A/Prof Oliver is a translational researcher supported by a NHMRC Career Development Fellowship 2 (Industry) – the aim of which is to identify and develop new ways of treating respiratory diseases.
My scientific training began at the National Heart and Lung Institute, UK, where I mastered the isolation and in-vitro culture of several types of human lung cells. I then had further training in both molecular biology (two publications: we discovered a new gene in humans, and examined epigenetic programming events during embryogenesis) (University of Leeds) and then virology at Prof Sebastian Johnston’s laboratory at Imperial College, UK before commencing my PhD at The University of Sydney (supervised by Prof Judith Black).
I am now head of the Respiratory Molecular Pathogenesis group with laboratory facilities located at both UTS and the Woolcock Institute . The work from my group is recognised to be amongst the best in the world, evidenced by selection for presentation at symposia at both national and large international conferences as well as resulting in prestigious publications.
Service to the field / professional activities
I accepted an invitation to join the Thoracic Society of Australia and New Zealand NSW executive committee in 2007, and have now become branch treasurer. In this role my aim is to improve collaboration between physicians and scientists by integrating basic research programs into the clinical arena.
In 2013, I was the driving force behind the establishment of the TSANZ NSW annual scientific meeting, which for the first time has brought respiratory researchers from across NSW together.
I am a member of the TSANZ, the European Respiratory Society, the American Thoracic Society and the American Physiological Society.
Associate member F1000
Editor BioMed Research International 2013 onwards
Can supervise: YES
A/Prof Oliver is a translational researcher supported by a NHMRC Career Development Fellowship leve 2 (Industry) – the aim of which is to identify and develop new ways of treating respiratory diseases.
My research can be divided into two main areas:
Respiratory infectious diseases
I am interested in understanding why respiratory infections can lead to the development of lung diseases, and also why the same infections can cause an acute increase in symptoms of preexisiting lung diseases.
These are examples of my research in this area.
My team were the first to demonstrate that primary human lung cells from people with asthma have an increased inflammatory response to rhinovirus infection (Resp Res 2006). This increased response is virus specific, and related to differential transcription factor recruitment to inflammatory gene promoters. Since rhinovirus-induced inflammation correlates with both the occurrence and severity of asthma exacerbations this finding helps to explain why exacerbations occur.
We discovered important cellular mechanisms which increase the risk of post-viral secondary infections (Thorax 2008). Specifically we found that virus-infected alveolar macrophages have both a marked inability to release bacterial-induced proinflammatory cytokines and impaired bacterial phagocytosis.
In a local collaboration, we were the first group in the world to show that exhaled breath contains viable respiratory viruses (CID 2008 & JMV 2009); a finding that has now been confirmed by other groups. This important finding is beginning to change the paradigms surrounding respiratory viral transmission.
My group have recently developed an in-vitro model of rhinovirus-induced asthma exacerbations (AJRCMB 2010) which is providing new insight into why β2-agonists, commonly used asthma medications, may be ineffective during exacerbations. Using this model we have recently discovered the cause of β2-adronergic desensitisation (PLoS One 2012).
We have been investigating the potential reasons why viral infections may promote the development of asthma. In asthma the airways are fibrotic, but the reason for this is not known. We hypothesised that fibrosis may occur as a consequence of virus infection. My group has recently published our findings that primary airway cells from people with asthma produce a different panel of rhinovirus-induced ECM proteins in comparison to cells from people without asthma. Kuo C, et al Oliver BG. Rhinovirus infection induces extracellular matrix protein deposition in asthmatic and non-asthmatic airway smooth muscle cells A J Physiology – LCMP (2011) 300 L951-L957
My undergraduate degree in Human Biology sparked an interest which has now become one of my research foci. I am intrigued why respiratory diseases develop, and why therapeutics often are not as effective as we would hope.
The following are examples of my research in this area
We have been investigating the β2-adronergic pathway, and its regulation, in airway smooth muscle cells from people with asthma, compared to people without asthma. we discovered that a key enzyme which regulates this pathway (PDE4) is overexpressed in asthma, functionally impairing the β2-adronergic pathway (Trian T, ….. and Oliver BG. PLoS ONE 6(5): e20000 2011 doi:10.1371/journal.pone.0020000). I have also discovered that, contrary to observations in other species, PDE4 is not upregulated by β2-agonists, and therefore is not involved in β2-agonist-induced β2- adronergic tachiphylaxis (Niimi K, ….and Oliver BG). Am J Physiol Lung Cell Mol Physiol 302:L334-L342 2012).
We found that cigarette smoke, the major cause of COPD in developed countries, is a profibrotic stimulus to fibroblasts from only people with COPD. The reason why fibroblasts only from people with COPD respond is intriguing and raises many questions regarding the pathogenesis of COPD.1. Krimmer DI, et al, Oliver BG. Matrix proteins from smoke exposed fibroblasts are proproliferative Am J Respir Cell (2012) 46 1 34-39.
We have been investigating the aeitology of fibrosis in asthma, and have discovered that tumstatin, an endogenous regulator of angiogenesis, is missing from the airways of people with asthma. We tested the affect of addition of tumstatin using a chronic animal model of asthma, and found that airways hyperresponsiveness, inflammation and angiogenesis were inhibited - demonstrating the complex interaction between the matrix and lung pathophysiology. Burgess, J. K.; el al; Oliver, BG. Reduction of tumstatin in asthmatic airways contributes to angiogenesis, inflammation, and hyperresponsiveness Am J Respir Crit Care Med (2010)
There is increasing evidence that inflammation and fibrosis develop concurrently, but along independent pathways in lung diseases such as asthma and pulmonary fibrosis. To explore this in-vitro we examined the effect of simulating primary human lung epithelial, smooth muscle and fibroblasts with the pro-inflammatory leukotrienes and the anti-inflammatory prostaglandins. We found the ECM deposition was induced by only prostaglandins supporting the notion that inflammation is not the driving force behind lung fibrosis. Van Ly D, et al, Oliver BG Prostaglandins but not leukotrienes alter extracellular matrix protein deposition & cytokine release in primary human airway smooth muscle cells and fibroblasts Am J Physiol Lung Cell Mol Physiol (2012) 303 L239-L250
My group was the first to show that primary human lung mesenchymal cells are capable of incorporating exogenously produced soluble extracellular matrix proteins into the deposited extracellular matrix around the cells. This highlights the complexity of ECM deposition in-vivo, and the need to study multiple cell type in-vitro to understand how the ECM is formed in-vivo. Chen L, et al Oliver BG Differential regulation of extracellular matrix and soluble fibulin-1 levels by TGF-β1 in airway smooth muscle cells PLoS ONE (2013) 8:2
IIn the last five years he has published 65 journal articles (110 career total), of which he was first/senior on 23 (with a major role in all publications). In the last 5 years he has had 6 publications in the top 4 highest ranked of 59 journals in the field respiratory system, and 4 in the top 2 highest ranked of 17 journals in the field allergy of the InCites 2016 JCR Science Edition. Using data from Scopus, his research papers have been cited 1955 times (the highest individual article has 179 citations). When considering only the last five years his i10 index (the number of papers with at least 10 citations in the last 5 years) is 55 (only available from Google Scholar).
I teach in courses in the Faculty of Science
Adkinson, NF, Bochner, BS, Burks, AW, Busse, WW, Holgate, ST, Lemanske, RF & O'Hehir, RE 2013, Middleton's Allergy: Principles and Practice: Eighth Edition.
© 2014 Elsevier Inc. All rights reserved. Boasting a worldwide reputation as the leading text in allergy and immunology, Middletons Allergy continues its steadfast tradition of providing comprehensive coverage of state-of-the-art basic science, as well as authoritative guidance on the clinical concepts of day-to-day diagnosis and management of allergic disorders. Offering timely information that's suited for clinicians and researchers alike, Middleton's is a user-friendly and versatile source for the knowledge you need to provide optimal care to your patients!. "A valuable source of reference and pre-sifted information ...the editors are to be commending in keeping the book up-to-date and clinically valuable." Reviewed by: Imnunology News Date: March 2015.
Bradbury, P, Patel, BS, Cidem, A, Nader, CP, Oliver, BG & Ammit, AJ 2019, 'Prostaglandin E 2, but not cAMP nor β 2 -agonists, induce tristetraprolin (TTP) in human airway smooth muscle cells', Inflammation Research.View/Download from: UTS OPUS or Publisher's site
© 2019, Springer Nature Switzerland AG. Tristetraprolin (TTP) is an anti-inflammatory molecule known to post-transcriptionally regulate cytokine production and is, therefore, an attractive drug target for chronic respiratory diseases driven by inflammation, such as asthma and chronic obstructive pulmonary disease. Our recent in vitro studies in primary human airway smooth (ASM) cells have confirmed the essential anti-inflammatory role played by TTP as a critical partner in a cytokine regulatory network. However, several unanswered questions remain. While prior in vitro studies have suggested that TTP is regulated in a cAMP-mediated manner, raising the possibility that this may be one of the ways in which β 2 -agonists achieve beneficial effects beyond bronchodilation, the impact of β 2 -agonists on ASM cells is unknown. Furthermore, the effect of prostaglandin E 2 (PGE 2 ) on TTP expression in ASM cells has not been reported. We address this herein and reveal, for the first time, that TTP is not regulated by cAMP-activating agents nor following treatment with long-acting β 2 -agonists. However, PGE 2 does induce TTP mRNA expression and protein upregulation in ASM cells. Although the underlying mechanism of action remains undefined, we can confirm that PGE 2 -induced TTP upregulation is not mediated via cAMP, or EP 2 /EP 4 receptor activation, and occurred in a manner independent of the p38 MAPK-mediated pathway. Taken together, these data confirm that β 2 -agonists do not upregulate TTP in human ASM cells and indicate that another way in which PGE 2 may achieve beneficial effects in asthma and COPD may be via upregulation of the master controller of inflammation—TTP.
E-cigarettes induce greater inflammatory mediators from COPD lung cells; therefore, the risks of e-cigarette use in COPD might be greater than in people without COPD http://ow.ly/xmnN30nzDhX.
Wood, LG, Li, Q, Scott, HA, Rutting, S, Berthon, BS, Gibson, PG, Hansbro, PM, Williams, E, Horvat, J, Simpson, JL, Young, P, Oliver, BG & Baines, KJ 2019, 'Saturated fatty acids, obesity, and the nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in asthmatic patients.', Allergy and Clinical Immunology, vol. 143, no. 1, pp. 305-315.View/Download from: UTS OPUS or Publisher's site
BACKGROUND:Both obesity and high dietary fat intake activate the nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome. OBJECTIVE:We aimed to examine NLRP3 inflammasome activity in the airways of obese asthmatic patients after macronutrient overload and in immune cells challenged by inflammasome triggers. METHODS:Study 1 was a cross-sectional observational study of nonobese (n = 51) and obese (n = 76) asthmatic adults. Study 2 was a randomized, crossover, acute feeding study in 23 asthmatic adults (n = 12 nonobese and n = 11 obese subjects). Subjects consumed 3 isocaloric meals on 3 separate occasions (ie, saturated fatty acid, n-6 polyunsaturated fatty acid, and carbohydrate) and were assessed at 0 and 4 hours. For Studies 1 and 2, airway inflammation was measured based on sputum differential cell counts, IL-1β protein levels (ELISA), and sputum cell gene expression (Nanostring nCounter). In Study 3 peripheral blood neutrophils and monocytes were isolated by using Ficoll density gradient and magnetic bead separation and incubated with or without palmitic acid, LPS, or TNF-α for 24 hours, and IL-1β release was measured (ELISA). RESULTS:In Study 1 NLRP3 and nucleotide oligomerization domain 1 (NOD1) gene expression was upregulated, and sputum IL-1β protein levels were greater in obese versus nonobese asthmatic patients. In Study 2 the saturated fatty acid meal led to increases in sputum neutrophil percentages and sputum cell gene expression of Toll-like receptor 4 (TLR4) and NLRP3 at 4 hours in nonobese asthmatic patients. In Study 3 neutrophils and monocytes released IL-1β when challenged with a combination of palmitic acid and LPS or TNF-α. CONCLUSION:The NLRP3 inflammasome is a potential therapeutic target in asthmatic patients. Behavioral interventions that reduce fatty acid exposure, such as weight loss and dietary saturated fat restriction, warrant further exploration.
Rutting, S, Xenaki, D, Malouf, M, Horvat, JC, Wood, LG, Hansbro, PM & Oliver, BG 2019, 'Short-chain fatty acids increase TNFα-induced inflammation in primary human lung mesenchymal cells through the activation of p38 MAPK.', American journal of physiology. Lung cellular and molecular physiology, vol. 316, no. 1, pp. L157-L174.View/Download from: UTS OPUS or Publisher's site
Short-chain fatty acids (SCFAs), produced as by-products of dietary fiber metabolism by gut bacteria, have anti-inflammatory properties and could potentially be used for the treatment of inflammatory diseases, including asthma. The direct effects of SCFAs on inflammatory responses in primary human lung mesenchymal cells have not been assessed. We investigated whether SCFAs can protect against tumor necrosis factor (TNF)α-induced inflammation in primary human lung fibroblasts (HLFs) and airway smooth muscle (ASM) cells in vitro. HLFs and ASM cells were exposed to SCFAs, acetate (C2:0), propionate (C3:0), and butyrate (C4:0) (0.01-25 mM) with or without TNFα, and the release of proinflammatory cytokines, IL-6, and CXCL8 was measured using ELISA. We found that none of the SCFAs suppressed TNFα-induced cytokine release. On the contrary, challenge with supraphysiological concentrations (10-25 mM), as might be used therapeutically, of propionate or butyrate in combination with TNFα resulted in substantially greater IL-6 and CXCL8 release from HLFs and ASM cells than challenge with TNFα alone, demonstrating synergistic effects. In ASM cells, challenge with acetate also enhanced TNFα-induced IL-6, but not CXCL8 release. Synergistic upregulation of IL-6 and CXCL8 was mediated through the activation of free fatty acid receptor (FFAR)3, but not FFAR2. The signaling pathways involved were further examined using specific inhibitors and immunoblotting, and responses were found to be mediated through p38 MAPK signaling. This study demonstrates that proinflammatory, rather than anti-inflammatory effects of SCFAs are evident in lung mesenchymal cells.
Rutting, S, Zakarya, R, Bozier, J, Xenaki, D, Horvat, JC, Wood, LG, Hansbro, PM & Oliver, BG 2019, 'Dietary Fatty Acids Amplify Inflammatory Responses to Infection through p38 MAPK Signaling', AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, vol. 60, no. 5, pp. 554-568.View/Download from: UTS OPUS or Publisher's site
McAlinden, KD, Deshpande, DA, Ghavami, S, Xenaki, D, Sohal, SS, Oliver, BG, Haghi, M & Sharma, P 2019, 'Autophagy Activation in Asthma Airways Remodeling.', American Journal of Respiratory Cell and Molecular Biology.View/Download from: UTS OPUS or Publisher's site
Current asthma therapies fail to target airway remodeling which correlates with asthma severity driving disease progression that ultimately leads to loss of lung function. Macroautophagy (here after autophagy) is a fundamental cell recycling mechanism in all eukaryotic cells; emerging evidence suggests that it is dysregulated in asthma. We investigated the interrelationship between autophagy and airway remodeling and assessed preclinical efficacy of a known autophagy inhibitor in murine models of asthma. Human asthmatic and non-asthmatic lung tissues were histologically evaluated and were immuno-stained for key autophagy markers. The percent area of positive staining was quantified in the epithelium and airway smooth muscle (ASM) bundles using ImageJ software. Furthermore, autophagy inhibitor chloroquine (CQ) was tested (i.n.) in prophylactic (3-week) and treatment (5-week) models of allergic asthma in mice. Human asthmatic tissues showed greater tissue inflammation and demonstrated hallmark features of airway remodeling displaying thickened epithelium (p<0.001) and reticular basement membrane (p<0.0001), greater lamina propria depth (p<0.005), and increase in ASM bundles (p<0.001) with higher expression of Beclin1 (p<0.01) and ATG5 (p<0.05) along with reduced p62 (p<0.05) compared to non-asthmatic controls. Beclin1 expression was significantly higher in asthmatic epithelium and ciliated cells (p<0.05) suggesting potential role of ciliophagy in asthma. Murine asthma models demonstrated effective preclinical efficacy (reduced key features of allergic asthma: airway inflammation, AHR and airway remodeling) of autophagy inhibitor CQ. Our data demonstrates cell-context dependent, and selective activation of autophagy in structural cells in asthma. Further, this pathway can be effectively targeted to ameliorate airway remodeling in asthma.
Ng, SW, Chan, Y, Chellappan, DK, Madheswaran, T, Zeeshan, F, Chan, YL, Collet, T, Gupta, G, Oliver, BG, Wark, P, Hansbro, N, Hsu, A, Hansbro, PM, Dua, K & Panneerselvam, J 2019, 'Molecular modulators of celastrol as the keystones for its diverse pharmacological activities', BIOMEDICINE & PHARMACOTHERAPY, vol. 109, pp. 1785-1792.View/Download from: UTS OPUS or Publisher's site
Mitchell, AB, Tang, B, Shojaei, M, Barnes, LS, Nalos, M, Oliver, BG & McLean, AS 2018, 'A novel sampling method to detect airborne influenza and other respiratory viruses in mechanically ventilated patients: a feasibility study.', Annals of intensive care, vol. 8, no. 45.View/Download from: UTS OPUS or Publisher's site
Respiratory viruses circulate constantly in the ambient air. The risk of opportunistic infection from these viruses can be increased in mechanically ventilated patients. The present study evaluates the feasibility of detecting airborne respiratory viruses in mechanically ventilated patients using a novel sample collection method involving ventilator filters.We collected inspiratory and expiratory filters from the ventilator circuits of mechanically ventilated patients in an intensive care unit over a 14-month period. To evaluate whether we could detect respiratory viruses collected in these filters, we performed a reverse transcription polymerase chain reaction on the extracted filter membrane with primers specific for rhinovirus, respiratory syncytial virus, influenza virus A and B, parainfluenza virus (type 1, 2 and 3) and human metapneumovirus. For each patient, we also performed a full virology screen (virus particles, antibody titres and virus-induced biomarkers) on respiratory samples (nasopharyngeal swab, tracheal aspirate or bronchoalveolar fluid) and blood samples.Respiratory viruses were detected in the ventilator filters of nearly half the patients in the study cohort (n = 33/70). The most common virus detected was influenza A virus (n = 29). There were more viruses detected in the inspiratory filters (n = 18) than in the expiratory filters (n = 15). A third of the patients with a positive virus detection in the ventilator filters had a hospital laboratory confirmed viral infection. In the remaining cases, the detected viruses were different from viruses already identified in the same patient, suggesting that these additional viruses come from the ambient air or from cross-contamination (staff or visitors). In patients in whom new viruses were detected in the ventilator filters, there was no evidence of clinical signs of an active viral infection. Additionally, the levels of virus-induced biomarker in these patients were not statistically different fro...
