Cooperative Research Center for Asthma and Airways

Glebe, Australia

Cooperative Research Center for Asthma and Airways

Glebe, Australia
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King G.G.,The Woolcock Institute of Medical Research | King G.G.,University of Sydney | King G.G.,Cooperative Research Center for Asthma and Airways | King G.G.,Royal North Shore Hospital
Pulmonary Pharmacology and Therapeutics | Year: 2011

Medical imaging has been increasingly used in respiratory research due to the rapid and ongoing development of medical technology. Current imaging is almost entirely 3-dimensional and allows the measurement of structure and function, often both simultaneously. The information complements other measurement methods in airway research because imaging's greatest contributions are those of topographical information, direct visualisation of functional or structural change, sampling of the whole organ (in contrast to for example bronchoscopy) and potential for in vivo imaging in a repeated, prospective nature. Medical imaging modalities of high-resolution computed tomography (HRCT), magnetic resonance imaging (MRI), ultra-high resolution imaging, positron emission computed tomography (PET) and single photon emission computed tomography (SPECT) are reviewed in relation to research in airways disease. © 2011 Elsevier Ltd.

Thompson B.R.,Monash University | Thompson B.R.,Cooperative Research Center for Asthma and Airways | Douglass J.A.,Royal Melbourne Hospital | Ellis M.J.,Monash University | And 7 more authors.
Journal of Allergy and Clinical Immunology | Year: 2013

Background: Exacerbations of asthma are thought to be caused by airflow obstruction resulting from airway inflammation, bronchospasm, and mucus plugging. Histologic evidence suggests the small airways, including acinar air spaces, are involved; however, this has not been corroborated in vivo by measurements of peripheral small-airway function. Objective: We sought to determine whether asthma severity is linked to small-airway function, particularly in patients with acute severe asthma. Methods: Eighteen subjects admitted for an asthma exacerbation underwent lung function testing, including measures of acinar ventilation heterogeneity (Sacin) and conductive ventilation heterogeneity (Scond) using the multiple-breath nitrogen washout. Treatment requirement was defined according to Global Initiative for Asthma scores. Data were compared with those obtained in 19 patients with stable asthma. Results: For the asthma exacerbation group, the median FEV1 was 59% of predicted value (95% CI, 45% to 75% of predicted value), the median Scond value was 185% of predicted value (95% CI, 119% to 245% of predicted value), and the median Sacin value was 225% of predicted value (95% CI, 143% to 392% of predicted value). FEV1 (percent predicted) was correlated with Sacin (percent predicted) values (Spearman rho = -0.67, P =.006) but not with Scond (percent predicted) values (P >.1). The Global Initiative for Asthma score was significantly related to Sacin (percent predicted) (Spearman rho = 0.59, P =.016) but not to Scond (percent predicted) values (P >.1). The unstable group was characterized by considerably lower forced vital capacity (P <.001) and higher Scond (P =.001) values than the unstable group. In a subgroup of 11 unstable patients who could be reviewed after 4 weeks, FEV1, forced vital capacity, Sacin, and Scond values showed marked improvements. Conclusion: Our findings suggest that unstable asthma is characterized by a combined abnormality in the acinar and conductive lung zones, both of which are partly reversible. Functional abnormality in the acinar lung zone in particular showed a direct correlation with airflow obstruction and treatment requirement in patients with acute severe asthma. © 2012 American Academy of Allergy, Asthma & Immunology.

Farah C.S.,Woolcock Institute of Medical Research | Farah C.S.,University of Sydney | Farah C.S.,Cooperative Research Center for Asthma and Airways | King G.G.,Woolcock Institute of Medical Research | And 14 more authors.
Journal of Allergy and Clinical Immunology | Year: 2012

