%0 Journal Article
%~ PubMed
%A Niimi, Kyoko
%A Ge, Qi
%A Moir, Lyn M
%A Ammit, Alaina J
%A Trian, Thomas
%A Burgess, Janette K
%A Black, Judith L
%A Oliver, Brian G G
%T β2-agonists upregulate PDE4 mRNA but not protein, or activity in human airway smooth muscle cells from asthmatic and non asthmatic volunteers.
%B American Journal of Physiology. Lung Cellular and Molecular Physiology
%D 2012
%C United States
%I American Physiological Society
%V 302
%N 3
%P L334-L342
%@ 1522-1504
%X ?2-adrenergic receptor (?2AR) 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 ?2 agonists (LABAs) 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 non asthmatic 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)-?1, formoterol and/or budesonide. PDE4D mRNA was assessed by real time-PCR (RT-PCR), or PCR to assess splice variant production. PDE4D protein was assessed by western blotting, and 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 timepoints 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 ?2AR agonists is unlikely to cause PDE4 mediated tachyphylaxis.
%Z FOR Codes: 111602 30406


%0 Journal Article
%~ PubMed
%A Essilfie, Ama-Tawiah
%A Simpson, Jodie L
%A Dunkley, Margaret L
%A Morgan, Lucy C
%A Oliver, Brian G
%A Gibson, Peter G
%A Foster, Paul S
%A Hansbro, Philip M
%T Combined Haemophilus influenzae respiratory infection and allergic airways disease drives chronic infection and features of neutrophilic asthma.
%B Thorax
%D 2012
%C United Kingdom
%I BMJ Group
%V 67
%N 7
%P 588-599
%@ 0040-6376
%X 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. The relationship between chronic airway colonisation and the development of steroid-resistant neutrophilic asthma is unclear.
%Z FOR Codes: 110203


%0 Journal Article
%~ PubMed
%A Baraket, Melissa
%A Oliver, Brian G G
%A Burgess, Janette K
%A Lim, Sam
%A King, Gregory G
%A Black, Judith L
%T Is low dose inhaled corticosteroid therapy as effective for inflammation and remodeling in asthma? A randomized, parallel group study.
%B Respiratory Research
%D 2012
%C United Kingdom
%I BioMed Central Ltd.
%V 13
%N 
%P 11
%@ 1465-993X
%X 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, it is uncertain whether low dose ICSs are as effective as high dose in the treatment of inflammation and remodeling.
%Z FOR Codes: 110203


%0 Journal Article
%~ PubMed
%A Weckmann, Markus
%A Moir, Lyn Margaret
%A Heckman, Caroline Akemi
%A Black, Judith Lee
%A Oliver, Brian Gregory
%A Burgess, Janette Kay
%T Lamstatin - a novel inhibitor of lymphangiogenesis derived from collagen IV.
%B Journal of Cellular and Molecular Medicine
%D 2012
%C United Kingdom
%I Wiley-Blackwell Publishing Ltd.
%V 16
%N 12
%P 3062-3073
%@ 1582-4934
%X 
%Z FOR Codes: 111501


%0 Journal Article
%~ PubMed
%A Krimmer, David I
%A Burgess, Janette K
%A Wooi, Teh K
%A Black, Judith L
%A Oliver, Brian Gg
%T Matrix Proteins from Smoke Exposed Fibroblasts are Pro-proliferative.
%B American Journal of Respiratory Cell and Molecular Biology
%D 2012
%C United States
%I American Thoracic Society
%V 46
%N 1
%P 34-39
%@ 1535-4989
%X Background: 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. Methods: Lung fibroblasts isolated from patients with COPD or other lung disease were exposed to cigarette smoke extract (CSE) and 5ng/ml transforming growth factor (TGF)-??1 for 72 hours, in some experiments inhibitors of signaling molecules were added. Deposition of perlecan, fibronectin and elastin were measured using ELISA. Release of interleukin (IL)-8 and IL-13 were measured using ELISA. Unstimulated fibroblast cells were re-seeded onto deposited matrix and assessed for proliferation and cytokine release. Results: Five percent CSE 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 (STAT)-1/3 inhibitor pyridone 6, respectively. Five percent CSE increased IL-8 release from COPD fibroblasts more than non-COPD fibroblasts. This increase was attenuated by BMS-345541. Matrix deposited following 5% CSE stimulation increased proliferation of fibroblasts but did not alter cytokine release. Conclusion: ECM produced from COPD fibroblasts following CSE exposure has pro-proliferative effects. Thus the ECM in patients with COPD may create an environment which promotes airway remodeling.
%Z FOR Codes: 1116