Mitchell, AB, Mourad, B, Buddle, L, Peters, MJ, Oliver, BGG & Morgan, LC 2018, 'Viruses in bronchiectasis: a pilot study to explore the presence of community acquired respiratory viruses in stable patients and during acute exacerbations', BMC PULMONARY MEDICINE, vol. 18.View/Download from: Publisher's site
Eapen, MS, Kota, A, Vindin, H, McAlinden, KD, Xenaki, D, Oliver, BG, Deshpande, DA, Sohal, SS & Sharma, P 2018, 'Apoptosis signal-regulating kinase 1 (ASK1) inhibition attenuates human airway smooth muscle growth and migration in chronic obstructive pulmonary disease (COPD).', Clinical Science.View/Download from: UTS OPUS or Publisher's site
Increased airway smooth muscle (ASM) mass is observed in COPD which is correlated with disease severity and negatively impact lung function. Thus, there is clear unmet clinical need for finding new therapies which can target airway remodeling and disease progression in COPD. Apoptosis signal-regulating kinase 1 (ASK1) is a ubiquitously expressed mitogen-activated protein kinase kinase kinase activated by various stress stimuli, including reactive oxygen species, tumor necrosis factor-α, and lipopolysaccharide and is known to regulate cell proliferation. ASM cells from COPD patients are hyper-proliferative to mitogens in vitro However, the role of ASK1 in ASM growth is not established. Here, we aim to determine the effects of ASK1 inhibition on ASM growth and pro-mitogenic signaling in COPD patients. We found greater expression of ASK1 in ASM-bundles of COPD lung when compared with non-COPD. Pre-treatment of ASM cells with selective ASK1 inhibitor, TCASK10 resulted in a dose-dependent reduction in mitogen (FBS, PDGF and EGF)-induced ASM growth as measured by CyQuant assay. Further, molecular targeting of ASK1 using siRNA in ASM cells prevented mitogen-induced cell growth. In addition, to anti-mitogenic potential, ASK1 inhibitor also prevented TGFb1-induced migration of ASM cells in vitro Immunoblotting revealed that anti-mitogenic effects are mediated by JNK and p38MAP kinase-signaling pathways as evident by reduced phosphorylation of downstream effectors JNK1/2 and p38MAP kinases respectively with no effect on ERK1/2. Collectively, these findings establish the anti-mitogenic effect of ASK1 inhibition and identify a novel pathway that can be targeted to reduce or prevent excessive ASM mass in COPD.
Mitchell, AB, Mourad, B, Morgan, LC, Oliver, BGG & Glanville, AR 2018, 'Transplanting the pulmonary virome: Dynamics of transient populations', JOURNAL OF HEART AND LUNG TRANSPLANTATION, vol. 37, no. 9, pp. 1111-1118.View/Download from: Publisher's site
Nissen, G, Hollaender, H, Tang, FSM, Wegmann, M, Lunding, L, Vock, C, Bachmann, A, Lemmel, S, Bartels, R, Oliver, BG, Burgess, JK, Becker, T, Kopp, MV & Weckmann, M 2018, 'Tumstatin fragment selectively inhibits neutrophil infiltration in experimental asthma exacerbation', CLINICAL AND EXPERIMENTAL ALLERGY, vol. 48, no. 11, pp. 1483-1493.View/Download from: UTS OPUS or Publisher's site
Pech, M, Weckmann, M, Koenig, IR, Franke, A, Heinsen, F-A, Oliver, B, Ricklefs, I, Fuchs, O, Rabe, K, Hansen, G, Mutius, E & Kopp, M 2018, 'Rhinovirus infections change DNA methylation and mRNA expression in children with asthma', PLOS ONE, vol. 13, no. 11.View/Download from: UTS OPUS or Publisher's site
Copeland, E, Leonard, K, Carney, R, Kong, J, Forer, M, Naidoo, Y, Oliver, BGG, Seymour, JR, Woodcock, S, Burke, CM & Stow, NW 2018, 'Chronic Rhinosinusitis: Potential Role of Microbial Dysbiosis and Recommendations for Sampling Sites', Frontiers in Cellular and Infection Microbiology, vol. 8, pp. 1-14.View/Download from: UTS OPUS or Publisher's site
Rutting, S, Xenaki, D, Lau, E, Horvat, J, Wood, LG, Hansbro, PM & Oliver, BG 2018, 'Dietary omega-6, but not omega-3, polyunsaturated or saturated fatty acids increase inflammation in primary lung mesenchymal cells', AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, vol. 314, no. 6, pp. L922-L935.View/Download from: UTS OPUS or Publisher's site
Fricker, M, Goggins, BJ, Mateer, S, Jones, B, Kim, RY, Gellatly, SL, Jarnicki, AG, Powell, N, Oliver, BG, Radford-Smith, G, Talley, NJ, Walker, MM, Keely, S & Hansbro, PM 2018, 'Chronic cigarette smoke exposure induces systemic hypoxia that drives intestinal dysfunction.', JCI insight, vol. 3, no. 3.View/Download from: UTS OPUS or Publisher's site
Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract (GIT). Cigarette smoke (CS) exposure and chronic obstructive pulmonary disease (COPD) are risk factors for CD, although the mechanisms involved are poorly understood. We employed a mouse model of CS-induced experimental COPD and clinical studies to examine these mechanisms. Concurrent with the development of pulmonary pathology and impaired gas exchange, CS-exposed mice developed CD-associated pathology in the colon and ileum, including gut mucosal tissue hypoxia, HIF-2 stabilization, inflammation, increased microvasculature, epithelial cell turnover, and decreased intestinal barrier function. Subsequent smoking cessation reduced GIT pathology, particularly in the ileum. Dimethyloxaloylglycine, a pan-prolyl hydroxylase inhibitor, ameliorated CS-induced GIT pathology independently of pulmonary pathology. Prior smoke exposure exacerbated intestinal pathology in 2,4,6-trinitrobenzenesulfonic acid-induced (TNBS-induced) colitis. Circulating vascular endothelial growth factor, a marker of systemic hypoxia, correlated with CS exposure and CD in mice and humans. Increased mucosal vascularisation was evident in ileum biopsies from CD patients who smoke compared with nonsmokers, supporting our preclinical data. We provide strong evidence that chronic CS exposure and, for the first time to our knowledge, associated impaired gas exchange cause systemic and intestinal ischemia, driving angiogenesis and GIT epithelial barrier dysfunction, resulting in increased risk and severity of CD.
Rutting, S, Papanicolaou, M, Xenaki, D, Wood, LG, Mullin, AM, Hansbro, PM & Oliver, BG 2018, 'Dietary ω-6 polyunsaturated fatty acid arachidonic acid increases inflammation, but inhibits ECM protein expression in COPD.', Respiratory research, vol. 19, no. 1, pp. 211-211.View/Download from: UTS OPUS or Publisher's site
BACKGROUND:The obesity paradox in COPD describes protective effects of obesity on lung pathology and inflammation. However, the underlying relationships between obesity, diet and disease outcomes in COPD are not fully understood. In this study we measured the response to dietary fatty acids upon markers of inflammation and remodelling in human lung cells from people with and without COPD. METHODS:Pulmonary fibroblasts were challenged with ω-3 polyunsaturated fatty acids (PUFAs), ω-6 PUFAs, saturated fatty acids (SFAs) or the obesity-associated cytokine TNFα. After 48-72 h release of the pro-inflammatory cytokines interleukin (IL)-6 and CXCL8 was measured using ELISA and mRNA expression and deposition of the extracellular matrix (ECM) proteins fibronectin, type I collagen, tenascin and perlecan were measured using qPCR or ECM ELISA, respectively. RESULTS:Challenge with the ω-6 PUFA arachidonic acid (AA), but not ω-3 PUFAs or SFAs, resulted in increased IL-6 and CXCL8 release from fibroblasts, however IL-6 and CXCL8 release was reduced in COPD (n = 19) compared to non-COPD (n = 36). AA-induced cytokine release was partially mediated by downstream mediators of cyclooxygenase (COX)-2 in both COPD and non-COPD. In comparison, TNFα-induced IL-6 and CXCL8 release was similar in COPD and non-COPD, indicating a specific interaction of AA in COPD. In patients with or without COPD, regression analysis revealed no relationship between BMI and cytokine release. In addition, AA, but not SFAs or ω-3 PUFAs reduced the basal deposition of fibronectin, type I collagen, tenascin and perlecan into the ECM in COPD fibroblasts. In non-COPD fibroblasts, AA-challenge decreased basal deposition of type I collagen and perlecan, but not fibronectin and tenascin. CONCLUSIONS:This study shows that AA has disease-specific effects on inflammation and ECM protein deposition. The impaired response to AA in COPD might in part explain why obesity appears to have less detrimental effects in COPD, c...
Sukjamnong, S, Chan, YL, Zakarya, R, Nguyen, LT, Anwer, AG, Zaky, AA, Santiyanont, R, Oliver, BG, Goldys, E, Pollock, CA, Chen, H & Saad, S 2018, 'MitoQ supplementation prevent long-term impact of maternal smoking on renal development, oxidative stress and mitochondrial density in male mice offspring.', Scientific reports, vol. 8, no. 1.View/Download from: UTS OPUS or Publisher's site
To investigate the effect of maternal MitoQ treatment on renal disorders caused by maternal cigarette smoke exposure (SE). We have demonstrated that maternal SE during pregnancy increases the risk of developing chronic kidney disease (CKD) in adult offspring. Mitochondrial oxidative damage contributes to the adverse effects of maternal smoking on renal disorders. MitoQ is a mitochondria-targeted antioxidant that has been shown to protect against oxidative damage-related pathologies in many diseases. Female Balb/c mice (8 weeks) were divided into Sham (exposed to air), SE (exposed to cigarette smoke) and SEMQ (exposed to cigarette smoke with MitoQ supplemented from mating) groups. Kidneys from the mothers were collected when the pups weaned and those from the offspring were collected at 13 weeks. Maternal MitoQ supplementation during gestation and lactation significantly reversed the adverse impact of maternal SE on offspring's body weight, kidney mass and renal pathology. MitoQ administration also significantly reversed the impact of SE on the renal cellular mitochondrial density and renal total reactive oxygen species in both the mothers and their offspring in adulthood. Our results suggested that MitoQ supplementation can mitigate the adverse impact of maternal SE on offspring's renal pathology, renal oxidative stress and mitochondrial density in mice offspring.
Li, G, Saad, S, Oliver, BG & Chen, H 2018, 'Heat or Burn? Impacts of Intrauterine Tobacco Smoke and E-Cigarette Vapor Exposure on the Offspring's Health Outcome.', Toxics, vol. 6, no. 3.View/Download from: UTS OPUS or Publisher's site
Maternal smoking during pregnancy leads to gestational complications and organ disorders in the offspring. As nicotine replacement therapy is often ineffective for smoking cessation, pregnant women turn to alternatives such as heat-not-burn tobacco and e-cigarettes. Recently, the popularly of e-cigarettes has been increasing especially among the youth and pregnant women, mainly due to the advertisements claiming their safety. This has even led to some clinicians recommending their use during pregnancy. E-cigarettes heat e-liquid to produce an aerosol (e-vapor), delivering flavorings and nicotine to the user. However, e-vapor also contains toxins such as formaldehyde along with heavy metals and carcinogenic nitrosamines. In addition, specific flavoring compounds such as diacetyl can be toxic themselves or decompose into toxic compounds such as benzaldehydes. These compounds can induce toxicity, inflammation and oxidative stress in the mothers and can accumulate in the developing fetus, affecting intrauterine development. Recent animal studies suggest that maternal e-vapor exposure during pregnancy could cause respiratory and neurological disorders in the offspring. This review will examine the available literature to shed light on the current understanding of this problem-to-be from lessons learned in animal models.
Saad, S, Al-Odat, I, Chan, YL, McGrath, KC, Pollock, CA, Oliver, BG & Chen, H 2018, 'Maternal L-carnitine supplementation improves glucose and lipid profiles in female offspring of dams exposed to cigarette smoke.', Clinical and experimental pharmacology & physiology, vol. 45, no. 7, pp. 694-703.View/Download from: UTS OPUS or Publisher's site
Sex differences in disease susceptibility due to maternal programming have been reported. We previously observed that maternal smoking induced renal disease and neurological changes are restricted to males, while both male and female offspring develop metabolic disorders. We have also found that maternal L-carnitine supplementation during gestation and lactation can significantly improve glucose intolerance and hyperlipidaemia in male offspring. This study aimed to determine whether such beneficial effects can also occur in female offspring. Balb/c female mice were exposed to cigarette smoke (SE) 6 weeks prior to gestation, during gestation and lactation. A subgroup of the SE dams was given L-carnitine (1.5 mmol/L in drinking water) during gestation and lactation. Female offspring were studied at 20 days (weaning) and 13 weeks (adulthood). Maternal smoking increased liver weight (%) and blood glucose levels at 20 days, as well as glucose intolerance and plasma triglycerides levels at adulthood (P < .05). The hepatic lipid metabolic marker adipose triglyceride lipase was downregulated in the SE offspring at 20 days (P < .05). At 13 weeks, the hepatic pro-inflammatory markers IL-1β and TNF-α mRNA expression were upregulated, while the anti-inflammatory marker IL-10 mRNA expression was downregulated in the SE offspring (P < .05). Liver fibrosis was apparent at 20 days and 13 weeks. Maternal L-carnitine supplementation either normalised or suppressed the detrimental effects induced by maternal smoke exposure (P < .05). We conclude that maternal L-carnitine supplementation improves metabolic parameters in the female offspring of SE dams.
Tonga, KO, King, GG, Farah, CS, Thamrin, C, Tang, FS, Santos, J, Sharma, P, Chapman, DG & Oliver, BG 2018, 'Steroid insensitive fixed airflow obstruction is not related to airway inflammation in older non-smokers with asthma.', Respiratory research, vol. 19, no. 1, pp. 176-176.View/Download from: UTS OPUS or Publisher's site
There is limited evidence linking airway inflammation and lung function impairment in older non-smoking asthmatics with fixed airflow obstruction (FAO), which can develop despite treatment with inhaled corticosteroids (ICS). We assessed lung function (spirometry, forced oscillation technique (FOT)), lung elastic recoil and airway inflammation using bronchoalveolar lavage (BAL) in non-smoking adult asthmatics with FAO, following 2 months treatment with high-dose ICS/long-acting beta-agonist. Subjects demonstrated moderate FAO, abnormal FOT indices and loss of lung elastic recoil. This cross-sectional study showed a lack of a relationship between BAL neutrophils, eosinophils, inflammatory cytokines and lung function impairment. Other inflammatory pathways or the effect of inflammation on lung function over time may explain FAO development.
Chen, H, Li, G, Chan, YL, Chapman, DG, Sukjamnong, S, Nguyen, T, Annissa, T, McGrath, KC, Sharma, P & Oliver, BG 2018, 'Maternal E-Cigarette Exposure in Mice Alters DNA Methylation and Lung Cytokine Expression in Offspring.', American Journal of Respiratory Cell and Molecular Biology, vol. 58, no. 3, pp. 366-377.View/Download from: UTS OPUS or Publisher's site
E-cigarette usage is increasing, especially among the young, with both the general population and physicians perceiving them as a safe alternative to tobacco smoking. Worryingly, e-cigarettes are commonly used by pregnant women. As nicotine is known to adversely affect children in utero, we hypothesized that nicotine delivered via e-cigarettes would negatively affect lung development. To test this, we developed a mouse model of maternal e-vapor (nicotine and nicotine-free) exposure and investigated the impact on the growth and lung inflammation in both offspring and mothers. Female Balb/c mice were exposed to e-fluid vapor containing nicotine (18 mg/ml nicotine E-cigarette [E-cig18], equivalent to two cigarettes per treatment, twice daily,) or nicotine free (E-cig0 mg/ml) from 6 weeks before mating until pups weaned. Male offspring were studied at Postnatal Day (P) 1, P20, and at 13 weeks. The mothers were studied when the pups weaned. In the mothers' lungs, e-cigarette exposure with and without nicotine increased the proinflammatory cytokines IL-1β, IL-6, and TNF-α. In adult offspring, TNF-α protein levels were increased in both E-cig18 and E-cig0 groups, whereas IL-1β was suppressed. This was accompanied by global changes in DNA methylation. In this study, we found that e-cigarette exposure during pregnancy adversely affected maternal and offspring lung health. As this occurred with both nicotine-free and nicotine-containing e-vapor, the effects are likely due to by-products of vaporization rather than nicotine.
Chen, H, Chan, YL, Linnane, C, Mao, Y, Anwer, AG, Sapkota, A, Annissa, TF, Herok, G, Vissel, B, Oliver, BG, Saad, S & Gorrie, CA 2018, 'L-Carnitine and extendin-4 improve outcomes following moderate brain contusion injury.', Scientific reports, vol. 8, no. 1.View/Download from: UTS OPUS or Publisher's site
There is a need for pharmaceutical agents that can reduce neuronal loss and improve functional deficits following traumatic brain injury (TBI). Previous research suggests that oxidative stress and mitochondrial dysfunction play a major role in neuronal damage after TBI. Therefore, this study aimed to investigate two drugs known to have antioxidant effects, L-carnitine and exendin-4, in rats with moderate contusive TBI. L-carnitine (1.5 mM in drinking water) or exendin-4 (15 µg/kg/day, ip) were given immediately after the injury for 2 weeks. Neurological function and brain histology were examined (24 h and 6 weeks post injury). The rats with TBI showed slight sensory, motor and memory functional deficits at 24 h, but recovered by 6 weeks. Both treatments improved sensory and motor functions at 24 h, while only exendin-4 improved memory. Both treatments reduced cortical contusion at 24 h and 6 weeks, however neither affected gliosis and inflammatory cell activation. Oxidative stress was alleviated and mitochondrial reactive oxygen species was reduced by both treatments, however only mitochondrial functional marker protein transporter translocase of outer membrane 20 was increased at 24 h post injury. In conclusion, L-carnitine and exendin-4 treatments immediately after TBI can improve neurological functional outcome and tissue integrity by reducing oxidative stress.
Chen, H, Li, G, Chan, YL, Nguyen, T, van Reyk, D, Saad, S & Oliver, BG 2018, 'Modulation of neural regulators of energy homeostasis, and of inflammation, in the pups of mice exposed to e-cigarettes.', Neuroscience letters, vol. 684, pp. 61-66.View/Download from: UTS OPUS or Publisher's site
BACKGROUND:Maternal smoking can lead to perturbations in central metabolic regulators such as neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) signalling components in offspring. With the growing interest in e-cigarettes as a tobacco replacement, this short report assessed central metabolic regulation in offspring of mouse dams exposed to e-cigarettes. We examined the impact of continuous use of e-cigarettes, and e-cigarette replacement of tobacco cigarettes during pregnancy. Supplementation of an antioxidant l-carnitine was also co-used with tobacco cigarette in the mother to determine whether the impact of maternal tobacco smoking was oxidative stress driven. METHODS:Balb/c mice were exposed to either nicotine-containing (E-cig18) or nicotine-free (E-cig0) e-cigarette aerosols or tobacco smoke (SE) prior to mating and until their pups were weaned. After mating, two SE sub-groups were changed to E-cig18 exposure (Replacement), or supplementation l-carnitine while SE was continued. Male offspring were studied at weaning age. RESULTS:The offspring of E-cig0 dams were the heaviest with the most body fat. Replacing SE with E-cig18 during pregnancy resulted in offspring with significantly less body fat. E-cig0 offspring had significantly increased mRNA expression of brain NPY and iNOS. Maternal SE upregulated mRNA expression of NPY, NPY Y1 receptor, POMC downstream components, and iNOS expression, which were normalised in Replacement offspring, but only partially normalised with maternal L-carnitine supplementation during gestation and lactation. CONCLUSIONS:Maternal exposure to either tobacco and nicotine-free e-cigarettes lead to disturbances in the level of central homeostatic control markers in offspring, suggesting that maternal exposure to e-cigarettes is not without risks.
Burgess, JK, Ketheson, A, Faiz, A, Limbert Rempel, KA, Oliver, BG, Ward, JPT & Halayko, AJ 2018, 'Phenotype and Functional Features of Human Telomerase Reverse Transcriptase Immortalized Human Airway Smooth Muscle Cells from Asthmatic and Non-Asthmatic Donors.', Scientific Reports, vol. 8, no. 1, pp. 805-805.View/Download from: UTS OPUS or Publisher's site
Asthma is an obstructive respiratory disease characterised by chronic inflammation with airway hyperresponsiveness. In asthmatic airways, there is an increase in airway smooth muscle (ASM) cell bulk, which differs from non-asthmatic ASM in characteristics. This study aimed to assess the usefulness of hTERT immortalisation of human ASM cells as a research tool. Specifically we compared proliferative capacity, inflammatory mediator release and extracellular matrix (ECM) production in hTERT immortalised and parent primary ASM cells from asthmatic and non-asthmatic donors. Our studies revealed no significant differences in proliferation, IL-6 and eotaxin-1 production, or CTGF synthesis between donor-matched parent and hTERT immortalised ASM cell lines. However, deposition of ECM proteins fibronectin and fibulin-1 was significantly lower in immortalised ASM cells compared to corresponding primary cells. Notably, previously reported differences in proliferation and inflammatory mediator release between asthmatic and non-asthmatic ASM cells were retained, but excessive ECM protein deposition in asthmatic ASM cells was lost in hTERT ASM cells. This study shows that hTERT immortalised ASM cells mirror primary ASM cells in proliferation and inflammatory profile characteristics. Moreover, we demonstrate both strengths and weaknesses of this immortalised cell model as a representation of primary ASM cells for future asthma pathophysiological research.