Background: Asthma guidelines recommend inhaled corticosteroid (ICS) dose titration for patients on the basis of an assessment of current asthma control. However, the physiological determinants of asthma symptom control are poorly understood and spirometry is a poor predictor of symptomatic response. Objective: To determine the role of small airway measurements in predicting the symptom response following ICS dose titration. Methods: Adult asthmatic patients had the Asthma Control Questionnaire (ACQ) scores and lung function measured at baseline and after 8 weeks. Tests included spirometry, plethysmography, sputum cell count, exhaled nitric oxide, airway hyperresponsiveness to mannitol, respiratory system mechanics using the forced oscillation technique, and ventilation heterogeneity using the multiple breath nitrogen washout. The parameters ventilation heterogeneity in convection-dependent airways and ventilation heterogeneity in diffusion-dependent airways were derived as measures of ventilation heterogeneity in the small airways. The dose of ICS was doubled if the ACQ score was greater than or equal to 1.5 (uptitration) and quartered if the ACQ score was less than 1.5 (downtitration). The relationships between baseline physiological parameters and the change in the symptom-only 5-item ACQ (deltaACQ-5) were examined by using Spearman correlations, forward stepwise linear regressions, and receiver operator curve analyses. Results: ICS dose uptitration (n = 20) improved ACQ-5 scores (1.76 to 1.16; P =.04). Baseline fraction of exhaled nitric oxide (r = -0.55; P =.01) and ventilation heterogeneity in convection-dependent airways (r = -0.64; P =.002) correlated with deltaACQ-5, but ventilation heterogeneity in convection-dependent airways was the only independent predictor (r 2 = 0.34; P = 0.007). ICS dose downtitration (n = 41) worsened ACQ-5 scores (0.46 to 0.80; P <.001), with 29% of the patients having a deltaACQ-5 of greater than 0.5. Only baseline ventilation heterogeneity in diffusion-dependent airways correlated with deltaACQ-5 (r = 0.40; P =.009) and identified subjects with deltaACQ-5 of greater than 0.5 (receiver operator curve area under the curve = 0.78; P =.0003). Conclusions: Ventilation heterogeneity predicts symptomatic responses to ICS dose titration. Worse small airways function predicts symptomatic improvement to ICS dose uptitration and loss of symptom control during downtitration. © 2012 American Academy of Allergy, Asthma & Immunology.

Ge Q.,University of Sydney | Moir L.M.,University of Sydney | Black J.L.,University of Sydney | Black J.L.,Cooperative Research Center for Asthma and Airways | And 4 more authors.
Journal of Cellular Physiology | Year: 2010

Human bronchial epithelial (HBE) cells contribute to asthmatic airway inflammation by secreting cytokines, chemokines, and growth factors, including interleukin (IL)-6, IL-8 and transforming growth factor (TGF) β1, all of which are elevated in asthmatic airways. This study examines the signaling pathways leading to TGFβ1 induced IL-6 and IL-8 in primary HBE cells from asthmatic and non-asthmatic volunteers. HBE cells were stimulated with TGFβ1 in the presence or absence of signaling inhibitors. IL-6 and IL-8 protein and mRNA were measured by ELISA and real-time PCR respectively, and cell signaling kinases by Western blot. TGFβ1 increased IL-6, but inhibited IL-8 production in both asthmatic and non-asthmatic cells; however, TGF induced significantly more IL-6 in asthmatic cells. Inhibition of JNK MAP kinase partially reduced TGFβ1 induced IL-6 in both cell groups. TGFβ1 induced Smad2 phosphorylation, and blockade of Smad2/3 prevented both the TGFβ1 modulated IL-6 increase and the decrease in IL-8 production in asthmatic and non-asthmatic cells. Inhibition of Smad2/3 also increased basal IL-8 release in asthmatic cells but not in non-asthmatic cells. Using CHIP assays we demonstrated that activated Smad2 bound to the IL-6, but not the IL-8 promoter region. We conclude that the Smad2/3 pathway is the predominant TGFβ1 signaling pathway in HBE cells, and this is altered in asthmatic bronchial epithelial cells. Understanding the mechanism of aberrant pro-inflammatory cytokine production in asthmatic airways will allow the development of alternative ways to control airway inflammation. © 2010 Wiley-Liss, Inc.