%0 Journal Article
%~ PubMed
%A Van Ly, David
%A Burgess, Janette K
%A Brock, Thomas G
%A Lee, Tak H
%A Black, Judith L
%A Oliver, Brian G G
%T Prostaglandins but not leukotrienes alter extracellular matrix protein deposition and cytokine release in primary human airway smooth muscle cells and fibroblasts.
%B American Journal of Physiology: Lung Cellular and Molecular Physiology
%D 2012
%C United States
%I American Physiological Society
%V 303
%N 3
%P L239-L250
%@ 1522-1504
%X Eicosanoids are lipid-signaling mediators released by many cells in response to various stimuli. Increasing evidence suggests that eicosanoids such as leukotrienes and prostaglandins (PGs) may directly mediate remodeling. In this study, we assessed whether these substances could alter extracellular matrix (ECM) proteins and the inflammatory profiles of primary human airway smooth muscle cells (ASM) and fibroblasts. PGE(2) decreased both fibronectin and tenascin C in fibroblasts but only fibronectin in ASM. PGD(2) decreased both fibronectin and tenascin C in both ASM and fibroblasts, whereas PGF(2??) had no effect on ECM deposition. The selective PGI(2) analog, MRE-269, decreased fibronectin but not tenascin C in both cell types. All the PGs increased IL-6 and IL-8 release in a dose-dependent manner in ASM and fibroblasts. Changes in ECM deposition and cytokine release induced by prostaglandins in both ASM and fibroblasts were independent of an effect on cell number. Neither the acute nor repeated stimulation with leukotrienes had an effect on the deposition of ECM proteins or cytokine release from ASM or fibroblasts. We concluded that, collectively, these results provide evidence that PGs may contribute to ECM remodeling to a greater extent than leukotrienes in airway cells.
%Z FOR Codes: 60104


%0 Journal Article
%~ PubMed
%A Ichimaru, Yukikazu
%A Krimmer, David I
%A Burgess, Janette K
%A Black, Judith L
%A Oliver, Brian G G
%T TGF-β enhances deposition of perlecan from COPD airway smooth muscle.
%B American journal of physiology. Lung Cellular and Molecular Physiology
%D 2012
%C United States
%I American Physiological Society
%V 302
%N 3
%P L325-L333
%@ 1522-1504
%X 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-??(1) (TGF-??(1)) before perlecan deposition and cytokine release were analyzed. In some experiments, inhibitors of signaling molecules were added. Perlecan domains I-V were seeded on tissue culture plates at 10 ??g/ml with 1 ??g/ml collagen I as a control. ASM was incubated on top of the peptides before being analyzed for attachment, proliferation, and wound healing. TGF-??(1) upregulated deposition of perlecan by ASMC from COPD subjects only. TGF-??(1) upregulated release of IL-6 into the supernatant of ASMC from all subjects. Inhibitors of SMAD and JNK signaling molecules decreased TGF-??(1)-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-??(1)-induced perlecan deposition may enhance attachment of migrating ASMC in vivo and thus may be a mechanism for ASMC layer hypertrophy in COPD.
%Z FOR Codes: 111602