Wang, J, Faiz, A, Ge, Q, Vermeulen, CJ, Van der Velden, J, Snibson, KJ, van de Velde, R, Sawant, S, Xenaki, D, Oliver, B, Timens, W, Ten Hacken, N, van den Berge, M, James, A, Elliot, JG, Dong, L, Burgess, JK & Ashton, AW 2018, 'Unique mechanisms of connective tissue growth factor regulation in airway smooth muscle in asthma: Relationship with airway remodelling.', Journal of Cellular and Molecular Medicine, vol. 22, no. 5, pp. 2826-2837.View/Download from: UTS OPUS or Publisher's site
Neovascularization, increased basal membrane thickness and increased airway smooth muscle (ASM) bulk are hallmarks of airway remodelling in asthma. In this study, we examined connective tissue growth factor (CTGF) dysregulation in human lung tissue and animal models of allergic airway disease. Immunohistochemistry revealed that ASM cells from patients with severe asthma (A) exhibited high expression of CTGF, compared to mild and non-asthmatic (NA) tissues. This finding was replicated in a sheep model of allergic airways disease. In vitro, transforming growth factor (TGF)-β increased CTGF expression both in NA- and A-ASM cells but the expression was higher in A-ASM at both the mRNA and protein level as assessed by PCR and Western blot. Transfection of CTGF promoter-luciferase reporter constructs into NA- and A-ASM cells indicated that no region of the CTGF promoter (-1500 to +200 bp) displayed enhanced activity in the presence of TGF-β. However, in silico analysis of the CTGF promoter suggested that distant transcription factor binding sites may influence CTGF promoter activation by TGF-β in ASM cells. The discord between promoter activity and mRNA expression was also explained, in part, by differential post-transcriptional regulation in A-ASM cells due to enhanced mRNA stability for CTGF. In patients, higher CTGF gene expression in bronchial biopsies was correlated with increased basement membrane thickness indicating that the enhanced CTGF expression in A-ASM may contribute to airway remodelling in asthma.
Faiz, A, Weckmann, M, Tasena, H, Vermeulen, CJ, Van den Berge, M, Ten Hacken, NHT, Halayko, AJ, Ward, JPT, Lee, TH, Tjin, G, Black, JL, Haghi, M, Xu, C-J, King, GG, Farah, CS, Oliver, BG, Heijink, IH & Burgess, JK 2018, 'Profiling of healthy and asthmatic airway smooth muscle cells following interleukin-1β treatment: a novel role for CCL20 in chronic mucus hypersecretion.', European Respiratory Journal, vol. 52, no. 2, pp. 1-12.View/Download from: UTS OPUS or Publisher's site
Chronic mucus hypersecretion (CMH) contributes to the morbidity and mortality of asthma, and remains uncontrolled by current therapies in the subset of patients with severe, steroid-resistant disease. Altered cross-talk between airway epithelium and airway smooth muscle cells (ASMCs), driven by pro-inflammatory cytokines such as interleukin (IL)-1β, provides a potential mechanism that influences CMH. This study investigated mechanisms underlying CMH by comparing IL-1β-induced gene expression profiles between asthma and control-derived ASMCs and the subsequent paracrine influence on airway epithelial mucus production in vitroIL-1β-treated ASMCs from asthmatic patients and healthy donors were profiled using microarray analysis and ELISA. Air-liquid interface (ALI)-cultured CALU-3 and primary airway epithelial cells were treated with identified candidates and mucus production assessed.The IL-1β-induced CCL20 expression and protein release was increased in ASMCs from moderate compared with mild asthmatic patients and healthy controls. IL-1β induced lower MIR146A expression in asthma-derived ASMCs compared with controls. Decreased MIR146A expression was validated in vivo in bronchial biopsies from 16 asthmatic patients versus 39 healthy donors. miR-146a-5p overexpression abrogated CCL20 release in ASMCs. CCL20 treatment of ALI-cultured CALU-3 and primary airway epithelial cells induced mucus production, while CCL20 levels in sputum were associated with increased levels of CMH in asthmatic patients.Elevated CCL20 production by ASMCs, possibly resulting from dysregulated expression of the anti-inflammatory miR-146a-5p, may contribute to enhanced mucus production in asthma.
Ghadiri, M, Young, PM, Jarolimek, W, Grau, GER, Oliver, BGG & Traini, D 2017, 'The effect of non-specific tight junction modulators on the transepithelial transport of poorly permeable drugs across airway epithelial cells.', Journal of Drug Targeting, vol. 25, no. 4, pp. 342-349.View/Download from: UTS OPUS or Publisher's site
The epithelial barrier in the respiratory system is a major obstacle for drug delivery to the systemic circulation in the lung. Epithelial barrier hinders the transport of large macromolecules or polar drugs. Essential components of this epithelial fence are physical intercellular structures termed tight junctions. Therefore, modulating tight junctions can enhance paracellular transport across epithelial barrier. In this study, the effect of some of non-specific tight junction modulators (TJMs); (Sodium (Na) decanoate, oleic acid and ethyleneglycol-bis-(β-aminoethyl ether)-N, N'-tetraacetic acid (EGTA)) with established effect on intestinal tight junctions was evaluated for its effects on bronchial epithelial cells (Calu-3 cells). It was demonstrated that the effect of TJMs especially Na decanoate resulted in a reversible opening of tight junctions evidenced by the decrease in the transepithelial resistance. It was also demonstrated that this reduction of TEER upon exposing the epithelial cells to the TJMs resulted in a significant increase in Flu-Na (paracellular marker) and PXS25 (anti-fibrotic compound) transepithelial transport through this barrier. In conclusion, among the investigated non-specific TJMs, Na decanoate fulfilled the requirements of an effective, non-toxic and reversible tight junction modulator for Calu-3 lung epithelial cells.
Patel, BS, Rahman, MM, Baehring, G, Xenaki, D, Tang, FS-M, Oliver, BG & Ammit, AJ 2017, 'Roflumilast N-Oxide in Combination with Formoterol Enhances the Antiinflammatory Effect of Dexamethasone in Airway Smooth Muscle Cells.', American Journal of Respiratory Cell and Molecular Biology, vol. 56, no. 4, pp. 532-538.View/Download from: UTS OPUS or Publisher's site
Roflumilast is an orally active phosphodiesterase 4 inhibitor approved for use in chronic obstructive pulmonary disease. Roflumilast N-oxide (RNO) is the active metabolite of roflumilast and has a demonstrated antiinflammatory impact in vivo and in vitro. To date, the effect of RNO on the synthetic function of airway smooth muscle (ASM) cells is unknown. We address this herein and investigate the effect of RNO on β2-adrenoceptor-mediated, cAMP-dependent responses in ASM cells in vitro, and whether RNO enhances steroid-induced repression of inflammation. RNO (0.001-1,000 nM) alone had no effect on AMP production from ASM cells, and significant potentiation of the long-acting β2-agonist formoterol-induced cAMP could only be achieved at the highest concentration of RNO tested (1,000 nM). At this concentration, RNO exerted a small, but not significantly different, potentiation of formoterol-induced expression of antiinflammatory mitogen-activated protein kinase phosphatase 1. Consequently, tumor necrosis factor-induced IL-8 secretion was unaffected by RNO in combination with formoterol. However, because there was the potential for phosphodiesterase 4 inhibitors and long-acting β2-agonists to interact with corticosteroids to achieve superior antiinflammatory efficacy, we examined whether RNO, alone or in combination with formoterol, enhanced the antiinflammatory effect of dexamethasone by measuring the impact on IL-8 secretion. Although RNO alone did not significantly enhance the cytokine repression achieved with steroids, RNO in combination with formoterol significantly enhanced the antiinflammatory effect of dexamethasone in ASM cells. This was linked to increased mitogen-activated protein kinase phosphatase 1 expression in ASM cells, suggesting that a molecular mechanism is responsible for augmented antiinflammatory actions of combination therapeutic approaches that include RNO.
Sharma, P, Yi, R, Nayak, A, Wang, N, Knight, MJ, Pan, S, Oliver, B & Deshpande, DA 2017, 'Bitter Taste Receptor Agonists Mitigate Features of Allergic Asthma in Mice.', Scientific Reports, vol. 7, pp. 1-14.View/Download from: UTS OPUS or Publisher's site
Ebenezer, JA, Christensen, JM, Oliver, BG, Oliver, RA, Tjin, G, Ho, J, Habib, AR, Rimmer, J, Sacks, R & Harvey, RJ 2017, 'Periostin as a marker of mucosal remodelling in chronic rhinosinusitis.', Rhinology, vol. 55, no. 3, pp. 234-241.View/Download from: UTS OPUS or Publisher's site
Although extracellular matrix (ECM) proteins are associated with irreversible lower airway changes, the relationship with upper airway remodelling which occurs during chronic rhinosinusitis (CRS) is poorly understood. This study assessed the expression of ECM proteins periostin, fibulin-1, fibronectin and collagenIV in nasal mucosa of patients with and without histologic features of remodelling.A cross-sectional study of sinonasal mucosal biopsies taken from patients, undergoing surgery for CRS was performed, where patients were grouped according to remodelling, defined by basement membrane thickening (BMT over 7.5 micrometer) and subepithelial fibrosis. An overall view and three random fields of immunostained tissue sections that included epithelium, basement membrane and submucosa, were imaged using Zeiss Zen software. The area and intensity of positive staining were scored by two blinded observers, using a 12-point ordinal scale of weak to strong.65 patients (47.6 +/- 13.4years, 44.6% female) were assessed. Patients were grouped as controls 26.2%, BMT/no fibrosis 38.5% or BMT and fibrosis 33.8%. Stronger grade of periostin expression was associated with remodelling changes and tissue eosinophilia over 10/HPF. Fibulin-1, fibronectin and collagenIV did not differ.Periostin expression was associated with the presence of BMT, fibrosis and tissue eosinophilia and may identify patients undergoing remodelling changes.
Turturice, BA, McGee, HS, Oliver, B, Baraket, M, Nguyen, BT, Ascoli, C, Ranjan, R, Rani, A, Perkins, DL & Finn, PW 2017, 'Atopic asthmatic immune phenotypes associated with airway microbiota and airway obstruction.', PLoS ONE, vol. 12, no. 10, pp. 1-18.View/Download from: UTS OPUS or Publisher's site
Differences in asthma severity may be related to inflammation in the airways. The lower airway microbiota has been associated with clinical features such as airway obstruction, symptom control, and response to corticosteroids.To assess the relationship between local airway inflammation, severity of disease, and the lower airway microbiota in atopic asthmatics.A cohort of young adult, atopic asthmatics with intermittent or mild/moderate persistent symptoms (n = 13) were assessed via bronchoscopy, lavage, and spirometry. These individuals were compared to age matched non-asthmatic controls (n = 6) and to themselves after six weeks of treatment with fluticasone propionate (FP). Inflammation of the airways was assessed via a cytokine and chemokine panel. Lower airway microbiota composition was determined by metagenomic shotgun sequencing.Unsupervised clustering of cytokines and chemokines prior to treatment with FP identified two asthmatic phenotypes (AP), termed AP1 and AP2, with distinct bronchoalveolar lavage inflammatory profiles. AP2 was associated with more obstruction, compared to AP1. After treatment with FP reduced MIP-1β and TNF-α and increased IL-2 was observed. A module of highly correlated cytokines that include MIP-1β and TNF-α was identified that negatively correlated with pulmonary function. Independently, IL-2 was positively correlated with pulmonary function. The airway microbiome composition correlated with asthmatic phenotypes. AP2, prior to FP treatment, was enriched with Streptococcus pneumoniae. Unique associations between IL-2 or the cytokine module and the microbiota composition of the airways were observed in asthmatics subjects prior to treatment but not after or in controls.The underlying inflammation in atopic asthma is related to the composition of microbiota and is associated with severity of airway obstruction. Treatment with inhaled corticosteroids was associated with changes in the airway inflammatory response to microbiota.
Comas, M, Gordon, CJ, Oliver, BG, Stow, NW, King, G, Sharma, P, Ammit, AJ, Grunstein, RR & Phillips, CL 2017, 'A circadian based inflammatory response – implications for respiratory disease and treatment', Sleep Science and Practice, vol. 1, no. 18, pp. 1-19.View/Download from: UTS OPUS or Publisher's site
Circadian clocks regulate the daily timing of many of our physiological, metabolic and biochemical functions. The immune system also displays circadian oscillations in immune cell count, synthesis and cytokine release, clock gene expression in cells and organs of the immune system as well as clock-controlled genes that regulate immune function. Circadian disruption leads to dysregulation of immune responses and inflammation which can further disrupt circadian rhythms. The response of organisms to immune challenges, such as allergic reactions also vary depending on time of the day, which can lead to detrimental responses particularly during the rest and early active periods. This review evaluates what is currently known in terms of circadian biology of immune response and the cross-talk between circadian and immune system. We discuss the circadian pattern of three respiratory-related inflammatory diseases, chronic obstructive pulmonary disease, allergic rhinitis and asthma. Increasing our knowledge on circadian patterns of immune responses and developing chronotherapeutic studies in inflammatory diseases with strong circadian patterns will lead to preventive measures as well as improved therapies focussing on the circadian rhythms of symptoms and the daily variation of the patients' responses to medication.
Sukjamnong, S, Chan, YL, Zakarya, R, Saad, S, Sharma, P, Santiyanont, R, Chen, H & Oliver, BG 2017, 'Effect of long-term maternal smoking on the offspring's lung health.', American Journal of Physiology - Lung Cellular and Molecular Physiology, vol. 313, no. 2, pp. L416-L423.View/Download from: UTS OPUS or Publisher's site
Maternal smoking during pregnancy contributes to long-term health problems in offspring, especially respiratory disorders that can manifest in either childhood or adulthood. Receptors for advanced glycation end products (RAGE) are multiligand receptors abundantly localized in the lung, capable of responding to by-products of reactive oxygen species and proinflammatory responses. RAGE signaling is a key regulator of inflammation in cigarette smoking-related pulmonary diseases. However, the impact of maternal cigarette smoke exposure on lung RAGE signaling in the offspring is unclear. This study aims to investigate the effect of maternal cigarette smoke exposure (SE), as well as mitochondria-targeted antioxidant [mitoquinone mesylate (MitoQ)] treatment, during pregnancy on the RAGE-mediated signaling pathway in the lung of male offspring. Female Balb/c mice (8 wk) were divided into a sham group (exposed to air), an SE group (exposed to cigarette smoke), and an SE + MQ group (exposed to cigarette smoke with MitoQ supplement from mating). The lungs from male offspring were collected at 13 wk. RAGE and its downstream signaling, including nuclear factor-κB and mitogen-activated protein kinase family consisting of extracellular signal-regulated kinase 1, ERK2, c-JUN NH2-terminal kinase (JNK), and phosphorylated JNK, in the lung were significantly increased in the SE offspring. Mitochondrial antioxidant manganese superoxide dismutase was reduced, whereas IL-1β and oxidative stress response nuclear factor (erythroid-derived 2)-like 2 were significantly increased in the SE offspring. Maternal MitoQ treatment normalized RAGE, IL-1β, and Nrf-2 levels in the SE + MQ offspring. Maternal SE increased RAGE and its signaling elements associated with increased oxidative stress and inflammatory cytokines in offspring lungs, whereas maternal MitoQ treatment can partially normalize these changes.
Chan, YL, Saad, S, Al-Odat, I, Oliver, BG, Pollock, C, Jones, NM & Chen, H 2017, 'Maternal L-Carnitine Supplementation Improves Brain Health in Offspring from Cigarette Smoke Exposed Mothers.', Frontiers in Molecular Neuroscience, vol. 10, pp. 1-15.View/Download from: UTS OPUS or Publisher's site
Maternal cigarette smoke exposure (SE) causes detrimental changes associated with the development of chronic neurological diseases in the offspring as a result of oxidative mitochondrial damage. Maternal L-Carnitine administration has been shown to reduce renal oxidative stress in SE offspring, but its effect in the brain is unknown. Here, we investigated the effects of maternal L-Carnitine supplementation on brain markers of oxidative stress, autophagy, mitophagy and mitochondrial energy producing oxidative phosphorylation (OXPHOS) complexes in SE offspring. Female Balb/c mice (8 weeks) were exposed to cigarette smoke prior to mating, during gestation and lactation with or without L-Carnitine supplementation (1.5 mM in drinking water). In 1 day old male SE offspring, brain mitochondrial damage was suggested by increased mitochondrial fusion and reduced autophagosome markers; whereas at 13 weeks, enhanced brain cell damage was suggested by reduced fission and autophagosome markers, as well as increased apoptosis and DNA fragmentation markers, which were partially reversed by maternal L-Carnitine supplementation. In female SE offspring, enhanced mitochondrial regeneration was suggested by decreased fission and increased fusion markers at day 1. At 13 weeks, there was an increase in brain energy demand, oxidative stress and mitochondrial turnover, reflected by the protein changes of OXPHOS complex, fission and autophagosome markers, as well as the endogenous antioxidant, which were also partially normalized by maternal L-Carnitine supplementation. However, markers of apoptosis and DNA fragmentation were not significantly changed. Thus L-Carnitine supplementation may benefit the brain health of the offspring from smoking mothers.
Kota, A, Deshpande, D, Haghi, M, Oliver, B & Sharma, P 2017, 'Autophagy and airway fibrosis: Is there a link?', F1000 Research, vol. 6, no. 409, pp. 1-10.View/Download from: UTS OPUS or Publisher's site
In the past decade, an emerging process named 'autophagy' has generated intense interest in many chronic lung diseases. Tissue remodeling and fibrosis is a common feature of many airway diseases, and current therapies do not prevent or reverse these structural changes. Autophagy has evolved as a conserved process for bulk degradation and recycling of cytoplasmic components to maintain basal cellular homeostasis and healthy organelle populations in the cell. Furthermore, autophagy serves as a cell survival mechanism and can also be induced by chemical and physical stress to the cell. Accumulating evidence demonstrates that autophagy plays an essential role in vital cellular processes, including tissue remodeling. This review will discuss some of the recent advancements made in understanding the role of this fundamental process in airway fibrosis with emphasis on airway remodeling, and how autophagy can be exploited as a target for airway remodeling in asthma and chronic obstructive pulmonary disease.
Chan, YL, Saad, S, Machaalani, R, Oliver, BG, Vissel, B, Pollock, C, Jones, NM & Chen, H 2017, 'Maternal Cigarette Smoke Exposure Worsens Neurological Outcomes in Adolescent Offspring with Hypoxic-Ischemic Injury.', Frontiers in Molecular Neuroscience, vol. 10, pp. 1-17.View/Download from: UTS OPUS or Publisher's site
Hypoxic-ischemic (HI) encephalopathy occurs in approximately 6 per 1000 term newborns leading to devastating neurological consequences, such as cerebral palsy and seizures. Maternal smoking is one of the prominent risk factors contributing to HI injury. Mitochondrial integrity plays a critical role in neural injury and repair during HI. We previously showed that maternal cigarette smoke exposure (SE) can reduce brain mitochondrial fission and autophagosome markers in male offspring. This was accompanied by increased brain cell apoptosis (active caspase-3) and DNA fragmentation (TUNEL staining). Here, we aimed to investigate whether maternal SE leads to more severe neurological damage after HI brain injury in male offspring. Female BALB/c mice (8 weeks) were exposed to cigarette smoke prior to mating, during gestation, and lactation. At postnatal day 10, half of the pups from each litter underwent left carotid artery occlusion, followed by exposure to 8% oxygen (92% nitrogen). At postnatal day 40-44, maternal SE reduced grip strength in grip traction and foot fault tests, which were also reduced by HI injury to similar levels regardless of the maternal group. Limb coordination was impaired by maternal SE which was not worsened by HI injury. Maternal SE increased anxiety level in the offspring, which was normalized by HI injury. Apoptosis markers were increased in different brain regions by maternal SE, with the cortex having further increased TUNEL by HI injury, along with increased markers of inflammation and mitophagy. We conclude that maternal SE can worsen HI-induced cellular damage in male offspring well into adolescence.