Hardy C.L.,Monash University | Hardy C.L.,Cooperative Research Center for Asthma and Airways | Lemasurier J.S.,Monash University | Lemasurier J.S.,Cooperative Research Center for Asthma and Airways | And 12 more authors.
Journal of Immunology | Year: 2013

There is increasing interest in the use of engineered particles for biomedical applications, although questions exist about their proinflammatory properties and potential adverse health effects. Lung macrophages and dendritic cells (DC) are key regulators of pulmonary immunity, but little is known about their uptake of different sized particles or the nature of the induced immunological imprint. We investigated comparatively the immunological imprints of inert nontoxic polystyrene nanoparticles 50 nm in diameter (PS50G) and 500 nm in diameter (PS500G). Following intratracheal instillation into naive mice, PS50G were preferentially taken up by alveolar and nonalveolar macrophages, B cells, and CD11b+ and CD103+ DC in the lung, but exclusively by DC in the draining lymph node (LN). Negligible particle uptake occurred in the draining LN 2 h postinstillation, indicating that particle translocation does not occur via lymphatic drainage. PS50G but not PS500G significantly increased airway levels of mediators that drive DC migration/maturation and DC costimulatory molecule expression. Both particles decreased frequencies of stimulatory CD11b+ MHC class IIhi allergen-laden DC in the draining LN, with PS50G having the more pronounced effect. These distinctive particle imprints differentially modulated induction of acute allergic airway inflammation, with PS50G but not PS500G significantly inhibiting adaptive allergen-specific immunity. Our data show that nanoparticles are taken up preferentially by lung APC stimulate cytokine/chemokine production and pulmonary DC maturation and translocate to the lung-draining LN via cell-associated transport. Collectively, these distinctive particle imprints differentially modulate development of subsequent lung immune responses. These findings support the development of lung-specific particulate vaccines, drug delivery systems, and immunomodulators. Copyright © 2013 by The American Association of Immunologists, Inc.

Wood L.G.,Hunter Medical Research Institute | Wood L.G.,University of Newcastle | Wood L.G.,Cooperative Research Center for Asthma and Airways | Gibson P.G.,Hunter Medical Research Institute | And 2 more authors.
British Journal of Nutrition | Year: 2010

Dietary antioxidants are important in protecting against oxidative stress. We have previously demonstrated that circulating dietary antioxidant levels are reduced in asthma. The present study examined the variation in dietary antioxidant levels in asthma, according to airway responsiveness, asthma control and clinical asthma pattern. Peripheral blood was collected from forty-one subjects with stable, persistent asthma. Airway responsiveness was assessed by hypertonic saline challenge. Asthma control was assessed using the Asthma Control Questionnaire. Clinical asthma pattern was determined using Global Initiative for Asthma (GINA) criteria. Whole-blood carotenoids (-carotene, lycopene,-carotene,-cryptoxanthin, lutein/zeaxanthin) and tocopherols (-,-,-tocopherol) were measured by HPLC. Plasma antioxidant potential (AOP) was determined by colorimetric assay (OxisResearch, Portland, OR, USA). Asthmatic subjects with airway hyper-responsiveness (AHR) had reduced levels of-carotene and-tocopherol compared with those without AHR. Subjects with uncontrolled asthma had low levels of AOP compared with those with controlled or partly controlled asthma. Subjects with a severe persistent clinical asthma pattern had reduced levels of-tocopherol compared with those with a mild to moderate asthma pattern. We conclude that asthmatic subjects with AHR, uncontrolled asthma and a severe asthma pattern have impaired antioxidant defences and are thus most susceptible to the damaging effects of oxidative stress. This highlights the potential role for antioxidant supplementation in these subjects. © 2010 The Author.

Kaiko G.E.,University of Newcastle | Kaiko G.E.,Cooperative Research Center for Asthma and Airways | Kaiko G.E.,Hunter Medical Research Institute | Phipps S.,University of Newcastle | And 5 more authors.
Journal of Immunology | Year: 2010

Severe respiratory syncytial virus (RSV) infection has long been associated with an increased risk for the development of childhood asthma and exacerbations of this disorder. Despite much research into the induction of Th2 responses by allergens and helminths, the factors associated with viral infection that predispose to Th2-regulated asthma remain unknown. Recently, clinical studies have shown reduced numbers of NK cells in infants suffering from a severe RSV infection. Here we demonstrate that NK cell deficiency during primary RSV infection of BALB/c mice results in the suppression of IFN-γ production and the development of an RSV-specific Th2 response and subsequent allergic lung disease. The outgrowth of the Th2 responses was dependent on airway epithelial cell-derived IL-25, which induced the upregulation of the notch ligand Jagged1 on dendritic cells. This study identifies a novel pathway underlying viral-driven Th2 responses that may have functional relevance to viral-associated asthma. Copyright © 2010 by The American Association of Immunologists, Inc.