%0 Journal Article
%~ PubMed
%A Tan, Xiahui
%A Khalil, Najwa
%A Tesarik, Candice
%A Vanapalli, Karunasri
%A Yaputra, Viki
%A Alkhouri, Hatem
%A Oliver, Brian G G
%A Armour, Carol L
%A Hughes, J Margaret
%T Th1 cytokine-induced syndecan-4 shedding by airway smooth muscle cells is dependent on mitogen-activated protein kinases.
%B American Journal of Physiology. Lung Cellular and Molecular Physiology
%D 2012
%C United States
%I American Physiological Society
%V 302
%N 7
%P L700-710
%@ 1522-1504
%X In asthma, airway smooth muscle (ASM) chemokine secretion can induce mast cell recruitment into the airways. The functions of the mast cell chemoattractant CXCL10, and other chemokines, are regulated by binding to heparan sulphates such as syndecan-4. This study is the first demonstration that airway smooth muscle cells (ASMC) from people with and without asthma express and shed syndecan-4 under basal conditions. Syndecan-4 shedding was enhanced by stimulation for 24 hr with the Th1 cytokines interleukin-1? (IL-1?) or tumour necrosis factor-? (TNF?), but not interferon-? (IFN?), nor the Th2 cytokines IL-4 and IL-13. ASMC stimulation with IL-1?, TNF? and IFN? (cytomix) induced the highest level of syndecan-4 shedding. Non-asthmatic and asthmatic ASM cell-associated syndecan-4 protein expression was also increased by TNF? or cytomix at 4-8 hr, with the highest levels detected in cytomix-stimulated asthmatic cells . Cell-associated syndecan-4 levels were decreased by 24 hr, whereas shedding remained elevated at 24 hr, consistent with newly synthesised syndecan-4 being shed. Inhibition of ASMC MMP-2 did not prevent syndecan-4 shedding, whereas inhibition of ERK MAPK activation reduced shedding from cytomix-stimulated ASMC. Although ERK inhibition had no effect on syndecan-4 mRNA levels stimulated by cytomix, it did cause an increase in cell-associated syndecan-4 levels, consistent with the shedding being inhibited. In conclusion, ASMC produce and shed syndecan-4 and although this is increased by the Th1 cytokines, the MAPK ERK only regulates shedding. ASMC syndecan-4 production during Th1 inflammatory conditions may regulate chemokine activity and mast cell recruitment to the ASM in asthma.
%Z FOR Codes: 111504 110203


%0 Journal Article
%~ PubMed
%A Ge, Qi
%A Moir, Lyn M
%A Trian, Thomas
%A Niimi, Kyoko
%A Poniris, Maree
%A Shepherd, Peter R
%A Black, Judith L
%A Oliver, Brian G
%A Burgess, Janette K
%T The phosphoinositide 3'-kinase p110δ modulates contractile protein production and IL-6 release in human airway smooth muscle.
%B Journal of Cellular Physiology
%D 2012
%C United States
%I John Wiley & Sons, Inc.
%V 227
%N 8
%P 3044-3052
%@ 1097-4652
%X Transforming growth factor (TGF) ??1 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 TGF??1 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 TGF??1 induced pro-inflammatory cytokine and contractile proteins in ASM cells. Results: A cells expressed higher basal levels of p110?? mRNA compared to NA and COPD cells; however COPD cells produced more p110?? protein. TGF??1 increased 110d mRNA expression to the same extent in the three groups. Neither the p110?? inhibitor IC87114 (1, 10, 30 ??M), the p110?? inhibitor TGX221 (0.1, 1, 10 ??M) nor the PI3K pan inhibitor LY294002 (3, 10 ??M) had any effect on basal IL-6, calponin or smooth muscle ??-actin (??-SMA) expression. However, TGF??1 increased calponin and ??-SMA expression was inhibited by IC87114 and LY294002 in all three groups. IC87114, TGX221 and LY294002 reduced TGF??1 induced IL-6 release in a dose related manner in all groups of ASM cells. Conclusion: PI3K p110?? is important for TGF??1 induced production of the contractile proteins calponin and ??-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. J. Cell. Physiol. ?? 2011 Wiley Periodicals, Inc.
%Z FOR Codes: 60103