Capistrano, SJ, van Reyk, D, Chen, H & Oliver, BG 2017, 'Evidence of Biomass Smoke Exposure as a Causative Factor for the Development of COPD.', Toxics, vol. 5, no. 4, pp. 1-16.View/Download from: UTS OPUS or Publisher's site
Chronic obstructive pulmonary disease (COPD) is a progressive disease of the lungs characterised by chronic inflammation, obstruction of airways, and destruction of the parenchyma (emphysema). These changes gradually impair lung function and prevent normal breathing. In 2002, COPD was the fifth leading cause of death, and is estimated by the World Health Organisation (WHO) to become the third by 2020. Cigarette smokers are thought to be the most at risk of developing COPD. However, recent studies have shown that people with life-long exposure to biomass smoke are also at high risk of developing COPD. Most common in developing countries, biomass fuels such as wood and coal are used for cooking and heating indoors on a daily basis. Women and children have the highest amounts of exposures and are therefore more likely to develop the disease. Despite epidemiological studies providing evidence of the causative relationship between biomass smoke and COPD, there are still limited mechanistic studies on how biomass smoke causes, and contributes to the progression of COPD. This review will focus upon why biomass fuels are used, and their relationship to COPD. It will also suggest methodological approaches to model biomass exposure in vitro and in vivo.
Faiz, A, Donovan, C, Nieuwenhuis, MAE, van den Berge, M, Postma, DS, Yao, S, Park, CY, Hirsch, R, Fredberg, JJ, Tjin, G, Halayko, AJ, Rempel, KL, Ward, JPT, Lee, T, Bossé, Y, Nickle, DC, Obeidat, M, Vonk, JM, Black, JL, Oliver, BG, Krishnan, R, McParland, B, Bourke, JE & Burgess, JK 2017, 'Latrophilin receptors: Novel bronchodilator targets in asthma', Thorax, vol. 72, pp. 74-82.View/Download from: UTS OPUS or Publisher's site
© 2016 BMJ Publishing Group Ltd & British Thoracic Society.Background Asthma affects 300 million people worldwide. In asthma, the major cause of morbidity and mortality is acute airway narrowing, due to airway smooth muscle (ASM) hypercontraction, associated with airway remodelling. However, little is known about the transcriptional differences between healthy and asthmatic ASM cells. Objectives To investigate the transcriptional differences between asthmatic and healthy airway smooth muscle cells (ASMC) in culture and investigate the identified targets using in vitro and ex vivo techniques. Methods Human asthmatic and healthy ASMC grown in culture were run on Affymetrix_Hugene_1.0_ST microarrays. Identified candidates were confirmed by PCR, and immunohistochemistry. Functional analysis was conducted using in vitro ASMC proliferation, attachment and contraction assays and ex vivo contraction of mouse airways. Results We suggest a novel role for latrophilin (LPHN) receptors, finding increased expression on ASMC from asthmatics, compared with non-asthmatics in vivo and in vitro, suggesting a role in mediating airway function. A single nucleotide polymorphism in LPHN1 was associated with asthma and with increased LPHN1 expression in lung tissue. When activated, LPHNs regulated ASMC adhesion and proliferation in vitro, and promoted contraction of mouse airways and ASMC. Conclusions Given the need for novel inhibitors of airway remodelling and bronchodilators in asthma, the LPHN family may represent promising novel targets for future dual therapeutic intervention.
Liu, G, Cooley, MA, Nair, PM, Donovan, C, Hsu, AC, Jarnicki, AG, Haw, TJ, Hansbro, NG, Ge, Q, Brown, AC, Tay, H, Foster, PS, Wark, PA, Horvat, JC, Bourke, JE, Grainge, CL, Argraves, WS, Oliver, BG, Knight, DA, Burgess, JK & Hansbro, PM 2017, 'Airway remodelling and inflammation in asthma are dependent on the extracellular matrix protein fibulin-1c.', The Journal of Pathology, vol. 243, no. 4, pp. 510-523.View/Download from: UTS OPUS or Publisher's site
Asthma is a chronic inflammatory disease of the airways. It is characterized by allergic airway inflammation, airway remodelling, and airway hyperresponsiveness (AHR). Asthma patients, in particular those with chronic or severe asthma, have airway remodelling that is associated with the accumulation of extracellular matrix (ECM) proteins, such as collagens. Fibulin-1 (Fbln1) is an important ECM protein that stabilizes collagen and other ECM proteins. The level of Fbln1c, one of the four Fbln1 variants, which predominates in both humans and mice, is increased in the serum and airways fluids in asthma but its function is unclear. We show that the level of Fbln1c was increased in the lungs of mice with house dust mite (HDM)-induced chronic allergic airway disease (AAD). Genetic deletion of Fbln1c and therapeutic inhibition of Fbln1c in mice with chronic AAD reduced airway collagen deposition, and protected against AHR. Fbln1c-deficient (Fbln1c-/- ) mice had reduced mucin (MUC) 5 AC levels, but not MUC5B levels, in the airways as compared with wild-type (WT) mice. Fbln1c interacted with fibronectin and periostin that was linked to collagen deposition around the small airways. Fbln1c-/- mice with AAD also had reduced numbers of α-smooth muscle actin-positive cells around the airways and reduced airway contractility as compared with WT mice. After HDM challenge, these mice also had fewer airway inflammatory cells, reduced interleukin (IL)-5, IL-13, IL-33, tumour necrosis factor (TNF) and CXCL1 levels in the lungs, and reduced IL-5, IL-33 and TNF levels in lung-draining lymph nodes. Therapeutic targeting of Fbln1c reduced the numbers of GATA3-positive Th2 cells in the lymph nodes and lungs after chronic HDM challenge. Treatment also reduced the secretion of IL-5 and IL-13 from co-cultured dendritic cells and T cells restimulated with HDM extract. Human epithelial cells cultured with Fbln1c peptide produced more CXCL1 mRNA than medium-treated controls. Our data show that...
Tovey, ER, Liu-Brennan, D, Garden, FL, Oliver, BG, Perzanowski, MS & Marks, GB 2016, 'Time-Based Measurement of Personal Mite Allergen Bioaerosol Exposure over 24 Hour Periods', PLOS ONE, vol. 11, no. 5.View/Download from: UTS OPUS or Publisher's site
Ing, M, Oliver, RA, Oliver, BGG, Walsh, WR & Williamson, JP 2016, 'Evaluation of Transbronchial Lung Cryobiopsy Size and Freezing Time: A Prognostic Animal Study', Respiration, vol. 92, no. 1, pp. 34-39.View/Download from: UTS OPUS or Publisher's site
© 2016 S. Karger AG, BaselBackground: Transbronchial lung biopsy using a cryoprobe is a novel way of sampling lung parenchyma. Correlation of freezing time with biopsy size and complications has not been evaluated in vivo. Objectives: The primary aim of the study is to evaluate the correlation between transbronchial cryobiopsy freezing time and size. The secondary aims are to evaluate histological quality of the biopsy and evaluate procedure-associated complications. Methods: Transbronchial lung cryobiopsies were obtained from two anaesthetised sheep using a 1.9-mm cryoprobe inserted into a flexible bronchoscope under fluoroscopic guidance. Freezing times ranged from 1 to 6 s (n = 49). The cryobiopsies were evaluated histologically with respect to their size and quality. Complications of bleeding and pneumothorax were recorded. Results: The mean cross-sectional area of the cryobiopsy ranged from 4.7 ± 2.1 to 15.7 ± 15.3 mm2. There was a significant positive correlation between increasing freezing time and cryobiopsy cross-sectional area (p = 0.028). All biopsies contained lung tissue with preserved parenchyma. Crush and freeze artefacts were not observed and tissue architecture was intact in all specimens. Small blood vessels and terminal bronchioles were observed in 88% of specimens. All cryobiopsies caused nil or mild haemorrhage with the exception of only 1 episode of severe haemorrhage at 6 s freezing time. Pneumothoraces occurred at 2, 5 and 6 s freezing time and required chest tube insertion. The most significant haemorrhage and pneumothoraces occurred at 5 and 6 s. Our results suggest an initial freezing time of 3 s can provide the maximal biopsy size while minimising major complications. Conclusion: The optimal transbronchial cryobiopsy freezing time is initially 3 s. This time is associated with minimal complications and large artefact-free biopsies.
Mitchell, AB, Mourad, B, Tovey, E, Buddle, L, Peters, M, Morgan, L & Oliver, BG 2016, 'Spirometry filters can be used to detect exhaled respiratory viruses', JOURNAL OF BREATH RESEARCH, vol. 10, no. 4.View/Download from: UTS OPUS or Publisher's site
Mitchell, AB, Oliver, BGG & Glanville, AR 2016, 'Translational Aspects of the Human Respiratory Virome', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, vol. 194, no. 12, pp. 1458-1464.View/Download from: UTS OPUS or Publisher's site
Rumzhum, NN, Rahman, MM, Oliver, BG & Ammit, AJ 2016, 'Effect of Sphingosine 1-Phosphate on Cyclo-Oxygenase-2 Expression, Prostaglandin E2 Secretion, and β2-Adrenergic Receptor Desensitization.', American journal of respiratory cell and molecular biology, vol. 54, no. 1, pp. 128-135.View/Download from: UTS OPUS or Publisher's site
Tachyphylaxis of the β2-adrenergic receptor limits the efficacy of bronchodilatory β2-agonists in respiratory disease. Cellular studies in airway smooth muscle (ASM) have shown that inflammatory mediators and infectious stimuli reduce β2-adrenergic responsiveness in a cyclo-oxygenase (COX)-2-mediated, prostaglandin E2 (PGE2)-dependant manner. Herein, we show that sphingosine 1-phosphate (S1P), a bioactive sphingolipid that plays an important role in pathophysiology of asthma, also induces β2-adrenergic receptor desensitization in bronchial ASM cells and exerts hyporesponsiveness to β2-agonists. We treated ASM cells with S1P (1 μM) for up to 24 hours and then examined the temporal kinetics of COX-2 mRNA expression, protein up-regulation, and PGE2 secretion. S1P significantly enhanced COX-2 expression and PGE2 secretion, and this was repressed by the selective COX-2 inhibitor celecoxib, the corticosteroid dexamethasone, or small interfering RNA (siRNA) knockdown of COX-2 expression. In combination with another proinflammatory mediator found elevated in asthmatic airways, the cytokine TNF-α, we observed that S1P-induced COX-2 mRNA expression and protein up-regulation and PGE2 secretion from ASM cells were significantly enhanced. Notably, S1P induced heterologous β2-adrenergic desensitization, as measured by inhibition of cyclic adenosine monophosphate production in response to the short-acting β2-agonist, salbutamol, and the long-acting β2-agonist, formoterol. Taken together, these data indicate that S1P represses β2-adrenergic activity in ASM cells by increasing COX-2-mediated PGE2 production, and suggest that this bioactive sphingolipid found elevated in asthma may contribute to β2-adrenergic desensitization.
Tang, FSM, Van Ly, D, Spann, K, Reading, PC, Burgess, JK, Hartl, D, Baines, KJ & Oliver, BG 2016, 'Differential neutrophil activation in viral infections: Enhanced TLR-7/8-mediated CXCL8 release in asthma', RESPIROLOGY, vol. 21, no. 1, pp. 172-179.View/Download from: UTS OPUS or Publisher's site
Rumzhum, NN, Patel, BS, Prabhala, P, Gelissen, IC, Oliver, BG & Ammit, AJ 2016, 'IL-17A increases TNF-alpha-induced COX-2 protein stability and augments PGE(2) secretion from airway smooth muscle cells: impact on beta(2)-adrenergic receptor desensitization', ALLERGY, vol. 71, no. 3, pp. 387-396.View/Download from: UTS OPUS or Publisher's site
Patel, BS, Rahman, MM, Rumzhum, NN, Oliver, BG, Verrills, NM & Ammit, AJ 2016, 'Theophylline Represses IL-8 Secretion From ASM Cells Independently of PDE Inhibition: Novel Role as a PP2A Activator.', American journal of respiratory cell and molecular biology, vol. 54, no. 6, pp. 792-801.View/Download from: UTS OPUS or Publisher's site
Theophylline is an old drug experiencing a renaissance due to its beneficial anti-inflammatory effects in chronic respiratory diseases, such as asthma and COPD. Multiple modes of anti-inflammatory action have been reported, including inhibition of the enzymes that degrade cAMP - phosphodiesterase (PDE). Utilizing primary cultures of airway smooth muscle (ASM) cells, we recently revealed that PDE4 inhibitors can potentiate the anti-inflammatory action of β2-agonists by augmenting cAMP-dependent expression of the phosphatase that deactivates MAPK - MKP-1. Therefore the aim of this study was to address whether theophylline repressed cytokine production in a similar, PDE-dependent, MKP-1-mediated manner. Notably, theophylline did not potentiate cAMP release from ASM cells treated with the long-acting β2-agonist formoterol. Moreover, theophylline (0.1-10 µM) did not increase formoterol-induced MKP-1 mRNA expression nor protein upregulation; consistent with the lack of cAMP generation. However, theophylline (at 10 µM) was anti-inflammatory and repressed secretion of the neutrophil chemoattractant cytokine, IL-8, produced in response to tumor necrosis factor α (TNFα). Because theophylline's effects were independent of PDE4 inhibition or anti-inflammatory MKP-1, we then wished to elucidate novel mechanisms responsible. We investigated the impact of theophylline on protein phosphatase 2A (PP2A), a master controller of multiple inflammatory signaling pathways, and show that theophylline increases TNFα-induced PP2A activity in ASM cells. Confirmatory results were obtained in A549 lung epithelial cells. PP2A activators have beneficial effects in ex vivo and in vivo models of respiratory disease. Thus, our study is the first to link theophylline with PP2A activation as a novel mechanism to control respiratory inflammation.
Oliver, BGG & Black, J 2016, 'Asthma: Airways That Are Hyperactive by Design', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, vol. 193, no. 6, pp. 596-598.View/Download from: Publisher's site
Tang, FS, Hansbro, PM, Burgess, JK, Ammit, AJ, Baines, KJ & Oliver, BG 2016, 'A novel immunomodulatory function of neutrophils on rhinovirus-activated monocytes in vitro.', Thorax, vol. 71, no. 11, pp. 1039-1049.View/Download from: UTS OPUS or Publisher's site
Rhinovirus (RV) infections are the major precipitant of asthma exacerbations. While neutrophilic lung inflammation occurs during such infections, its role remains unclear. Neutrophilic inflammation is associated with increased asthma severity and steroid refractory disease. Neutrophils are vital for controlling infections but also have immunomodulatory functions. Previously, we found that neutrophils respond to viral mimetics but not replication competent RV. We aimed to investigate if neutrophils are activated and/or modulate immune responses of monocytes during RV16 infection.Primary human monocytes and autologous neutrophils were cocultured with or without RV16, in direct contact or separated by transwells. RV16-stimulated monocytes were also exposed to lysed neutrophils, neutrophil membrane components or soluble neutrophil intracellular components. Interleukin 6 (IL-6) and C-X-C motif (CXC)L8 mRNA and proteins were measured by quantitative PCR and ELISA at 24 hours.RV16 induced IL-6 and CXCL8 in monocytes, but not neutrophils. RV16-induced IL-6 and CXCL8 from monocytes was reduced in the presence of live neutrophils. Transwell separation abolished the inhibitory effects. Lysed neutrophils inhibited RV16-induced IL-6 and CXCL8 from monocytes. Neutrophil intracellular components alone effectively inhibited RV16-induced monocyte-derived IL-6 and CXCL8. Neutrophil intracellular components reduced RV16-induced IL-6 and CXCL8 mRNA in monocytes.Cell contact between monocytes and neutrophils is required, and preformed neutrophil mediator(s) are likely to be involved in the suppression of cytokine mRNA and protein production. This study demonstrates a novel regulatory function of neutrophils on RV-activated monocytes in vitro, challenging the paradigm that neutrophils are predominantly proinflammatory.
Liu, G, Cooley, MA, Jarnicki, AG, Hsu, AC-Y, Nair, PM, Haw, TJ, Fricker, M, Gellatly, SL, Kim, RY, Inman, MD, Tjin, G, Wark, PAB, Walker, MM, Horvat, JC, Oliver, BG, Argraves, WS, Knight, DA, Burgess, JK & Hansbro, PM 2016, 'Fibulin-1 regulates the pathogenesis of tissue remodeling in respiratory diseases', JCI INSIGHT, vol. 1, no. 9.View/Download from: UTS OPUS or Publisher's site
Capistrano, SJ, Zakarya, R, Chen, H & Oliver, BG 2016, 'Biomass Smoke Exposure Enhances Rhinovirus-Induced Inflammation in Primary Lung Fibroblasts', INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 17, no. 9.View/Download from: UTS OPUS or Publisher's site
Chan, YL, Saad, S, Al-Odat, I, Zaky, AA, Oliver, B, Pollock, C, Li, W, Jones, NM & Chen, H 2016, 'Impact of maternal cigarette smoke exposure on brain and kidney health outcomes in female offspring.', Clinical and experimental pharmacology & physiology, vol. 43, pp. 1168-1176.View/Download from: UTS OPUS or Publisher's site
Increased oxidative stress in the brain can lead to increased sympathetic tone that may further induce kidney dysfunction. Previously we have shown that maternal cigarette smoke exposure (SE) leads to significantly increased oxidative stress and inflammation in both brain and kidney, as well as reduced brain and kidney mitochondrial activity. This is closely associated with significant kidney underdevelopment and abnormal function in adulthood in the male offspring. This study aimed to investigate the impact of maternal SE on brain and kidney health in the female offspring. In this study, the mouse dams were exposed to 2 cigarettes, twice daily for 6 weeks prior to gestation, during pregnancy and lactation. Brains and kidneys from the female offspring were collected at 20 days (P20) and 13 weeks (W13) and were subject to further analysis. We found that mRNA expression of brain inflammatory markers interleukin-1 receptor and Toll-like receptor 4 were significantly increased in the SE offspring at both P20 and W13. Their brain mitochondrial activity markers were however increased at W13 with increased antioxidant activity. Kidney development and function in the female SE offspring were not different from the control offspring. We concluded that although brain inflammatory markers were upregulated in the SE female offspring, they were protected from some of the indicators of brain oxidative stress, such as endogenous antioxidant and mitochondrial dysfunction, as well as abnormal kidney development and function in adulthood. This article is protected by copyright. All rights reserved.
