peribronchial angiogenesis. Furthermore, HDM or IL-4 treatment of primary lung macrophages resulted in significant production of both VEGF-A and CXCL1; inhibition of HIF-1α activity abrogated the production of these factors via an up-regulation of PHD1 and PHD3. These findings suggest that novel strategies to reduce the expression and activation of HIF-1α in lung macrophages may be used to attenuate allergen-induced airway inflammation and angiogenesis through the modulation of VEGF-A and CXCL1 expression.

Clinical Relevance

This study provides new insights into the role of HIF-1α in the development of peribronchial angiogenesis and inflammation in a murine model of allergic airway disease. These findings indicate that strategies to reduce activation of macrophage derived HIF-1α may be used as a target to improve asthma pathology.

Citation: Byrne AJ, Jones CP, Gowers K, Rankin SM, Lloyd CM (2013) Lung Macrophages Contribute to House Dust Mite Driven Airway Remodeling via HIF-1α. PLoS ONE 8(7): e69246. doi:10.1371/journal.pone.0069246

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Editor: Marco Idzko, University Hospital Freiburg, Germany

Received: May 2, 2013; Accepted: June 5, 2013; Published: July 23, 2013

Copyright: © 2013 Byrne et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported by the Welcome Trust (grants 057704 and 085851/Z/08/Z). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

An Anti-Human ICAM-1 Antibody Inhibits Rhinovirus-Induced Exacerbations of Lung Inflammation

Abstract

Human rhinoviruses (HRV) cause the majority of common colds and acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Effective therapies are urgently needed, but no licensed treatments or vaccines currently exist. Of the 100 identified serotypes, ~90% bind domain 1 of human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor, making this an attractive target for development of therapies; however, ICAM-1 domain 1 is also required for host defence and regulation of cell trafficking, principally via its major ligand LFA-1. Using a mouse anti-human ICAM-1 antibody (14C11) that specifically binds domain 1 of human ICAM-1, we show that 14C11 administered topically or systemically prevented entry of two major groups of rhinoviruses, HRV16 and HRV14, and reduced cellular inflammation, pro-inflammatory cytokine induction and virus load in vivo. 14C11 also reduced cellular inflammation and Th2 cytokine/chemokine production in a model of major group HRV-induced asthma exacerbation. Interestingly, 14C11 did not prevent cell adhesion via human ICAM-1/LFA-1 interactions in vitro, suggesting the epitope targeted by 14C11 was specific for viral entry. Thus a human ICAM-1 domain-1-specific antibody can prevent major group HRV entry and induction of airway inflammation in vivo.

Author Summary

Viruses exploit receptors on the host cell to cause infection. Therapies aimed at blocking virus-receptor interactions have the potential to prevent viral disease. Cellular receptors are also important for normal host cell function. Therefore, new therapies targeting these receptors to block viral infection may also inadvertently alter the physiology of the host cell. Viral pathogens, such as the cold virus (rhinovirus), are believed to be the major cause of asthma attacks and exacerbations in chronic obstructive pulmonary disease (COPD). In this study, we show that it is possible to identify novel therapeutic antibodies that block infection with rhinovirus without impairing the receptors' main function of cell adhesion. We then use animal models that show that an antibody can inhibit virus-induced lung inflammation and disease. Moreover, we show that this antibody can also inhibit a virally induced asthma exacerbation. This work is relevant in that it shows that antibodies can be tailored to distinct regions of viral receptors to block infection without inhibiting the receptors' normal cellular function. This is important for the development of new treatments that will prevent diseases caused by infection with rhinovirus, such as exacerbations of asthma and COPD.

Citation: Traub S, Nikonova A, Carruthers A, Dunmore R, Vousden KA, et al. (2013) An Anti-Human ICAM-1 Antibody Inhibits Rhinovirus-Induced Exacerbations of Lung Inflammation. PLoS Pathog 9(8): e1003520. doi:10.1371/journal.ppat.1003520

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Editor: Andrew Pekosz, Johns Hopkins University - Bloomberg School of Public Health, United States of America

Received: October 4, 2012; Accepted: May 29, 2013; Published: August 1, 2013

Copyright: © 2013 Traub et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported by AstraZeneca and MedImmune and by a Chair from Asthma UK (CH11SJ), MRC Centre Grant G1000758, ERC FP7 Advanced grant 233015, Predicta FP7 Collaborative Project grant 260895 and the Wellcome Trust sponsored Centre for Respiratory Infection (CRI). AN is a recipient of an EAACI & GA2LEN Exchange Research Fellowship 2009 and European Respiratory Society Fellowship (number 682). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The following authors (AC, RD, KAV, WH, QZ, AH, RK, MAS, KB, MD, TW, AJL) are full time employees of MedImmune Ltd. or MedImmune LLC, wholly owned subsidiaries of Astrazeneca PLC. As employees they also receive shares and share options in the Astrazeneca Group. During the course of the study the following authors (AJL, TW) were employees of Astrazeneca PLC and received shares and share options. Astrazeneca is a global pharmaceutical company that conducts basic research and clinical trials in respiratory diseases such as severe asthma and chronic obstructive pulmonary disease. This work was in part funded by MedImmune and Astrazeneca PLC. This does not alter our adherence to all PLoS Pathogens policies on sharing data and materials.

Inflammation Research

August 2013,

Open Access

Knockdown of neurokinin-1 receptor expression by small interfering RNA prevents the development of allergic rhinitis in rats

• Hong Wang, 
• Ruxin Zhang, 
• Jing Wu, 
• Hua Hu

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Abstract

Objective and design

This study is aimed at exploring the role of neurokinin-1 receptor (NK-1R) in the development of allergic rhinitis (AR) in rats.

Methods

Sprague–Dawley rats were sensitized and challenged with ovalbumin to induce AR. The rats were treated intranasally with saline, control, or NK-1R-specific small interfering RNA (siRNA) before and during the challenge period. The numbers of sneezes and nose rubs and amount of nasal secretion in individual rats were measured. The levels of NK-1R expression in the nasal mucosal tissues after the last challenge were determined. The numbers of eosinophils in the collected nasal lavage fluid and the levels of serum interleukin (IL)-5 in individual rats were determined.

Results

The levels of NK-1R expression in the nasal mucosal tissues of the AR rats that had been treated with saline or control siRNA were significantly higher than those in the healthy controls and the rats treated with NK-1R-specific siRNA, demonstrating NK-1R silencing. Furthermore, knockdown of NK-1R expression significantly reduced the amounts of sneezing, nose rubbing, and nasal secretions in AR rats. Knockdown of NK-1R expression also significantly eliminated eosinophil infiltration in the nasal tissues and reduced the levels of serum IL-5 in rats.

Conclusions

Knockdown of NK-1R expression decreased allergic inflammation in nasal mucosal tissues and alleviated the allergic rhinitis symptoms, suggesting that NK-1R may be a critical mediator of the development of AR.

Responsible Editor: Michael Parnham.