%0 Journal Article
%~ PubMed
%A Trian, Thomas
%A Burgess, Janette K
%A Niimi, Kyoko
%A Moir, Lyn M
%A Ge, Qi
%A Berger, Patrick
%A Liggett, Stephen B
%A Black, Judith L
%A Oliver, Brian G
%T β(2)-Agonist Induced cAMP Is Decreased in Asthmatic Airway Smooth Muscle Due to Increased PDE4D.
%B PloS one
%D 2011
%C United States
%I Public Library of Science
%V 6
%N 5
%P e20000
%@ 1932-6203
%X 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 ??-agonist induced ASM relaxation in asthmatics, but the mechanism is not known.
%Z FOR Codes: 601 1115 110203


%0 Journal Article
%~ PubMed
%A Moir, Lm
%A Ng, Hy
%A Poniris, Mh
%A Santa, T
%A Burgess, Jk
%A Oliver, Bgg
%A Krymskaya, Vp
%A Black, Jl
%T Doxycycline inhibits matrix metalloproteinase-2 secretion from TSC2-null mouse embryonic fibroblasts and lymphangioleiomyomatosis cells.
%B British journal of pharmacology
%D 2011
%C United Kingdom
%I John Wiley & Sons Ltd.
%V 164
%N 1
%P 83-92
%@ 0007-1188
%X 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).
%Z FOR Codes: 111501


%0 Journal Article
%~ PubMed
%A Van Ly, David
%A King, Nicholas J C
%A Moir, Lyn M
%A Burgess, Janette K
%A Black, Judith L
%A Oliver, Brian G
%T Effects of β(2) Agonists, Corticosteroids, and Novel Therapies on Rhinovirus-Induced Cytokine Release and Rhinovirus Replication in Primary Airway Fibroblasts.
%B Journal of Allergy
%D 2011
%C United States
%I Hindawi Publishing Corporation
%V 2011
%N 
%P 457169
%@ 1687-9791
%X 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 ?(2) 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; ?(2) 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.
%Z FOR Codes: 602


%0 Journal Article
%~ PubMed
%A Moir, Lyn M
%A Trian, Thomas
%A Ge, Qi
%A Shepherd, Peter R
%A Burgess, Janette K
%A Oliver, Brian G G
%A Black, Judith L
%T Phosphatidylinositol 3-kinase isoform-specific effects in airway mesenchymal cell function.
%B Journal of Pharmacology and Experimental Therapeutics
%D 2011
%C United States
%I American Society for Pharmacology and Experimental Therapeutics
%V 337
%N 2
%P 557-566
%@ 0022-3565
%X 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 site of pharmacological intervention for treating the disease, it is important to know which isoforms contribute to this process. Therefore, we used a pharmacological approach to investigate the roles of the three class IA PI3K isoforms (p110??, p110??, and p110??) in airway remodeling using airway smooth muscle (ASM) cells derived from asthmatic subjects and ASM cells and lung fibroblasts from nonasthmatic subjects. These studies used the inhibitors N''-[(E)-(6-bromoimidazo[1,2-a]pyridin-3-yl)methylidene]-N,2-dimethyl-5-nitrobenzenesulfonohydrazide (PIK75) (which selectively inhibits p110??), 7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one (TGX221) (which selectively inhibits p110??), and 2-[(6-amino-9H-purin-9-yl)methyl]-5-methyl-3-(2-methylphenyl)-4(3H)-quinazolinone (IC87114) (which selectively inhibits p110??). Cells were stimulated with transforming growth factor-?? (TGF??) and/or 10% fetal bovine serum in the presence or absence of inhibitor or vehicle control (dimethyl sulfoxide). PIK75, but not TGX221 or IC87114, attenuated TGF??-induced fibronectin deposition in all cell types tested. PIK75 and TGX221 each decreased secretion of vascular endothelial growth factor and interleukin-6 in nonasthmatic ASM cells and lung fibroblasts, whereas TGX221 was not as effective in asthmatic ASM cells. In addition, PIK75 decreased cell survival in TGF??-stimulated asthmatic, but not nonasthmatic, ASM cells. In conclusion, specific PI3K isoforms may play a role in pathophysiological events relevant to airway wall remodeling.
%Z FOR Codes: 111501