Chan, YL, Saad, S, Pollock, C, Oliver, B, Al-Odat, I, Zaky, AA, Jones, N & Chen, H 2016, 'Impact of maternal cigarette smoke exposure on brain inflammation and oxidative stress in male mice offspring', SCIENTIFIC REPORTS, vol. 6.View/Download from: UTS OPUS or Publisher's site
Chen, H, Chan, YL, Nguyen, LT, Mao, Y, de Rosa, A, Beh, IT, Chee, C, Oliver, B, Herok, G, Saad, S & Gorrie, C 2016, 'Moderate traumatic brain injury is linked to acute behaviour deficits and long term mitochondrial alterations', CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, vol. 43, no. 11, pp. 1107-1114.View/Download from: UTS OPUS or Publisher's site
Stelzer-Braid, S, Tovey, ER, Willenborg, CM, Toelle, BG, Ampon, R, Garden, FL, Oliver, BG, Strachan, R, Belessis, Y, Jaffe, A, Reddel, HK, Crisafulli, D, Marks, GB & Rawlinson, WD 2016, 'Absence of back to school peaks in human rhinovirus detections and respiratory symptoms in a cohort of children with asthma', JOURNAL OF MEDICAL VIROLOGY, vol. 88, no. 4, pp. 578-587.View/Download from: UTS OPUS or Publisher's site
Patel, BS, Prabhala, P, Oliver, BG & Ammit, AJ 2015, 'Inhibitors of Phosphodiesterase 4, but Not Phosphodiesterase 3, Increase β2-Agonist-Induced Expression of Antiinflammatory Mitogen-Activated Protein Kinase Phosphatase 1 in Airway Smooth Muscle Cells.', American journal of respiratory cell and molecular biology, vol. 52, no. 5, pp. 634-640.View/Download from: UTS OPUS or Publisher's site
β2-agonists are principally used in asthma to provide bronchodilation; however, they also have antiinflammatory properties, due, in part, to their ability to up-regulate mitogen-activated protein kinase phosphatase (MKP) 1 in a cAMP-dependent manner. Phosphodiesterases (PDEs) are attractive targets for potentiating the antiinflammatory response. There are 11 subfamilies of PDE enzymes; among these, inhibition of PDE3 and PDE4 are the main targets for airway smooth muscle (ASM). PDE enzymes are important intracellular regulators that catalyze the breakdown of cyclic adenosine monophosphate (cAMP) and/or 3',5'-cyclic guanosine monophosphate to their inactive forms. Given that MKP-1 is cAMP dependent, and inhibition of PDE acts to increase β2-agonist-induced cAMP, it is possible that the presence of PDE inhibitors may enhance β2-adrenoceptor-mediated responses. We address this herein by comparing the ability of a panel of inhibitors against PDE3 (cilostamide, cilostazol, milrinone) or PDE4 (cilomilast, piclamilast, rolipram) to increase cAMP, MKP-1 mRNA expression, and protein up-regulation in ASM cells induced in response to the β2-agonist formoterol. Our data show that inhibitors of PDE4, but not PDE3, increase β2-agonist-induced cAMP and induce MKP-1 mRNA expression and protein up-regulation. When cAMP was increased, there was a concomitant increase in MKP-1 levels and significant inhibition of TNF-α-induced CXCL8 (IL-8). This result was consistent with all PDE4 inhibitors examined but not for the PDE3 inhibitors. These findings reinforce cAMP-dependent control of MKP-1 expression, and suggest that PDE4 is the predominant PDE isoform responsible for formoterol-induced cAMP breakdown in ASM cells. Our study is the first to demonstrate that PDE4 inhibitors augment antiinflammatory effects of β2-agonists via increased MKP-1 expression in ASM cells.
Van Ly, D & Oliver, BG 2015, 'Do we really need to keep redesigning β2-agonists for the management of asthma?', Current Drug Delivery, vol. 12, no. 1, pp. 9-15.View/Download from: UTS OPUS or Publisher's site
There is an enormous drive to refine therapeutic designs and delivery systems, but in this review we ask if this is always the right direction? We choose to play devil's advocate, and argue that refining drug design is not always needed, and what is actually needed is a greater understanding of the biology of the disease. Here we focus on asthma and the β2-agonist group of bronchodilators as an example of how a class of therapeutic has been developed and continues to be developmentally refined. In this review, we define viral-induced exacerbations as the greatest cause of lung attacks and the most crucial time β2-agonist therapy is needed. We explore the reasons why β2-agonist therapy fails in patients with rhinovirus-induced exacerbations, and explain why further "engineered" β2-agonist therapies are likely to continue to fail in this subset of asthmatic population. We justify our perspective by returning to the biology that underlies the cause of disease and highlight the need for "more research" into alternative therapies for this population of asthmatic patients.
Herbert, C, Sebesfi, M, Zeng, Q-X, Oliver, BG, Foster, PS & Kumar, RK 2015, 'Using multiple online databases to help identify microRNAs regulating the airway epithelial cell response to a virus-like stimulus', RESPIROLOGY, vol. 20, no. 8, pp. 1206-1212.View/Download from: UTS OPUS or Publisher's site
Ng, HY, Oliver, BGG, Burgess, JK, Krymskaya, VP, Black, JL & Moir, LM 2015, 'Doxycycline reduces the migration of tuberous sclerosis complex-2 null cells - effects on RhoA-GTPase and focal adhesion kinase', JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, vol. 19, no. 11, pp. 2633-2646.View/Download from: UTS OPUS or Publisher's site
Ge, Q, Zeng, Q, Tjin, G, Lau, E, Black, JL, Oliver, BGG & Burgess, JK 2015, 'Differential deposition of fibronectin by asthmatic bronchial epithelial cells', AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, vol. 309, no. 10, pp. L1093-L1102.View/Download from: UTS OPUS or Publisher's site
Tang, FSM, Foxley, GJ, Gibson, PG, Burgess, JK, Baines, KJ & Oliver, BG 2015, 'Altered Innate Immune Responses in Neutrophils from Patients with Well- and Suboptimally Controlled Asthma', MEDIATORS OF INFLAMMATION.View/Download from: UTS OPUS or Publisher's site
Ge, Q, Chen, L, Jaffar, J, Argraves, WS, Twal, WO, Hansbro, P, Black, JL, Burgess, JK & Oliver, B 2015, 'Fibulin1C peptide induces cell attachment and extracellular matrix deposition in lung fibroblasts', SCIENTIFIC REPORTS, vol. 5.View/Download from: UTS OPUS or Publisher's site
Haghi, M, Traini, D, Wood, LG, Oliver, B, Young, PM & Chrzanowski, W 2015, 'A 'soft spot' for drug transport: modulation of cell stiffness using fatty acids and its impact on drug transport in lung model', JOURNAL OF MATERIALS CHEMISTRY B, vol. 3, no. 13, pp. 2583-2589.View/Download from: UTS OPUS or Publisher's site
Haghi, M, Hittinger, M, Zeng, Q, Oliver, BG, Traini, D, Young, P, Huwer, H, Schneider-Daum, N & Lehr, CM 2015, 'Mono- and Cocultures of Bronchial and Alveolar Epithelial Cells Respond Differently to Proinflammatory Stimuli and Their Modulation by Salbutamol and Budesonide.', Molecular Pharmacology, vol. 12, no. 8, pp. 2625-2632.View/Download from: UTS OPUS or Publisher's site
The aim of this study was to investigate the changes in transport and effectiveness of salbutamol sulfate (SAL) and budesonide (BD) following stimulation with transforming growth factor-β (TGF-β) in mono- and coculture models of bronchial and alveolar epithelium. Primary bronchial and alveolar epithelial cells, grown at air interface on filters, either as monocultures or in coculture with airway smooth muscle cells or alveolar macrophages, respectively, were stimulated with TGF-β. The biological response was modulated by depositing aerosolized SAL and BD on bronchial and alveolar models, respectively. Barrier integrity, permeability to fluorescein-Na, transport of the deposited drug, and the pharmacological response to SAL (cAMP and IL-8 levels) or BD (IL-6 and -8 levels) were measured. While stimulation with TGF-β did not have any significant effect on the transepithelial electrical resistance and permeability to fluorescein-Na in mono- and coculture models, transport of SAL and BD were affected in cultures from some of the patients (6 out of 12 for bronchial and 2 out of 4 for alveolar cells). The bronchial coculture showed a better responsiveness to SAL in terms of cAMP release than the monoculture. In contrast, the difference between alveolar mono- and cocultures to TGF-β mediated interleukin release and its modulation by BD was less pronounced. Our data point to intrinsic differences in the transport of, and responsiveness to, SAL and BD when epithelial cell cultures originate from different patients. Moreover, if the biological responses (e.g., IL-8, cAMP) involve communication between different cell types, coculture models are more relevant to measure such effects than monocultures.
Tovey, ER, Stelzer-Braid, S, Toelle, BG, Oliver, BG, Reddel, HK, Willenborg, CM, Belessis, Y, Garden, FL, Jaffe, A, Strachan, R, Eyles, D, Rawlinson, WD & Marks, GB 2015, 'Rhinoviruses significantly affect day-to-day respiratory symptoms of children with asthma', JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, vol. 135, no. 3, pp. 663-U124.View/Download from: UTS OPUS or Publisher's site
Chan, YL, Saad, S, Simar, D, Oliver, B, McGrath, K, Reyk, DV, Bertrand, PP, Gorrie, C, Pollock, C & Chen, H 2015, 'Short term exendin-4 treatment reduces markers of metabolic disorders in female offspring of obese rat dams', International Journal of Developmental Neuroscience, vol. 46, pp. 67-75.View/Download from: UTS OPUS or Publisher's site
Maternal obesity imposes significant health risks in the offspring including diabetes and dyslipidemia. We previously showed that the hypoglycaemic agent exendin-4 (Ex-4) administered from weaning can reverse the maternal impact of 'transmitted disorders' in such offspring. However daily injection for six-weeks was required and the beneficial effect may lapse upon drug withdrawal. This study aimed to investigate whether short term Ex-4 treatment during suckling period in a rodent model can reverse transmitted metabolic disorders due to maternal obesity.
Maternal obesity was induced in female Sprague Dawley rats by high-fat diet feeding for 6 weeks, throughout gestation and lactation. Female offspring were treated with Ex-4 (5 μg/kg/day) between postnatal day (P) 4 and 14. Female offspring were harvested at weaning (P20). Lipid and glucose metabolic markers were measured in the liver and fat. Appetite regulators were measured in the plasma and hypothalamus.
Maternal obesity significantly increased body weight, fat mass, and liver weight in the offspring. There was an associated inhibition of peroxisomal proliferator activated receptor gamma coactivator 1α (PGC1α), increased fatty acid synthase (FASN) expression in the liver, and reduced adipocyte triglyceride lipase (ATGL) expression. It also increased the plasma gut hormone ghrelin and reduced glucagon-like peptide-1. Ex-4 treatment partially reversed the maternal impact on adiposity and impaired lipid metabolism in the offspring, with increased liver PGC1α and inhibition of FASN mRNA expression. Ex-4 treatment also increased the expression of a novel fat depletion gene a2-zinc-glycoprotein 1 in the fat tissue.
Short term Ex-4 treatment during the suckling period significantly improved the metabolic profile in the offspring from the obese mothers at weaning. Long-term studies are needed to follow such offspring to adulthood to examine the sustained effects of Ex-4 in p...
Oliver, BGG, Robinson, P, Peters, M & Black, J 2014, 'Viral infections and asthma: an inflammatory interface?', EUROPEAN RESPIRATORY JOURNAL, vol. 44, no. 6, pp. 1666-1681.View/Download from: UTS OPUS or Publisher's site
Herbert, C, Zeng, QX, Shanmugasundaram, R, Garthwaite, L, Oliver, BG & Kumar, RK 2014, 'Response of airway epithelial cells to double-stranded RNA in an allergic environment.', Translational Respiratory Medicine, vol. 2, pp. 1-11.View/Download from: UTS OPUS or Publisher's site
Respiratory viral infections are the most common trigger of acute exacerbations in patients with allergic asthma. The anti-viral response of airway epithelial cells (AEC) may be impaired in asthmatics, while cytokines produced by AEC may drive the inflammatory response. We investigated whether AEC cultured in the presence of Th2 cytokines associated with an allergic environment exhibited altered responses to double-stranded RNA, a virus-like stimulus.We undertook preliminary studies using the MLE-12 cell line derived from mouse distal respiratory epithelial cells, then confirmed and extended our findings using low-passage human AEC. Cells were cultured in the absence or presence of the Th2 cytokines IL-4 and IL-13 for 48 hours, then stimulated with poly I:C for 4 hours. Expression of relevant anti-viral response and cytokine genes was assessed by quantitative real-time PCR. Secretion of cytokine proteins was assessed by immunoassay.Following stimulation with poly I:C, MLE-12 cells pre-treated with Th2 cytokines exhibited significantly higher levels of expression of mRNA for the cytokine genes Cxcl10 and Cxcl11, as well as a trend towards increased expression of Cxcl9 and Il6. Expression of anti-viral response genes was mostly unchanged, although Stat1, Ifit1 and Ifitm3 were significantly increased in Th2 cytokine pre-treated cells. Human AEC pre-treated with IL-4 and IL-13, then stimulated with poly I:C, similarly exhibited significantly higher expression of IL8, CXCL9, CXCL10, CXCL11 and CCL5 genes. In parallel, there was significantly increased secretion of CXCL8 and CCL5, as well as a trend towards increased secretion of CXCL10 and IL-6. Again, expression of anti-viral response genes was not decreased. Rather, there was significantly enhanced expression of mRNA for type III interferons, RNA helicases and other interferon-stimulated genes.The Th2 cytokine environment appears to promote increased production of pro-inflammatory chemokines by AEC in response to do...
Chen, L, Ge, Q, Tjin, G, Alkhouri, H, Deng, L, Brandsma, C, Adcock, I, Timens, W, Postma, DS, Burgess, JK, Black, JL & Oliver, BG 2014, 'Effects of cigarette smoke extract on human airway smooth muscle cells in COPD', European Respiratory Journal, vol. 44, no. 3, pp. 634-646.View/Download from: UTS OPUS or Publisher's site
We hypothesised that the response to cigarette smoke in airway smooth muscle (ASM) cells from smokers with chronic obstructive pulmonary disease (COPD) would be intrinsically different from smokers without COPD, producing greater pro-inflammatory mediators and factors relating to airway remodelling. ASM cells were obtained from smokers with or without COPD, and then stimulated with cigarette smoke extract (CSE) or transforming growth factor-ß1. The production of chemokines and matrix metalloproteinases (MMPs) were measured by ELISA, and the deposition of collagens by extracellular matrix ELISA. The effects of CSE on cell attachment and wound healing were measured by toluidine blue attachment and cell tracker green wound healing assays. CSE increased the release of CXCL8 and CXCL1 from human ASM cells, and cells from smokers with COPD produced more CSE-induced CXCL1. The production of MMP-1, -3 and -10, and the deposition of collagen VIII alpha 1 (COL8A1) were increased by CSE, especially in the COPD group which had higher production of MMP-1 and deposition of COL8A1. CSE decreased ASM cell attachment and wound healing in the COPD group only. ASM cells from smokers with COPD were more sensitive to CSE stimulation, which may explain, in part, why some smokers develop COPD.
Banville, N, Burgess, JK, Jaffar, J, Tjin, G, Richeldi, L, Cerri, S, Persiani, E, Black, JL & Oliver, BG 2014, 'A Quantitative Proteomic Approach to Identify Significantly Altered Protein Networks in the Serum of Patients with Lymphangioleiomyomatosis (LAM)', PLoS One, vol. 9, no. 8.View/Download from: UTS OPUS or Publisher's site
Lymphangioleiomyomatosis (LAM) is a rare and progressive cystic lung condition affecting approximately 3.47.5/million women, with an average lag time between symptom onset and diagnosis of upwards of 4 years. The aim of this work was to identify altered proteins in LAM serum which may be potential biomarkers of disease. Serum from LAM patient volunteers and healthy control volunteers were pooled and analysis carried out using quantitative 4-plex iTRAQ technology. Differentially expressed proteins were validated using ELISAs and pathway analysis was carried out using Ingenuity Pathway Analysis. Fourteen proteins were differentially expressed in LAM serum compared to control serum (p<0.05). Further screening validated the observed differences in extracellular matrix remodelling proteins including fibronectin (30% decrease in LAM, p = 0.03), von Willebrand Factor (40% reduction in LAM, p = 0.03) and Kallikrein III (25% increase in LAM, p = 0.03). Pathway networks elucidated the relationships between the ECM and cell trafficking in LAM. This study was the first to highlight an imbalance in networks important for remodelling in LAM, providing a set of novel potential biomarkers. These understandings may lead to a new effective treatment for LAM in the future.
Alkhouri, H, Rumzhum, N, Rahman, M, FitzPatrick, M, De Pedro, M, Oliver, BG, Bourke, J & Ammit, A 2014, 'TLR2 activation causes tachyphylaxis to ß2-agonists in vitro and ex vivo: modelling bacterial exacerbation', Allergy, vol. 69, no. 9, pp. 1215-1222.View/Download from: UTS OPUS or Publisher's site
Background Asthma is a widespread chronic health problem exacerbated by common viral and bacterial infections. Further research is required to understand how infection worsens asthma control in order to advance therapeutic options in the future. Recent research has revealed that ß2-adrenergic receptor (ß2-AR) agonists lose bronchodilatory efficacy because the receptor-mediated molecular pathways responsible for their beneficial actions are desensitized by infection. To date, most studies have focussed on viral infection, leaving the impact of bacterial infection on ß2-AR desensitization relatively under-investigated. We address this in this study. Methods and Results Utilizing an in vitro model of bacterial exacerbation in airway smooth muscle (ASM) cells, we show that activation of toll-like receptor 2 (TLR2; mimicking bacterial infection) in the presence of an inflammatory stimulus leads to ß2-AR desensitization. This occurs via TLR2-dependent upregulation of cyclooxygenase 2 (COX-2) mRNA expression and increased secretion of PGE2. Importantly, PGE2 causes heterologous ß2-AR desensitization and reduces cAMP production in response to short-acting (salbutamol) and long-acting (formoterol) ß2-agonists. Thus, bacterial infectious stimuli act in a PGE2-dependent manner to severely curtail the beneficial actions of ß2-agonists. The impact of ß2-AR desensitization is demonstrated by reduced gene expression of the critical anti-inflammatory molecule MKP-1 in response to ß2-agonists, as well as impaired bronchodilation in a mouse lung slices. Conclusions Taken together, our results show that, like viruses, bacteria induce prostanoid-dependent ß2-AR desensitization on ASM cells. Notably, COX-2 inhibition with the specific inhibitor celecoxib represses PGE2 secretion, presenting a feasible pharmacological option for treatment of infectious exacerbation in asthma in the future.
Jaffar, J, Unger, S, Corte, TJ, Keller, M, Wolters, PJ, Richeldi, L, Cerri, S, Prêle, CM, Hansbro, PM, Argraves, WS, Oliver, RA, Oliver, BG, Black, JL & Burgess, JK 2014, 'Fibulin-1 predicts disease progression in patients with idiopathic pulmonary fibrosis.', Chest, vol. 146, no. 4, pp. 1055-1063.View/Download from: Publisher's site
Background The underlying mechanisms of idiopathic pulmonary fibrosis (IPF) are unknown. This progressive disease has high mortality rates and current models for prediction of mortality have limited value in identifying which patients will progress. We previously showed that the glycoprotein fibulin-1 is involved in enhanced proliferation and wound repair by mesenchymal cells, thus may contribute to lung fibrosis in IPF. Methods Serum, lung tissue and lung function values were obtained from four independent locations (Sydney and Perth, Australia, San Francisco, USA and Modena, Italy). Patients with IPF were followed for a minimum of one year and progression was defined as a significant decline in lung function or death. Primary parenchymal lung fibroblasts of 15 patients with and without IPF were cultured under non-stimulatory conditions. Fibulin-1 levels in serum and secreted or deposited by fibroblasts were measured by western blot and in lung tissue by immunohistochemistry. Results Serum fibulin-1 levels were increased in patients with IPF compared to subjects without lung disease (p=0.006). Furthermore, tissue fibulin-1 levels were increased in patients with IPF (p=0.02) and correlated negatively with lung function (r=-0.9, p<0.05). Primary parenchymal fibroblasts from patients with IPF produced more fibulin-1 than those from subjects without IPF (p<0.05). Finally, serum fibulin-1 levels at first blood draw predicted disease progression in IPF within 1 year (AUC 0.71, 95%CI 0.57 0.86, p=0.012). Conclusions Fibulin-1 is a novel potential biomarker for disease progression IPF and raise the possibility that it could be used as a target for the development of new treatments.