Kranich J.,Garvan Institute of Medical Research | Kranich J.,Cooperative Research Center for Asthma and Airways | Maslowski K.M.,Garvan Institute of Medical Research | Maslowski K.M.,Cooperative Research Center for Asthma and Airways | And 2 more authors.
Seminars in Immunology | Year: 2011

The gut microbiota has recently been recognized for its role in immune regulation, and changes in gut microbiota may be the basis for an increased incidence of autoimmune diseases and asthma in developed countries. Beneficial microbes produce factors that are distributed systemically, and therefore can influence peripheral inflammatory responses. Such symbiosis factors are important for the control and resolution of inflammation and autoimmune diseases. Here we discuss immune regulation by recently identified symbiosis factors and how certain environmental factors favor their production and influence the composition of the gut microflora. © 2011 Elsevier Ltd.

Burgess J.K.,Woolcock Institute of Medical Research | Burgess J.K.,University of Sydney | Burgess J.K.,Cooperative Research Center for Asthma and Airways | Weckmann M.,Cooperative Research Center for Asthma and Airways | Weckmann M.,University of Lübeck
Pharmacology and Therapeutics | Year: 2012

The extracellular matrix is a complex network of fibrous and nonfibrous molecules that not only provide structure to the lung but also interact with and regulate the behaviour of the cells which it surrounds. Recently it has been recognised that components of the extracellular matrix proteins are released, often through the action of endogenous proteases, and these fragments are termed matrikines. Matrikines have biological activities, independent of their role within the extracellular matrix structure, which may play important roles in the lung in health and disease pathology. Integrins are the primary cell surface receptors, characterised to date, which are used by the matrikines to exert their effects on cells. However, evidence is emerging for the need for co-factors and other receptors for the matrikines to exert their effects on cells. The potential for matrikines, and peptides derived from these extracellular matrix protein fragments, as therapeutic agents has recently been recognised. The natural role of these matrikines (including inhibitors of angiogenesis and possibly inflammation) make them ideal targets to mimic as therapies. A number of these peptides have been taken forward into clinical trials. The focus of this review will be to summarise our current understanding of the role, and potential for highly relevant actions, of matrikines in lung health and disease. © 2012 Elsevier Inc. All rights reserved.

Franklin P.J.,University of Western Australia | Franklin P.J.,Cooperative Research Center for Asthma and Airways | Loveday J.,University of Western Australia | Loveday J.,Cooperative Research Center for Asthma and Airways | And 2 more authors.
Thorax | Year: 2012

Background: Unflued gas heaters (UFGHs) and cookers are a major contributor to air pollution in homes. Gas appliances have been associated with adverse respiratory outcomes in children and, less consistently, adults. There have been very few studies on the effects of gas appliances on the respiratory health of older people. Objectives: This study investigated the daily lung function and respiratory symptoms of older people (>55 years of age) who did and did not use an UFGH as a primary source of heating. Methods: 71 patients with asthma were recruited for the study. Each patient participated for one 12-week winter period. All patients recorded daytime and nighttime symptoms in a diary and completed morning and evening peak flow and forced expiratory volume in 1 s for the study period. General estimating equations were used to measure the associations between symptoms and lung function outcomes and same and previous day (lag 1) UFGH exposure. Results: Same and previous day (lag 1) UFGH exposure was associated with significantly increased ORs for wheeze and dyspnoea compared with days on which no heating was used. Furthermore, there were significant increases in the average odds of reported wheeze and dyspnoea per hour of UFGH heater use. Small but significant reductions in morning to evening peak flow and forced expiratory volume in 1 s were observed on the days an UFGH was used compared with days when other heating was used or there was no heating. Conclusion: Exposure to UFGHs may have a detrimental effect on symptoms and lung function in older people with mild to moderate asthma.

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