%0 Journal Article
%~ PubMed
%A Kuo, Curtis
%A Lim, Sam
%A King, Nicholas J C
%A Bartlett, Nathan W
%A Walton, Ross P
%A Zhu, Jie
%A Glanville, Nicholas
%A Aniscenko, Julia
%A Johnston, Sebastian L
%A Burgess, Janette K
%A Black, Judith L
%A Oliver, Brian G
%T Rhinovirus infection induces expression of airway remodelling factors in vitro and in vivo.
%B Respirology
%D 2011
%C Australia, Japan
%I Wiley-Blackwell Publishing Asia
%V 16
%N 2
%P 367-377
%@ 1440-1843
%X 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. We evaluated whether rhinovirus (RV) infection induces airway remodelling, as assessed by ECM deposition.
%Z FOR Codes: 60106


%0 Journal Article
%~ PubMed
%A Kuo, Curtis
%A Lim, Sam
%A King, Nicholas J C
%A Johnston, Sebastian L
%A Burgess, Janette K
%A Black, Judith L
%A Oliver, Brian G
%T Rhinovirus infection induces extracellular matrix protein deposition in asthmatic and non-asthmatic airway smooth muscle cells.
%B American Journal of Physiology: Lung Cellular and Molecular Physiology
%D 2011
%C United States
%I American Physiological Society
%V 300
%N 6
%P L951-L957
%@ 1522-1504
%X Airway remodeling, which includes increases in the extracellular matrix (ECM), is a characteristic feature of asthma and is correlated to disease severity. Rhinovirus (RV) infections are associated with increased risk of asthma development in young children and are the most common cause of asthma exacerbations. We examined whether viral infections can increase ECM deposition and whether this increased ECM modulates cell proliferation and migration. RV infection of nonasthmatic airway smooth muscle (ASM) cells significantly increased the deposition of fibronectin (40% increase, n = 12) and perlecan (80% increase, n = 14), while infection of asthmatic ASM cells significantly increased fibronectin (75% increase, n = 9) and collagen IV (15% increase, n = 9). We then treated the ASM cells with the Toll-like receptor (TLR) agonists polyinosinic:polycytidylic acid, imiquimod, and pure RV RNA and were able to show that the mechanism through which RV induced ECM deposition was via the activation of TLR3 and TLR7/8. Finally, we assessed whether the virus-induced ECM was bioactive by measuring the amount of migration and proliferation of virus-naive cells that seeded onto the ECM. Basically, ECM from asthmatic ASM cells induced twofold greater migration of virus-naive ASM cells than ECM from nonasthmatic ASM cells, and these rates of migration were further increased on RV-modulated ECM. Increased migration on the RV-modulated ECM was not due to increased cell proliferation, as RV-modulated ECM decreased the proliferation of virus-naive cells. Our results suggest that viruses may contribute to airway remodeling through increased ECM deposition, which in turn may contribute to increased ASM mass via increased cell migration.
%Z FOR Codes: 111501 60506


%0 Journal Article
%~ PubMed
%A Krimmer, D I
%A Oliver, B G G
%T What can in vitro models of COPD tell us?
%B Pulmonary pharmacology & therapeutics
%D 2011
%C United Kingdom
%I Academic Press
%V 24
%N 5
%P 471-7
%@ 1522-9629
%X 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.
%Z FOR Codes: 60114