Grafton, K, Moir, L, Black, J, Hansbro, N, Hansbro, P, Burgess, J & Oliver, BG 2014, 'LF-15 & T7, Synthetic Peptides Derived from Tumstatin, Attenuate Aspects of Airway Remodelling in a Murine Model of Chronic OVA-Induced Allergic Airway Disease', PLoS ONE, vol. 9, no. 1, pp. 1-6.View/Download from: UTS OPUS or Publisher's site
Background: Tumstatin is a segment of the collagen-IV protein that is markedly reduced in the airways of asthmatics. Tumstatin can play an important role in the development of airway remodelling associated with asthma due to its anti-angiogenic propertie
Krimmer, D, Ichimaru, Y, Burgess, J, Black, J & Oliver, BG 2013, 'Exposure to Biomass Smoke Extract Enhances Fibronectin Release from Fibroblasts', Plos One, vol. 8, no. 12.View/Download from: UTS OPUS or Publisher's site
COPD induced following biomass smoke exposure has been reported to be associated with a more fibrotic phenotype than cigarette smoke induced COPD. This study aimed to investigate if biomass smoke induced extracellular matrix (ECM) protein production from
Keglowich, L, Roth, M, Philippova, M, Resink, T, Tjin, G, Oliver, BG, Lardinois, D, Dessus-babus, S, Gosens, R, Haack, K, Tamm, M & Borger, P 2013, 'Bronchial Smooth Muscle Cells of Asthmatics Promote Angiogenesis through Elevated Secretion of CXC-Chemokines (ENA-78, GRO-alpha, and IL-8)', Plos One, vol. 8, no. 12.View/Download from: UTS OPUS or Publisher's site
Background: Airway wall remodelling is a key pathology of asthma. It includes thickening of the airway wall, hypertrophy and hyperplasia of bronchial smooth muscle cells (BSMC), as well as an increased vascularity of the sub-epithelial cell layer. BSMC a
Van Ly, D, De Pedro, M, James, P, Morgan, L, Black, J, Burgess, J & Oliver, BG 2013, 'Inhibition of phosphodiesterase 4 modulates cytokine induction from toll like receptor activated, but not rhinovirus infected, primary human airway smooth muscle', Respiratory Research, vol. 14.View/Download from: UTS OPUS or Publisher's site
Background: Virus-induced exacerbations of Chronic Obstructive Pulmonary Disease (COPD) are a significant health burden and occur even in those receiving the best current therapies. Rhinovirus (RV) infections are responsible for half of all COPD exacerba
Hirota, J, Im, H, Rahman, M, Rumzhum, N, Manetsch, M, Pascoe, C, Bunge, K, Alkhouri, H, Oliver, BG & Ammit, A 2013, 'The Nucleotide-Binding Domain and Leucine-Rich Repeat Protein-3 Inflammasome Is Not Activated in Airway Smooth Muscle Upon Toll-Like Receptor-2 Ligation', American Journal Of Respiratory Cell And Molecular Biology, vol. 49, no. 4, pp. 517-524.View/Download from: UTS OPUS or Publisher's site
Inflammasomes have emerged as playing key roles in inflammation and innate immunity. A growing body of evidence has suggested that the nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome is important in chronic airway disease
Chen, L, Ge, Q, Black, J, Deng, L, Burgess, J & Oliver, BG 2013, 'Differential Regulation of Extracellular Matrix and Soluble Fibulin-1 Levels by TGF-beta(1) in Airway Smooth Muscle Cells', Plos One, vol. 8, no. 6.View/Download from: UTS OPUS or Publisher's site
Fibulin-1 (FBLN-1) is a secreted glycoprotein that is associated with extracellular matrix (ECM) formation and rebuilding. Abnormal and exaggerated deposition of ECM proteins is a hallmark of many fibrotic diseases, such as chronic obstructive pulmonary
Yeganeh, B, Xia, C, Movassagh, H, Koziol-white, C, Chang, Y, Al-alwan, L, Bourke, J & Oliver, BG 2013, 'Emerging mediators of airway smooth muscle dysfunction in asthma', Pulmonary Pharmacology & Therapeutics, vol. 26, no. 1, pp. 105-111.View/Download from: UTS OPUS or Publisher's site
Phenotypic changes in airway smooth muscle are integral to the pathophysiological changes that constitute asthma namely inflammation, airway wall remodelling and bronchial hyperresponsiveness. In vitro and in vivo studies have shown that the proliferativ
Im, H, Hirota, J, Rahman, M, Rumzhum, N, Manetsch, M, Pascoe, C, Oliver, BG & Ammit, A 2013, 'The NLRP3 inflammasome is not activated in airway smooth muscle upon TLR2 ligation', European Respiratory Journal, vol. 42, no. S57, pp. 559-559.
Inflammasomes have emerged as playing key roles in inflammation and innate immunity. A growing body of evidence has suggested that the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome is important in chronic airway diseases such as asthma and COPD. Inflammasome activation results, in part, in pro-IL-1ß processing and secretion of the pro-inflammatory cytokine IL-1ß. Because asthma exacerbations are associated with elevated levels of secreted IL-1ß we addressed whether the NLRP3 inflammasome is activated under in vitro conditions that mimic infectious exacerbation in asthma. Primary cultures of airway smooth muscle (ASM) cells were treated with infectious stimuli (mimicked using the TLR2 agonist Pam3CSK4, a synthetic bacterial lipopeptide). While Pam3CSK4 robustly upregulated ASM cytokine expression in response to TNFa and significantly enhanced IL-1ß mRNA expression, we were unable to detect IL-1ß in the cell supernatants. Thus, IL-1ß was not secreted and therefore unable to act in an autocrine manner to promote amplification of ASM inflammatory responses. Moreover, TLR2 ligation did not enhance NLRP3 mRNA expression in ASM cells, nor was NLRP3 protein detected in the airway smooth muscle layer of tracheal sections from human donors. In conclusion, these data demonstrate that enhanced synthetic function of ASM cells, induced by infectious exacerbation of airway inflammation, is NLRP3 inflammasome and IL-1ß-independent. Activation of NLRP3 inflammasome by invading pathogens may prove cell-type specific in exacerbation of airway inflammation in asthma.
Tan, X, Alrashdan, YA, Alkhouri, H, Oliver, BG, Armour, CL & Hughes, JM 2013, 'Airway smooth muscle CXCR3 ligand production: regulation by JAK-STAT1 and intracellular Ca2+', American Journal of Physiology - Lung Cellular and Molecular Physiology, vol. 304, no. 11, pp. 790-802.View/Download from: UTS OPUS or Publisher's site
In asthma, airway smooth muscle (ASM) chemokine (C-X-C motif) receptor 3 (CXCR3) ligand production may attract mast cells or T lymphocytes to the ASM, where they can modulate ASM functions. In ASM cells (ASMCs) from people with or without asthma, we aimed to investigate JAK-STAT1, JNK, and Ca2+ involvement in chemokine (C-X-C motif) ligand (CXCL)10 and CXCL11 production stimulated by interferon-?, IL-1ß, and TNF-a combined (cytomix). Confluent, growth-arrested ASMC were treated with inhibitors for pan-JAK (pyridone-6), JAK2 (AG-490), JNK (SP-600125), or the sarco(endo)plasmic reticulum Ca2+ATPase (SERCA) pump (thapsigargin), Ca2+ chelator (BAPTA-AM), or vehicle before and during cytomix stimulation for up to 24 h. Signaling protein activation as well as CXCL10/CXCL11 mRNA and protein production were examined using immunoblot analysis, real-time PCR, and ELISA, respectively. Cytomix-induced STAT1 activation was lower and CXCR3 ligand mRNA production was more sensitive to pyridone-6 and AG-490 in asthmatic than nonasthmatic ASMCs, but CXCL10/CXCL11 release was inhibited by the same proportion. Neither agent caused additional inhibition of release when used in combination with the JNK inhibitor SP-600125. Conversely, p65 NF-?B activation was higher in asthmatic than nonasthmatic ASMCs. BAPTA-AM abolished early CXCL10/CXCL11 mRNA production, whereas thapsigargin reduced it in asthmatic cells and inhibited CXCL10/CXCL11 release by both ASMC types. Despite these inhibitory effects, neither Ca2+ agent affected early activation of STAT1, JNK, or p65 NF-?B. In conclusion, intracellular Ca2+ regulated CXCL10/CXCL11 production but not early activation of the signaling molecules involved. In asthma, reduced ASM STAT1-JNK activation, increased NF-?B activation, and altered Ca2+ handling may contribute to rapid CXCR3 ligand production and enhanced inflammatory cell recruitment.
Beckett, EL, Stevens, RL, Jarnicki, AG, Kim, RY, Hanish, I, Hansbro, NG, Deane, A, Keely, S, Horvat, JC, Yang, M, Oliver, BG, van Rooijen, N, Inman, MD, Adachi, R, Soberman, RJ, Hamadi, S, Wark, PA, Foster, PS & Hansbro, PM 2013, 'A new short-term mouse model of chronic obstructive pulmonary disease identifies a role for mast cell tryptase in pathogenesis', JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, vol. 131, no. 3, pp. 752-+.View/Download from: UTS OPUS or Publisher's site
Faiz, A, Tjin, G, Harkness, L, Weckmann, M, Bao, S, Black, J, Oliver, BG & Burgess, J 2013, 'The Expression and Activity of Cathepsins D, H and K in Asthmatic Airways', Plos One, vol. 8, no. 3.View/Download from: UTS OPUS or Publisher's site
Tumstatin is an anti-angiogenic collagen IV alpha 3 fragment, levels of which are reduced in the airways of asthmatics. Its reduction may be due to the degradation by extracellular matrix (ECM) proteases. Cathepsins play a role in ECM remodelling, with c
Van Ly, D, Faiz, A, Jenkins, C, Crossett, B, Black, J, Mcparland, B, Burgess, J & Oliver, BG 2013, 'Characterising the Mechanism of Airway Smooth Muscle beta(2) Adrenoceptor Desensitization by Rhinovirus Infected Bronchial Epithelial Cells', Plos One, vol. 8, no. 2.View/Download from: Publisher's site
Rhinovirus (RV) infections account for approximately two thirds of all virus-induced asthma exacerbations and often result in an impaired response to beta 2 agonist therapy. Using an in vitro model of RV infection, we investigated the mechanisms underlyi
Van Ly, D, Burgess, JK, Brock, TG, Lee, TH, Black, JL & Oliver, BGG 2012, 'Prostaglandins but not leukotrienes alter extracellular matrix protein deposition and cytokine release in primary human airway smooth muscle cells and fibroblasts', AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, vol. 303, no. 3, pp. L239-L250.View/Download from: UTS OPUS or Publisher's site
Bosse, Y, Vagula, MC, Rawding, RS, Pun, M, Black, JL, Burgess, J, Oliver, B, Berger, P, Marthan, R & Adner, M 2012, 'Comments on Point:Counterpoint: Alterations in airway smooth muscle phenotype do/do not cause airway hyperresponsiveness in asthma.', Journal of applied physiology (Bethesda, Md. : 1985), vol. 113, no. 5, pp. 844-846.View/Download from: Publisher's site
Weckmann, M, Moir, L, Heckman, C, Black, J, Oliver, BG & Burgess, J 2012, 'Lamstatin - a novel inhibitor of lymphangiogenesis derived from collagen IV', Journal of Cellular and Molecular Medicine, vol. 16, no. 12, pp. 3062-3073.View/Download from: UTS OPUS or Publisher's site
The lymphatic system is essential for the maintenance of tissue homeostasis and immunity. Its dysfunction in disease (such as lymphangioleiomyomatosis) can lead to chylous effusions, oedema or dissemination of malignant cells. Collagen IV has six a chain
Ge, Q, Moir, LM, Trian, T, Niimi, K, Poniris, M, Shepherd, PR, Black, JL, Oliver, BG & Burgess, JK 2012, 'The phosphoinositide 3'-kinase p110d modulates contractile protein production and IL-6 release in human airway smooth muscle', Journal of Cellular Physiology, vol. 227, no. 8, pp. 3044-3052.View/Download from: UTS OPUS or Publisher's site
Transforming growth factor (TGF) ß1 increases pro-inflammatory cytokines and contractile protein expression by human airway smooth muscle (ASM) cells, which could augment airway inflammation and hyperresponsiveness. Phosphoinositide 3' kinase (PI3K) is one of the signaling pathways implicated in TGFß1 stimulation, and may be altered in asthmatic airways. This study compared the expression of PI3K isoforms by ASM cells from donors with asthma (A), chronic obstructive pulmonary disease (COPD), or neither disease (NA), and investigated the role of PI3K isoforms in the production of TGFß1 induced pro-inflammatory cytokine and contractile proteins in ASM cells. A cells expressed higher basal levels of p110d mRNA compared to NA and COPD cells; however COPD cells produced more p110d protein. TGFß1 increased 110d mRNA expression to the same extent in the three groups. Neither the p110d inhibitor IC87114 (1, 10, 30?µM), the p110ß inhibitor TGX221 (0.1, 1, 10?µM) nor the PI3K pan inhibitor LY294002 (3, 10?µM) had any effect on basal IL-6, calponin or smooth muscle a-actin (a-SMA) expression. However, TGFß1 increased calponin and a-SMA expression was inhibited by IC87114 and LY294002 in all three groups. IC87114, TGX221, and LY294002 reduced TGFß1 induced IL-6 release in a dose related manner in all groups of ASM cells. PI3K p110d is important for TGFß1 induced production of the contractile proteins calponin and a-SMA and the proinflammatory cytokine IL-6 in ASM cells, and may therefore be relevant as a potential therapeutic target to treat both inflammation and airway remodeling.
Tan, X, Khalil, N, Tesarik, C, Vanapalli, K, Yaputra, V, Alkhouri, H, Oliver, BG, Armour, C & Hughes, J 2012, 'Th1 cytokine-induced syndecan-4 shedding by airway smooth muscle cells is dependent on mitogen-activated protein kinases', American Journal Of Physiology-Lung Cellular And Molecular Physiology, vol. 302, no. 7, pp. 1700-1710.View/Download from: UTS OPUS or Publisher's site
Tan X, Khalil N, Tesarik C, Vanapalli K, Yaputra V, Alkhouri H, Oliver BG, Armour CL, Hughes JM. Th1 cytokine-induced syndecan-4 shedding by airway smooth muscle cells is dependent on mitogen-activated protein kinases. Am J Physiol Lung Cell Mol Physiol
Baraket, M, Oliver, BG, Burgess, J, Lim, S, King, G & Black, J 2012, 'Is low dose inhaled corticosteroid therapy as effective for inflammation and remodeling in asthma? A randomized, parallel group study', Respiratory Research, vol. 13.View/Download from: UTS OPUS or Publisher's site
Background: While most of the clinical benefits of inhaled corticosteroid (ICS) therapy may occur at low doses, results of dose-ranging studies are inconsistent. Although symptom/lung function response to low and high dose ICS medication is comparable, i
Borger, P, Oliver, B, Heijink, I & Hardavella, G 2012, 'Beyond the Immune System: The Role of Resident Cells in Asthma and COPD.', Journal of allergy, vol. 2012, p. 968039.View/Download from: UTS OPUS or Publisher's site
Krimmer, D, Burgess, JK, Wooi, TK, Black, JL & Oliver, BG 2012, 'Matrix Proteins from Smoke-Exposed Fibroblasts Are Pro-proliferative', American Journal of Respiratory Cell and Molecular Biology, vol. 46, no. 1, pp. 34-39.View/Download from: UTS OPUS or Publisher's site
Airway remodeling decreases lung function in chronic obstructive pulmonary disease (COPD). Extracellular matrix (ECM) deposition is increased in remodeled airways and drives cellular processes of proliferation, migration, and inflammation. We investigated the role of cigarette smoke in altering the ECM deposited from human lung fibroblasts. Lung fibroblasts isolated from patients with COPD or other lung disease were exposed to cigarette smoke extract (CSE) and 5 ng/ml transforming growth factor-ß1 for 72 hours; in some experiments, inhibitors of signaling molecules were added. Deposition of perlecan, fibronectin, and elastin were measured by ELISA, as was release of IL-8 and IL-13. Unstimulated fibroblast cells were reseeded onto deposited matrix and assessed for proliferation and cytokine release. CSE (5%) increased deposition of fibronectin and perlecan from only COPD fibroblasts. Fibronectin and perlecan deposition was attenuated by addition of the NF-?B inhibitor, BMS-345541, and the signal transduction and activator of transcription-1/3 inhibitor, pyridone 6, respectively. CSE (5%) increased IL-8 release from COPD fibroblasts more than non-COPD fibroblasts. This increase was attenuated by BMS-345541. Matrix deposited after 5% CSE stimulation increased proliferation of fibroblasts, but did not alter cytokine release. ECM produced from COPD fibroblasts after CSE exposure has proproliferative effects. Thus, the ECM in patients with COPD may create an environment that promotes airway remodeling.
Ichimaru, Y, Krimmer, D, Burgess, JK, Black, JL & Oliver, BG 2012, 'TGF-beta enhances deposition of perlecan from COPD airway smooth muscle', American Journal of Physiology - Lung Cellular and Molecular Physiology, vol. 302, no. 3, pp. 325-333.View/Download from: UTS OPUS or Publisher's site
Chronic obstructive pulmonary disease (COPD) and asthma are characterized by irreversible remodeling of the airway walls, including thickening of the airway smooth muscle layer. Perlecan is a large, multidomain, proteoglycan that is expressed in the lungs, and in other organ systems, and has been described to have a role in cell adhesion, angiogenesis, and proliferation. This study aimed to investigate functional properties of the different perlecan domains in relation to airway smooth muscle cells (ASMC). Primary human ASMC obtained from donors with asthma (n = 13), COPD (n = 12), or other lung disease (n = 20) were stimulated in vitro with 1 ng/ml transforming growth factor-ß1 (TGF-ß1) before perlecan deposition and cytokine release were analyzed. In some experiments, inhibitors of signaling molecules were added. Perlecan domains IV were seeded on tissue culture plates at 10 µg/ml with 1 µg/ml collagen I as a control. ASM was incubated on top of the peptides before being analyzed for attachment, proliferation, and wound healing. TGF-ß1 upregulated deposition of perlecan by ASMC from COPD subjects only. TGF-ß1 upregulated release of IL-6 into the supernatant of ASMC from all subjects. Inhibitors of SMAD and JNK signaling molecules decreased TGF-ß1-induced perlecan deposition by COPD ASMC. Attachment of COPD ASMC was upregulated by collagen I and perlecan domains IV and V, while perlecan domain II upregulated attachment only of asthmatic ASMC. Seeding on perlecan domains did not increase proliferation of any ASMC type. TGF-ß1-induced perlecan deposition may enhance attachment of migrating ASMC in vivo and thus may be a mechanism for ASMC layer hypertrophy in COPD.
Niimi, K, Ge, Q, Moir, LM, Ammit, A, Trian, T, Burgess, JK, Black, JL & Oliver, BG 2012, 'Beta2-Agonists upregulate PDE4 mRNA but not protein or activity in human airway smooth muscle cells from asthmatic and nonasthmatic volunteers', American Journal of Physiology - Lung Cellular and Molecular Physiology, vol. 302, no. 3, pp. 334-342.View/Download from: UTS OPUS or Publisher's site
ß2-Adrenergic receptor (ß2AR) agonists induce airway relaxation via cAMP. Phosphodiesterase (PDE)s degrade and regulate cAMP, and in airway smooth muscle (ASM) cells PDE4D degrades cAMP. Long-acting ß2-agonists are now contraindicated as monotherapy for asthma, and increased PDE4D has been speculated to contribute to this phenomenon. In this study we investigated the expression of PDE4D in asthmatic and nonasthmatic ASM cells and its regulation by formoterol and budesonide. Primary ASM cells from people with or without asthma were stimulated with transforming growth factor (TGF)-ß1, formoterol, and/or budesonide. PDE4D mRNA was assessed by real-time PCR, or PCR to assess splice variant production. PDE4D protein was assessed by Western blotting, and we investigated the effect of formoterol on cAMP production and PDE activity. Interleukin (IL)-6 was assessed using ELISA. PDE4D mRNA was dose dependently upregulated by formoterol, with a single splice variant, PDE4D5, present. Formoterol did not induce PDE4D protein at time points between 3 to 72 h, whereas it did induce and increase IL-6 secretion. We pretreated cells with actinomycin D and a proteasome inhibitor, MG132, and found no evidence of alterations in mRNA, protein expression, or degradation of PDE4D. Finally PDE activity was not altered by formoterol. This study shows, for the first time, that PDE4D5 is predominantly expressed in human ASM cells from people with and without asthma and that formoterol does not upregulate PDE4D protein production. This leads us to speculate that continual therapy with ß2AR agonists is unlikely to cause PDE4-mediated tachyphylaxis.