%0 Journal Article
%~ PubMed
%A Lau, Justine Y
%A Oliver, Brian G
%A Moir, Lyn M
%A Black, Judith L
%A Burgess, Janette K
%T 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.
%B Respirology
%D 2010
%C Australia, Japan
%I Wiley-Blackwell Publishing Asia
%V 15
%N 2
%P 303-312
%@ 1440-1843
%X PPARgamma levels in asthma- and non-asthma-derived airway smooth muscle cells and PPARgamma activation-induced cell proliferation were investigated. In the presence of FBS, PPARgamma levels were higher in subconfluent asthma-derived cells but lower in confluent cells compared with non-asthma-derived. However, PPARgamma activation did not alter cell proliferation. 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 receptor-gamma (PPARgamma) regulates the cell cycle. It is suggested that PPARgamma agonists have anti-inflammatory effects, which may be valuable in the treatment of asthma, but information regarding their antiproliferative properties in ASM is lacking. Although corticosteroids reduce airway inflammation, in vitro they inhibit proliferation in only non-asthma ASM cells by reducing cyclin D1. We therefore investigated the effects of mitogenic stimulation (foetal bovine serum (FBS)), and a PPARgamma ligand (ciglitazone), on PPARgamma and cyclin D1 expression and proliferation of ASM cells. In addition, we examined the effects of ciglitazone on ASM cell proliferation. METHODS: We assessed PPARgamma and cyclin D1 mRNA and protein levels using quantitative PCR and immunoblotting. Cell proliferation was assessed using bromodeoxyuridine uptake. RESULTS: In the presence of 5% FBS, PPARgamma and cyclin D1 expression decreased over time in non-asthmatic cells but increased in asthmatic cells (compared with sub-confluent cells). FBS-induced proliferation of asthmatic cells increased at all time points, but occurred only at day 7 with non-asthmatic cells (compared with unstimulated time-matched control). Ciglitazone increased PPARgamma expression in both groups, but did not alter cell proliferation, while fluticasone increased PPARgamma protein only in asthmatic cells. CONCLUSIONS: Although in the presence of a mitogenic stimulus, PPARgamma was differentially expressed in asthma- and non-asthma-derived ASM; its expression was not related to the increased proliferation observed in asthmatic ASM.
%Z FOR Codes: 1004


%0 Journal Article
%~ PubMed
%A Lau, Justine Y
%A Oliver, Brian G
%A Baraket, Melissa
%A Beckett, Emma L
%A Hansbro, Nicole G
%A Moir, Lyn M
%A Wilton, Steve D
%A Williams, Carolyn
%A Foster, Paul S
%A Hansbro, Philip M
%A Black, Judith L
%A Burgess, Janette K
%T Fibulin-1 is increased in asthma - a novel mediator of airway remodeling?
%B PloS one
%D 2010
%C United States
%I Public Library of Science
%V 5
%N 10
%P pii: e13360
%@ 1932-6203
%X 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. However, the expression and function of fibulin-1, a secreted glycoprotein which interacts with fibronectin, has not been reported. Fibulin-1 is widely expressed in basement membranes in many organs including the lung. There are four isoforms in humans (A-D) of which fibulin-1C and 1D predominate. The objective of this study was to study the expression of fibulin-1 in volunteers with and without asthma, and to examine its function in vitro. METHODOLOGY/PRINCIPAL FINDINGS: We used immunohistochemistry and dot-blots to examine fibulin-1 levels in bronchial biopsies, bronchoalveolar lavage fluid and serum. Real-time PCR for fibulin-1C and 1D, and ELISA and western blotting for fibulin-1 were used to study the levels in airway smooth muscle cells. The function of fibulin-1C was determined by assessing its role, using an antisense oligonucleotide, in cell proliferation, migration and wound healing. A murine model of airway hyperresponsiveness (AHR) was used to explore the biological significance of fibulin-1. Levels of fibulin-1 were significantly increased in the serum and bronchoalveolar lavage fluid of 21 asthmatics compared with 11 healthy volunteers. In addition fibulin-1 was increased in asthma derived airway smooth muscle cells and fibulin-1C contributed to the enhanced proliferation and wound repair in these cells. These features were reversed when fibulin-1C was suppressed using an antisense oligomer. In a mouse model of AHR, treatment with an AO inhibited the development of AHR to methacholine. CONCLUSIONS: Our data collectively suggest fibulin-1C may be worthy of further investigation as a target for airway remodeling in asthma.
%Z FOR Codes: 1115