Essilfie, A, Simpson, J, Dunkley, M, Morgan, L, Oliver, BG, Gibson, P, Foster, P & Hansbro, P 2012, 'Combined Haemophilus influenzae respiratory infection and allergic airways disease drives chronic infection and features of neutrophilic asthma', Thorax, vol. 67, no. 7, pp. 588-599.View/Download from: UTS OPUS or Publisher's site
Background 20-30% of patients with asthma have neutrophilic airway inflammation and reduced responsiveness to steroid therapy. They often have chronic airway bacterial colonisation and Haemophilus influenzae is one of the most commonly isolated bacteria.
Kuo, C, Lim, S, King, NJC, Johnston, SL, Burgess, JK, Black, JL & Oliver, BG 2011, 'Rhinovirus infection induces extracellular matrix protein deposition in asthmatic and nonasthmatic airway smooth muscle cells', AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, vol. 300, no. 6, pp. L951-L957.View/Download from: UTS OPUS or Publisher's site
Trian, T, Burgess, JK, Niimi, K, Moir, LM, Ge, Q, Berger, P, Liggett, SB, Black, JL & Oliver, BG 2011, 'b2-Agonist Induced cAMP Is Decreased in Asthmatic Airway Smooth Muscle Due to Increased PDE4D', PLoS One, vol. 6, no. 5, pp. 1-7.View/Download from: UTS OPUS or Publisher's site
Background and Objective: Asthma is associated with airway narrowing in response to bronchoconstricting stimuli and increased airway smooth muscle (ASM) mass. In addition, some studies have suggested impaired b-agonist induced ASM relaxation in asthmatics, but the mechanism is not known. Objective: To characterize the potential defect in b-agonist induced cAMP in ASM derived from asthmatic in comparison to non-asthmatic subjects and to investigate its mechanism. Methods: We examined b2-adrenergic (b2AR) receptor expression and basal b-agonist and forskolin (direct activator of adenylyl cyclase) stimulated cAMP production in asthmatic cultured ASM (n = 15) and non-asthmatic ASM (n = 22). Based on these results, PDE activity, PDE4D expression and cell proliferation were determined. Results: In the presence of IBMX, a pan PDE inhibitor, asthmatic ASM had ,50% lower cAMP production in response to isoproterenol, albuterol, formoterol, and forskolin compared to non-asthmatic ASM. However when PDE4 was specifically inhibited, cAMP production by the agonists and forskolin was normalized in asthmatic ASM. We then measured the amount and activity of PDE4, and found ,2-fold greater expression and activity in asthmatic ASM compared to non-asthmatic ASM. Furthermore, inhibition of PDE4 reduced asthmatic ASM proliferation but not that of non-asthmatic ASM. Conclusion: Decreased b-agonist induced cAMP in ASM from asthmatics results from enhanced degradation due to increased PDE4D expression. Clinical manifestations of this dysregulation would be suboptimal b-agonist-mediated bronchodilation and possibly reduced control over increasing ASM mass. These phenotypes appear to be ``hard-wired into ASM from asthmatics, as they do not require an inflammatory environment in culture to be observed.
Moir, L, Trian, T, Ge, Q, Shepherd, P, Burgess, J, Oliver, BG & Black, J 2011, 'Phosphatidylinositol 3-Kinase Isoform-Specific Effects in Airway Mesenchymal Cell Function', Journal Of Pharmacology And Experimental Therapeutics, vol. 337, no. 2, pp. 557-566.View/Download from: UTS OPUS or Publisher's site
The phosphatidylinositol 3-kinase (PI3K) signal transduction pathway is implicated in the airway remodeling associated with asthma. The class IA PI3K isoforms are known to be activated by growth factors and cytokines. Because this pathway is a possible s
Kuo, C, Lim, S, King, N, Bartlett, N, Walton, R, Zhu, J, Glanville, N, Aniscenko, J, Johnston, S, Burgess, J, Black, J & Oliver, BG 2011, 'Rhinovirus infection induces expression of airway remodelling factors in vitro and in vivo', Respirology, vol. 16, no. 2, pp. 367-377.View/Download from: UTS OPUS or Publisher's site
Background and objective: A hallmark of asthma is airway remodelling, which includes increased deposition of extracellular matrix (ECM) protein. Viral infections may promote the development of asthma and are the most common causes of asthma exacerbations
Van Ly, D, King, NJ, Moir, LM, Burgess, JK, Black, JL & Oliver, BG 2011, 'Effects of ß2 Agonists, Corticosteroids, and Novel Therapies on Rhinovirus-Induced Cytokine Release and Rhinovirus Replication in Primary Airway Fibroblasts', Journal of Allergy, vol. 2011.View/Download from: UTS OPUS or Publisher's site
Rhinovirus-(RV-) induced asthma exacerbations account for high asthma-related health costs and morbidity in Australia. The cellular mechanism underlying this pathology is likely the result of RV-induced nuclear-factor-kappa-B-(NF-?B-) dependent inflammation. NF-?B may also be important in RV replication as inhibition of NF-?B inhibits replication of other viruses such as human immunodeficiency virus and cytomegalovirus. To establish the role of NF-?B inhibitors in RV-induced IL- 6 and IL-8 and RV replication, we used pharmacological inhibitors of NF-?B, and steroids and/or ß2 agonists were used for comparison. Primary human lung fibroblasts were infected with RV-16 in the presence of NF-?B inhibitors: BAY-117085 and dimethyl fumarate; ß2 agonist: salmeterol; and/or corticosteroids: dexamethasone; fluticasone. RV-induced IL-6 and IL-8 and RV replication were assessed using ELISAs and virus titration assays. RV replicated and increased IL-6 and IL-8 release. Salmeterol increased, while dexamethasone and fluticasone decreased RV-induced IL-6 and IL-8 (P < 0.05). The NF-?B inhibitor BAY-117085 inhibited only RV-induced IL-6 (P < 0.05) and dimethyl fumarate did not alter RV-induced IL-6 and IL-8. Dimethylfumarate increased RV replication whilst other drugs did not alter RV replication. These data suggest that inhibition of NF-?B alone is unlikely to be an effective treatment compared to current asthma therapeutics.
Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterised by chronic bronchitis, largely irreversible remodelling of the small airways, and emphysematous destruction of the alveoli. COPD is projected to be the third leading cause of death worldwide by 2020. COPD often results from prolonged exposure to irritants such as cigarette smoke or inhaled particulates. Current pharmacotherapies for COPD are unable to reverse the pathological changes of this disease, and this is partially due to a limited understanding of the intricate mechanisms by which chronic exposure lead to the different pathological components of COPD. This review examines how the mechanisms that underlie various components of COPD can be modelled in vitro, specifically using cigarette smoke extract with cells cultured from primary human lung tissue, and how the effectiveness of current and novel pharmacotherapies on successfully attenuating these pathological changes can also be examined in vitro.
moir, L, ng, H, Poniris, M, santa, T, Burgess, JK, Oliver, BG, krymskaya, V & Black, JL 2011, 'Doxycycline inhibits matrix metalloproteinase-2 secretion from TSC2-null mouse embryonic fibroblasts and lymphangioleiomyomatosis cells', British Journal Of Pharmacology, vol. 164, no. 1, pp. 83-92.View/Download from: UTS OPUS or Publisher's site
BACKGROUND AND PURPOSE Lymphangioleiomyomatosis (LAM) is characterized by the abnormal growth of smooth muscle-like cells (LAM cells) and cystic destruction of the lung parenchyma. LAM cell-derived matrix metalloproteinases (MMPs) are thought to play a prominent role in the tissue destruction. The aim of this study was to determine whether doxycycline, a known MMP inhibitor, can inhibit LAM cell proliferation or mitochondrial function and/or modulate MMPs and their tissue inhibitors (TIMPs). EXPERIMENTAL APPROACH Wild-type and tuberous sclerosis complex-2 (TSC2)-null mouse embryonic fibroblasts (MEFs) were cultured in DMEM containing 10% fetal bovine serum (FBS). Human LAM cells were derived from the lungs of LAM patients and airway smooth muscle cells from control subjects. Cells were stimulated with FBS with or without doxycycline for up to 9 days. Proliferation was assessed by manual cell counts and MTT assay, MMP production by zymography and ELISA, and TIMP production using ELISA. KEY RESULTS Doxycycline did not change FBS-induced proliferation in MEFs or human cells. However, doxycycline did reduce metabolic activity of both wild-type and TSC2-null MEFs and LAM cells, but had no effect on control cells. Furthermore, doxycycline reduced MMP-2 from MEFs and decreased active-MMP-2 from LAM cells but had no effect on TIMP-1 and TIMP-2 from human LAM cells. CONCLUSIONS AND IMPLICATIONS Doxycycline decreased MMP levels and cell metabolic activity, which raises the possibility of therapeutic efficacy in LAM.
Ge, Q, Moir, L, Black, J, Oliver, BG & Burgess, J 2010, 'TGF beta 1 Induces IL-6 and Inhibits IL-8 Release in Human Bronchial Epithelial Cells: The Role of Smad2/3', Journal of Cellular Physiology, vol. 225, no. 3, pp. 846-854.View/Download from: UTS OPUS or Publisher's site
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) beta 1, all of which are elevated in asthma
Trian, T, Moir, L, Ge, Q, Burgess, J, Kuo, C, King, N, Reddel, H, Black, J, Oliver, BG & Mcparland, B 2010, 'Rhinovirus-Induced Exacerbations of Asthma How Is the beta(2)-Adrenoceptor Implicated?', American Journal Of Respiratory Cell And Molecular Biology, vol. 43, no. 2, pp. 227-233.View/Download from: UTS OPUS or Publisher's site
Rhinovirus (RV) infections are the major cause of asthma exacerbations in children and adults. Under normal circumstances, asthmatic airway obstruction improves spontaneously or characteristically briskly in response to inhaled beta(2)-adrenergic recepto
Lau, J, Oliver, BG, Moir, L, Black, J & Burgess, J 2010, 'Differential expression of peroxisome proliferator activated receptor gamma and cyclin D1 does not affect proliferation of asthma- and non-asthma-derived airway smooth muscle cells', Respirology, vol. 15, no. 2, pp. 303-312.View/Download from: UTS OPUS or Publisher's site
Background and objective: Airway remodelling involves thickening of the airway smooth muscle (ASM) bulk. Proliferation of asthma-derived ASM cells is increased in vitro, but underlying mechanisms remain unknown. Peroxisome proliferators activated recepto
Ge, Q, Moir, LM, Black, JL, Oliver, BG & Burgess, JK 2010, 'TGFß1 induces IL-6 and inhibits IL-8 release in human bronchial epithelial cells: The role of Smad2/3', Journal of Cellular Physiology, vol. 225, no. 3, pp. 846-854.View/Download from: UTS OPUS or Publisher's site
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) ß1, all of which are elevated in asthmatic airways. This study examines the signaling pathways leading to TGFß1 induced IL-6 and IL-8 in primary HBE cells from asthmatic and non-asthmatic volunteers. HBE cells were stimulated with TGFß1 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. TGFß1 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 TGFß1 induced IL-6 in both cell groups. TGFß1 induced Smad2 phosphorylation, and blockade of Smad2/3 prevented both the TGFß1 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 TGFß1 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
Lau, J, Oliver, BG, Baraket, M, Beckett, E, Hansbro, N, Moir, L, Wilton, S, Williams, C, Foster, P, Hansbro, P, Black, J & Burgess, J 2010, 'Fibulin-1 Is Increased in Asthma - A Novel Mediator of Airway Remodeling?', Plos One, vol. 5, no. 10.View/Download from: UTS OPUS or Publisher's site
Background: The extracellular matrix is a dynamic and complex network of macromolecules responsible for maintaining and influencing cellular functions of the airway. The role of fibronectin, an extracellular matrix protein, is well documented in asthma.
Burgess, J, Boustany, S, Moir, L, Weckmann, M, Lau, J, Grafton, K, Baraket, M, Hansbro, P, Hansbro, N, Foster, P, Black, J & Oliver, BG 2010, 'Reduction of Tumstatin in Asthmatic Airways Contributes to Angiogenesis, Inflammation, and Hyperresponsiveness', American Journal Of Respiratory And Critical Care Medicine, vol. 181, no. 2, pp. 106-115.View/Download from: UTS OPUS or Publisher's site
Rationale Angiogenesis is a prominent feature of remodeling in asthma. Many proangiogenic factors are up-regulated in asthma, but little is known about levels of endogenous antiangiogenic agents. Collagen IV is decreased in the airway basement membrane i
Weckmann, M, Trian, T & Oliver, BGG 2009, 'Reconstruction is not renovation - The role of remodeling in asthma', Journal of Asthma and Allergy, no. 2, pp. 33-42.
The chronicity of asthma results not only in persistent lung inflammation but also in changes in structure and composition of this vital organ. These changes are most commonly referred to as remodeling, and include epithelial dysplasia, angiogenesis, changes in the extracellular matrix and increased smooth muscle mass. In this review we summarize recent findings on the contribution of remodeling to the pathological phenotype of asthma. We discuss how and why current treatment (such as corticosteroids) options fail to adequately treat remodeling. © 2009 Weckmann et al, publisher and licensee Dove Medical Press Ltd.
Black, J, Oliver, BG & Roth, M 2009, 'Molecular Mechanisms of Combination Therapy With Inhaled Corticosteroids and Long-Acting beta-Agonists', Chest, vol. 136, no. 4, pp. 1095-1100.View/Download from: UTS OPUS or Publisher's site
The treatment of asthma relies on the use of the following two major drug classes: beta(2)-agonists, both short acting and long acting; and corticosteroids (CSs). Although the properties of each drug class are well described, their use in combination del
Burgess, J, Ceresa, C, Johnson, S, Kanabar, V, Moir, L, Nguyen, T, Oliver, BG, Schuliga, M & Ward, J 2009, 'Tissue and matrix influences on airway smooth muscle function', Pulmonary Pharmacology & Therapeutics, vol. 22, no. 5, pp. 379-387.View/Download from: UTS OPUS or Publisher's site
Asthma is characterized by structural changes in the airways - airway remodelling. These changes include an increase in the bulk of the airway smooth muscle (ASM) and alterations in the profile of extracellular matrix (ECM) proteins in the airway wall. T
Fukuyama, S, Nakano, T, Matsumoto, T, Oliver, BG, Burgess, J, Moriwaki, A, Tanaka, K, Kubo, M, Hoshino, T, Tanaka, H, Mckenzie, A, Matsumoto, K, Aizawa, H, Nakanishi, Y, Yoshimura, A, Black, J & Inoue, H 2009, 'Pulmonary Suppressor of Cytokine Signaling-1 Induced by IL-13 Regulates Allergic Asthma Phenotype', American Journal Of Respiratory And Critical Care Medicine, vol. 179, no. 11, pp. 992-998.View/Download from: UTS OPUS or Publisher's site
Rationale: Th2 cytokines play an important role in allergic diseases. These cytokines activate signal transduction pathways, including Janus kinase/signal transducer and activator of transcription (STAT) signaling. Although the suppressor of cytokine sig
Krimmer, D, Loseli, M, Hughes, JM, Oliver, BG, Moir, LM, Hunt, NH, Black, JL & Burgess, JK 2009, 'CD40 and OX40 ligand are differentially regulated on asthmatic airway smooth muscle', Allergy, vol. 64, no. 7, pp. 1074-1082.View/Download from: UTS OPUS or Publisher's site
Background: CD40 and OX40 Ligand (OX40L) are cell-surface molecules expressed on airway smooth muscle (ASM) that can enhance inflammatory cell activation and survival. The aim of this study was to examine the effect of tumour necrosis factor-alpha (TNF-a) and interferon-gamma (IFN-?) on ASM CD40 and OX40L expression. Methods: CD40 and OX40L expression on human ASM cells from asthmatic and nonasthmatic donors following stimulation with TNF-a and/or IFN-? was measured using cell-surface enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Involvement of signalling pathway was investigated with pharmacological inhibitors. Soluble TNF receptor levels were quantified by ELISA. Results: Interferon-? and TNF-a synergistically increased CD40 expression to a greater extent on asthmatic than on nonasthmatic ASM. In contrast, IFN-? reduced TNF-a-induced OX40L expression to a similar extent in both cell types. TNF-a and IFN-? induced CD40 via nuclear factor-?B (NF-?B) and signal transducer and activator of transcription-3 in both cell types and modulated OX40L via NF-?B and c-Jun N terminal kinase in nonasthmatic cells. Similar effects on the induction of OX40L in asthmatic cells were seen with NF-?B, but these were not statistically significant. The reduced OX40L expression with TNF-a and IFN-? involved extracellular regulated kinase 1/2 activation. Conclusion: Asthmatic ASM may modulate airway inflammation locally by increasing CD40 and OX40L expression in response to cytokines. IFN-? may regulate ASM pro-inflammatory actions by differentially modulating ASM CD40 and OX40L expression.
p, S, merfort, I, Hughes, MJ, Oliver, BG, Tamm, M & Roth, M 2009, 'Dimethylfumarate inhibits NFkB function at multiple levels to limit airway smooth muscle cell cytokine secretion', American Journal of Physiology - Lung Cellular and Molecular Physiology, vol. 297, no. 2, pp. 326-339.View/Download from: UTS OPUS or Publisher's site
The antipsoriatic dimethylfumarate (DMF) has been anecdotically reported to reduce asthma symptoms and to improve quality of life of asthma patients. DMF decreases the expression of proinflammatory mediators by inhibiting the transcription factor NF-?B and might therefore be of interest for the therapy of inflammatory lung diseases. In this study, we determined the effect of DMF on platelet-derived growth factor (PDGF)-BB- and TNFa-induced asthma-relevant cytokines and NF-?B activation by primary human asthmatic and nonasthmatic airway smooth muscle cells (ASMC). Confluent nonasthmatic and asthmatic ASMC were incubated with DMF (0.1100 µM) and/or dexamethasone (0.00010.1 µM), NF-?B p65 siRNA (100 nM), the NF-?B inhibitor helenalin (1 µM) before stimulation with PDGF-BB or TNFa (10 ng/ml). Cytokine release was measured by ELISA. NF-?B, mitogen and stress-activated kinase (MSK-1), and CREB activation was determined by immunoblotting and EMSA. TNFa-induced eotaxin, RANTES, and IL-6 as well as PDGF-BB-induced IL-6 expression was inhibited by DMF and by dexamethasone from asthmatic and nonasthmatic ASMC, but the combination of both drugs showed no glucocorticoid sparing effect in either of the two groups. NF-?B p65 siRNA and/or the NF-?B inhibitor helenalin reduced PDGF-BB- and TNFa-induced cytokine expression, suggesting the involvement of NF-?B signaling. DMF inhibited TNFa-induced NF-?B p65 phosphorylation, NF-?B nuclear entry, and NF-?B-DNA complex formation, whereas PDGF-BB appeared not to activate NF-?B within 60 min. Both stimuli induced the phosphorylation of MSK-1, NF-?B p65 at Ser276, and CREB, and all were inhibited by DMF. These data suggest that DMF downregulates cytokine secretion not only by inhibiting NF-?B but a wider range of NF-?B-linked signaling proteins, which may explain its potential beneficial effect in asthma.
Stelzer-braid, S, Oliver, BG, Blazey, A, Argent, E, Newsome, T, Rawlinson, W & Tovey, E 2009, 'Exhalation of Respiratory Viruses by Breathing, Coughing, and Talking', Journal of Medical Virology, vol. 81, no. 9, pp. 1674-1679.View/Download from: UTS OPUS or Publisher's site
There is a lack of quantitative information about the generation of virus aerosols by infected subjects. The exhaled aerosols generated by coughing, talking, and breathing were sampled in 50 subjects using a novel mask, and analyzed using PCR for nine re
Oliver, BG, Lim, S, Wark, P, Laza-Stanca, V, King, N, Black, JL, Burgess, J, Roth, M & Johnston, SL 2008, 'Rhinovirus exposure impairs immune responses to bacterial products in human alveolar macrophages', Thorax, vol. 63, no. 6, pp. 519-525.View/Download from: UTS OPUS or Publisher's site
Background: Rhinovirus infection is responsible for considerable morbidity and mortality as the major cause of exacerbations of asthma, and is also known to induce exacerbations of cystic fibrosis and chronic obstructive pulmonary disease. Exacerbations of these diseases are also frequently associated with bacterial and atypical bacterial infection. Alveolar macrophages are the major immune cells in the airways and are important in defence against bacterial infections. Methods: The authors investigated whether rhinovirus modifies cytokine release, the pattern recognition receptor expression and phagocytosis by human alveolar macrophages in response to bacterial products. Results: Viable rhinovirus was detected in macrophages up to 3 days after exposure and viral RNA expression persisted for 10 days. Infectious but not UV inactivated rhinovirus increased tumour necrosis factor a (TNFa) and interleukin (IL)8 release by macrophages. In contrast, infectious rhinovirus impaired lipopolysaccharide and lipoteichoic acid induced TNFa and IL8 secretion by macrophages. Rhinovirus induced impairment of macrophage antibacterial immune responses did not involve IL10, prostaglandin E2 or downregulation of Toll-like receptor 2. Furthermore, the macrophage phagocytic response to labelled bacterial particles, but not to latex beads, was impaired. Conclusion: The authors have identified impairment of cytokine responses to bacterial lipopolysaccharide and lipoteichoic acid by alveolar macrophages in response to infectious rhinovirus. Virus induced impairment of antibacterial host defence has important implications in the pathogenesis of exacerbations of respiratory diseases.
Huynh, K, Oliver, BG, Stelzer, S, Rawlinson, W & Tovey, E 2008, 'A new method for sampling and detection of exhaled respiratory virus aerosols', Clinical Infectious Diseases, vol. 46, no. 1, pp. 93-95.View/Download from: UTS OPUS or Publisher's site
We have developed a mask sampler for exhaled respiratory viruses. Among a group of 9 patients with cold symptoms who had virus-positive nasal mucus specimens, as analyzed by multiplexed polymerase chain reaction, virus-positive mask samples were obtained
Ammit, AJ, Moir, LM, Oliver, BG, Hughes, JM, Alkhouri, H, Ge, Q, Burgess, JK, Black, JL & Roth, M 2007, 'Effect of IL-6 trans-signaling on the pro-remodeling phenotype of airway smooth muscle', AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, vol. 292, no. 1, pp. L199-L206.View/Download from: Publisher's site
Matsumoto, H, Moir, L, Oliver, BG, Burgess, J, Roth, M, Black, J & Mcparland, B 2007, 'Comparison of gel contraction mediated by airway smooth muscle cells from patients with and without asthma', Thorax, vol. 62, no. 10, pp. 848-854.View/Download from: Publisher's site
Backgrounds: Exaggerated bronchial constriction is the most significant and life threatening response of patients with asthma to inhaled stimuli. However, few studies have investigated the contractility of airway smooth muscle (ASM) from these patients.
The airway smooth muscle is the key determinant of airway narrowing in asthma but its function in the absence of disease is unknown. Evidence for an intrinsic abnormality in the muscle in asthma is only just emerging. The airway smooth muscle is not merely a contractile cell, but also one which determines the composition of, and interacts with the extracellular matrix, and which may participate in inflammatory and allergic reactions and viral infections. The reason for the differences which have been observed in the in vitro properties of airway smooth muscle derived from asthmatic individuals may result from an inherent "supercontractility", an increased tendency to proliferate due to the absence of an inhibitory transcription factor C/EBP-α, the influence of an altered extracellular matrix and/or a decrease in release of factors such as PGE2 which would under normal circumstances inhibit both proliferation and contraction. Although long acting beta agonists and corticosteroids are successful treatments for inflammation and bronchoconstriction, the structural changes which constitute airway remodelling may require additional therapeutic intervention, the nature of which will be determined by thorough investigation of the mechanisms underlying the asthmatic phenotype. ©2006 Japanese Society of Allergology.
Burgess, J, Oliver, BG, Poniris, M, Ge, Q, Boustany, S, Cox, N, Moir, L, Johnson, P & Black, J 2006, 'A phosphodiesterase 4 inhibitor inhibits matrix protein deposition in airways in vitro', Journal of Allergy and Clinical Immunology, vol. 118, no. 3, pp. 649-657.View/Download from: Publisher's site
Background: Airway smooth muscle (ASM) cells may contribute to airway remodeling through the release of growth factors, cytokines, and extracellular matrix (ECM) proteins. The effect of current asthma therapies on this release is not known. Objective: We
Oliver, BG, Johnston, S, Baraket, M, Burgess, J, King, N, Roth, M, Lim, S & Black, J 2006, 'Increased proinflammatory responses from asthmatic human airway smooth muscle cells in response to rhinovirus infection', Respiratory Research, vol. 7, pp. 1-11.View/Download from: UTS OPUS or Publisher's site
Background: Exacerbations of asthma are associated with viral respiratory tract infections, of which rhinoviruses (RV) are the predominant virus type. Airway smooth muscle is important in asthma pathogenesis, however little is known about the potential i
Sharma, R, von Haehling, S, Rauchhaus, M, Bolger, AP, Genth-Zotz, S, Doehner, W, Oliver, B, Poole-Wilson, PA, Volk, HD, Coats, AJS, Adcock, IM & Anker, SD 2005, 'Whole blood endotoxin responsiveness in patients with chronic heart failure: the importance of serum lipoproteins', EUROPEAN JOURNAL OF HEART FAILURE, vol. 7, no. 4, pp. 479-484.View/Download from: Publisher's site
Black, JL, Ge, Q, Boustany, S, Johnson, PRA, Poniris, MH, Glanville, AR, Oliver, BGG, Moir, LM & Burgess, JK 2005, 'In vitro studies of lymphangioleiomyomatosis', EUROPEAN RESPIRATORY JOURNAL, vol. 26, no. 4, pp. 569-576.View/Download from: Publisher's site
Huntriss, J, Hinkins, M, Oliver, B, Harris, SE, Beazley, JC, Rutherford, AJ, Gosden, RG, Lanzendorf, SE & Picton, HM 2004, 'Expression of mRNAs for DNA methyltransferases and methyl-CpG-binding proteins in the human female germ line, preimplantation embryos, and embryonic stem cells', MOLECULAR REPRODUCTION AND DEVELOPMENT, vol. 67, no. 3, pp. 323-336.View/Download from: Publisher's site
Roche, N, Stirling, RG, Lim, S, Oliver, BG & Chung, KF 2003, 'Regulation of protease-activated receptor-I in mononuclear cells by neutrophil proteases', RESPIRATORY MEDICINE, vol. 97, no. 3, pp. 228-233.View/Download from: Publisher's site
Roche, N, Stirling, RG, Lim, S, Oliver, BG, Oates, T, Jazrawi, E, Caramori, G & Chung, KF 2003, 'Effect of acute and chronic inflammatory stimuli on expression of proteaseactivated receptors 1 and 2 in alveolar macrophages', JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, vol. 111, no. 2, pp. 367-373.View/Download from: Publisher's site
Bolger, AP, Sharma, R, von Haehling, S, Doehner, W, Oliver, B, Rauchhaus, M, Coats, AJS, Adcock, IM & Anker, SD 2002, 'Effect of interleukin-10 on the production of tumor necrosis factor-alpha by peripheral blood mononuclear cells from patients with chronic heart failure', AMERICAN JOURNAL OF CARDIOLOGY, vol. 90, no. 4, pp. 384-389.View/Download from: Publisher's site
Huntriss, J, Gosden, R, Hinkins, M, Oliver, B, Miller, D, Rutherford, AJ & Picton, HM 2002, 'Isolation, characterization and expression of the human Factor In the Germline alpha (FIGLA) gene in ovarian follicles and oocytes', MOLECULAR HUMAN REPRODUCTION, vol. 8, no. 12, pp. 1087-1095.View/Download from: Publisher's site
Oliver, B, Tomita, K, Keller, A, Caramori, G, Adcock, I, Chung, KF, Barnes, PJ & Lim, S 2001, 'Low-dose theophylline does not exert its anti-inflammatory effects in mild asthma through upregulation of interleukin-10 in alveolar macrophages', ALLERGY, vol. 56, no. 11, pp. 1087-1090.View/Download from: Publisher's site
Lim, S, Tomita, K, Carramori, G, Jatakanon, A, Oliver, B, Keller, A, Adcock, I, Chung, KF & Barnes, PJ 2001, 'Low-dose theophylline reduces eosinophilic inflammation but not exhaled nitric oxide in mild asthma', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, vol. 164, no. 2, pp. 273-276.View/Download from: Publisher's site
Lim, S, Roche, N, Oliver, BG, Mattos, W, Barnes, PJ & Chung, KF 2000, 'Balance of matrix metalloprotease-9 and tissue inhibitor of metalloprotease-1 from alveolar macrophages in cigarette smokers - Regulation by interleukin-10', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, vol. 162, no. 4, pp. 1355-1360.View/Download from: Publisher's site
Chen, H, Chan, YL, Oliver, B, Pollock, C & Saad, S 2019, 'Maternal smoking and foetal brain outcome: mechanisms and possible solutions' in Preedy, V (ed), The Neuroscience of Nicotine: Mechanisms And Treatment., Academic Press-Elsevier., New York.View/Download from: UTS OPUS
Although it is well known that maternal cigarette smoke exposure (SE) is detrimental to the health of children, more than 20% of women continue to smoke during pregnancy. Children exposed to maternal smoking in utero have changes in their brain structure and size, often accompanied by cognitive defects. This may be due to increased brain oxidative stress and inflammatory response in the neonatal period, leading to neuron damage in adulthood. The mitochondria, a major source of cellular oxidative stress, are particularly vulnerable to the damage caused by the free radicals they produce. Interestingly, the female offspring seem to be protected by such adverse impact of maternal smoking. This chapter will specifically review the changes in brain inflammation and oxidative stress and the mechanism of mitophagy machinery. Potential therapeutic strategies will be suggested to mitigate the impact of maternal smoking.
Oliver, BG, Burgess, JK, Black, J & Panettieri, RA 2013, 'Noncontractile Functions of Airway Smooth Muscle' in Middleton's Allergy: Principles and Practice: Eighth Edition, Elsevier - Medicine Publishing Company, pp. 315-326.View/Download from: Publisher's site
Zakarya, R, Chen, H, Brandsma, CA, Adcock, IM & Oliver, BG 2018, 'Role of Histone Acetylation in Fibrosis in Chronic Obstructive Pulmonary Disease', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, International Conference of the American-Thoracic-Society, AMER THORACIC SOC, San Diego, CA.
Rutting, S, Papanicolaou, M, Xenaki, D, Wood, L, Horvat, J, Hansbro, P & Oliver, B 2018, 'THE EFFECT OF THE DIETARY omega-6 POLYUNSATURATED FATTY ACID, ARACHIDONIC ACID, ON AIRWAY INFLAMMATION AND REMODELING IN COPD', RESPIROLOGY, WILEY, pp. 70-70.View/Download from: UTS OPUS
Rutting, S, Xenaki, D, Wood, LG, Horvat, J, Hansbro, P & Oliver, BG 2018, 'Dietary Fatty Acids Induce Robust Inflammatory Responses in Human Lung Cells', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, International Conference of the American-Thoracic-Society, AMER THORACIC SOC, San Diego, CA.View/Download from: UTS OPUS
Sharma, P, McAlinden, K, Oliver, B & Haghi, M 2018, 'Autophagy Is Selectively Activated and Correlated with Airway Remodeling in Asthma', American Journal of Respiratory and Critical Care Medicine, American Thoracic Society, American Thoracic Society, San Diego.View/Download from: UTS OPUS
Rationale: Asthma affects more than 330 million people worldwide and poses a huge economic burden on the healthcare system. Current anti-asthma therapies provide symptomatic relief but fail to target airway remodeling which drives disease progression and loss of lung function with time. Macroautophagy (autophagy) is a fundamental process that occurs in all eukaryotic cells and can be referred to as the cell recycling mechanism. Emerging evidence suggest that autophagy is dysregulated in asthma and can modulate pro-fibrotic signaling in asthma. Autophagy modulation may be a novel effective therapy for unmanageable asthma. The aim of this study was to explore the role of autophagy in asthma by investigating the interrelationship between autophagy markers and features of airway remodeling in large airways obtained from asthmatics (n=6) and non-asthmatics (n=8). Methods: Selected asthmatic tissue with hallmark features of airway remodeling (correlates with severe disease) and non-asthmatics were immuno-stained for autophagy markers; Beclin1, ATG5, and p62. The percent area of positive staining was quantified in the epithelium and airway smooth muscle (ASM) using ImageJ software. Features of airway remodeling were also measured in the large airways of patients using H&E and Masson's Trichrome staining. Results: Asthmatic airways in comparison with non-asthmatic airways displayed greater epithelium (p<0.01), and reticular basement membrane thickness (p<0.0001) with greater lamina propria depth (p<0.0001), and increased ASM bundles (p<0.005). Overall they displayed hallmark features of airway remodeling. In the ASM bundles, expression of ATG5 was significantly higher (p<0.05), while there was a trend for increased expression of Beclin-1 (p=0.08) and reduced expression of p62 (p=0.18) in asthmatics when compared with non-asthmatics. We found no difference in the expression profile of autophagy markers in the epithelium of asthmatics vs non-asthmatics. Interestingly, in a...
Kota, A, Xenaki, D, Deshpande, D, Oliver, B & Sharma, P 2017, 'ASK1 Inhibition Prevented Mitogen-Induced Human Airway Smooth Muscle Growth in Chronic Obstructive Pulmonary Disease', American Journal of Respiratory and Critical Care Medicine, American Thoracic Society.View/Download from: UTS OPUS
McAlinden, K, Chan, Y, Kota, A, Chen, H, Oliver, B & Sharma, P 2017, 'Maternal E-cigarette Vaping Enhances Development of Allergic Asthma In the Offspring', American Journal of Respiratory and Critical Care Medicine, American Thoracic Society.View/Download from: UTS OPUS
Rationale: E-cigarettes (eCig) are being considered as an alternative to quit cigarette smoking (CS) while their long-term safety and effect on lung patho-physiology are not known. Maternal eCig-vaping may be considered as a safer CS-replacement during pregnancy. Thus the effect of maternal eCig vaping needs further assessment, particularly the effect this has on offspring and development of allergic asthma later in life. Combining mouse models of maternal vaping and allergic asthma and human airway smooth muscle cells (ASM) in vitro we tested whether maternal eCig vaping enhances features of allergic asthma in the offspring.
Methods: Female BALB/c mice were vaped with either eCig vapour (± nicotine) or CS+eCig (+nicotine) or room air (control group). The eCig vaping was started prior to mating and continued during gestation and lactation while CS-exposure was used prior to mating and replaced with eCig during gestation and mating. The female offspring from these mothers were subjected to an ovalbumin (OVA)-induced allergic asthma model. 24 hours after the last aerosolized OVA or saline challenge, lung function measurements were performed using flexiVent (Scireq, Canada) to increasing concentration of methacholine (MCh). Airway inflammation was assessed by counting total immune cell influx in BAL fluid. Human ASM cells were treated with varying concentrations of eCig liquid condensate and key parameters of mitochondrial function were measured with a Seahorse XF analyzer.
Results: Repeated allergen-exposure induced Th2-driven inflammation in OVA-exposed mice, characterized by massive influx of leukocytes predominantly eosinophils (OVA: 3x105±8.3x104 vs Saline: 1.1x102±1x102) and to some extent neutrophils (OVA: 1.3x104±4.4x103 vs Saline: 1.3x102±1.1x102) into the airways. The effect of allergen on airway eosinophilia was significantly enhanced in the offsprings from eCig OVA (+Nic)-exposed mothers when compared with eCig OVA (-Nic) or CS+eCig animals. OVA-exposed ...
Zakarya, R, Chen, H, Brandsma, C-A, Adcock, IM & Oliver, BGG 2017, 'Epigenetic control of TGF beta induced fibrosis in COPD', EUROPEAN RESPIRATORY JOURNAL, European-Respiratory-Society (ERS) International Congress, EUROPEAN RESPIRATORY SOC JOURNALS LTD, Milan, ITALY.View/Download from: Publisher's site
Mitchell, AB, Glanville, AR, Peters, M, Morgan, LC & Oliver, BG 2016, 'RESPIRATORY VIRUSES ARE COMMONLY DETECTED INASYMPTOMATIC ASTHMA AND COPD PATIENTS', Respirology, Wiley: 12 months, pp. 91-91.
Tovey, ER, Stelzer-Braid, S, Toelle, BG, Willenborg, CM, Reddel, HK, Garden, FL, Jaffe, A, Strachan, R, Oliver, BG, Belessis, YC, Marks, GB & Rawlinson, WD 2014, 'Asthma Symptoms and Rhinovirus In A Longitudinal Children's Cohort', JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI), MOSBY-ELSEVIER, San Diego, CA, pp. AB285-AB285.View/Download from: Publisher's site
Tovey, ER, Liu-Brennan, D, Rimmer, JS & Oliver, BG 2014, 'New methods for measuring the time course of personal exposure to biological particles including aeroallergens', Indoor Air 2014 - 13th International Conference on Indoor Air Quality and Climate, 13th International Conference on Indoor Air Quality and Climate, pp. 926-931.
We present early data on two methods to monitor personal allergen exposure.
Sharma, P, Yi, R, Nayak, A, Wang, N, Tang, F, Knight, M, Pan, S, Oliver, B & Deshpande, D 2017, 'Bitter Taste Receptor Agonists Mitigate Features of Allergic Asthma in Mice'.View/Download from: UTS OPUS
Asthma is characterized by airway inflammation, mucus secretion, remodeling and hyperresponsiveness (AHR). Recent research has established the bronchodilatory effect of bitter taste receptor (TAS2R) agonists in various models. Comprehensive pre-clinical studies aimed at establishing effectiveness of TAS2R agonists in disease models are lacking. Here we aimed to determine the effect of TAS2R agonists on features of asthma. Further, we elucidated a mechanism by which TAS2R agonists mitigate features of asthma. Asthma was induced in mice using intranasal house dust mite or aerosol ova-albumin challenge, and chloroquine or quinine were tested in both prophylactic and treatment models. Allergen challenge resulted in airway inflammation as evidenced by increased immune cells infiltration and release of cytokines and chemokines in the lungs, which were significantly attenuated in TAS2R agonists treated mice. TAS2R agonists attenuated features of airway remodeling including smooth muscle mass, extracellular matrix deposition and pro-fibrotic signaling, and also prevented mucus accumulation and development of AHR in mice. Mechanistic studies using human neutrophils demonstrated that inhibition of immune cell chemotaxis is a key mechanism by which TAS2R agonists blocked allergic airway inflammation and exerted anti-asthma effects. Our comprehensive studies establish the effectiveness of TAS2R agonists in mitigating multiple features of allergic asthma.
I have a growing international reputation and have numerous active collaborations with researchers in Australia, Europe, Asia and the USA.
My active academic collaborations external to UTS include:
Professor Philip Hansbro (Uni Newcastle)
Professor Ian Addcock (imperial Collage, UK)
Dr Corry-Anke Brandsma (Uni Groningen, the Nethterlands)
Professor Dirkje Postma and Win Timens (Uni Groningen, the Nethterlands)
Professor Patricia Finn (Uni Chicgo)
I also have a number of active collaborations with Industry, including GSK, AZ, and Pharmaxsis.