%0 Journal Article
%~ PubMed
%A Burgess, Janette K
%A Boustany, Sarah
%A Moir, Lyn M
%A Weckmann, Markus
%A Lau, Justine Y
%A Grafton, Karryn
%A Baraket, Melissa
%A Hansbro, Philip M
%A Hansbro, Nicole G
%A Foster, Paul S
%A Black, Judith L
%A Oliver, Brian G
%T Reduction of Tumstatin in Asthmatic Airways Contributes to Angiogenesis, Inflammation and Hyperresponsiveness.
%B American journal of respiratory and critical care medicine
%D 2010
%C United States
%I American Thoracic Society
%V 181
%N 2
%P 106-15
%@ 1073-449X
%X 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 in asthma. It has six alpha chains, of which the noncollagenous domain-1 domains have endogenous antiangiogenic properties.
%Z FOR Codes: 111501 110701


%0 Journal Article
%~ PubMed
%A Trian, Thomas
%A Ge, Qi
%A Moir, Lyn M
%A Burgess, Janette K
%A Kuo, Curtis
%A King, Nicholas J C
%A Reddel, Helen K
%A Black, Judith L
%A Oliver, Brian G
%A McParland, Brent E
%T Rhinovirus-induced Exacerbations of Asthma - How is the {beta}2-adrenoceptor Implicated?
%B American journal of respiratory cell and molecular biology
%D 2010
%C United States
%I American Thoracic Society
%V 43
%N 2
%P 227-33
%@ 1535-4989
%X 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 receptor (beta(2)AR) agonists. During virus-associated exacerbations, an impaired response to beta(2)AR agonists is observed; the reason for this is not known. The objective of this study was to determine the effect of RV infection on airway smooth muscle beta(2)AR function. The human cell line Beas-2B and primary human bronchial epithelial cells (HBECs) were infected with RV (multiplicity of infection = 1). After 1 or 5 days for primary and Beas-2B cells, respectively, cell culture supernatants were harvested, UV-irradiated to inactivate RV, and applied to human airway smooth muscle cells for 3 days to assess modifications of beta(2)AR function. RV conditioned medium from Beas-2B and HBECs decreased beta(2)AR agonist-induced cAMP by 50 and 65%, respectively (n = 5; P < 0.05). When cAMP was induced independently of the beta(2)AR using forskolin, no impairment was found. Using flow cytometry, we demonstrated that this decrease was likely the result of beta(2)AR desensitization because membrane but not total cell receptor beta(2)AR was decreased. Pretreatment of HBECs and Beas-2B cells but not human airway smooth muscle cells with the corticosteroids dexamethasone or fluticasone abolished virus-mediated beta(2)AR loss of function. This study shows that epithelial infection with RV induces a decrease of beta(2)AR function on airway smooth muscle cells, potentially explaining the clinical observation of loss of beta(2)AR agonist function during RV-induced asthma exacerbations.
%Z FOR Codes: 111501 110804 111601 110106


%0 Journal Article
%~ PubMed
%A Ge, Qi
%A Moir, Lyn M
%A Black, Judith L
%A Oliver, Brian G G
%A Burgess, Janette K
%T TGFbeta1 induces IL-6 and inhibits IL-8 release in human bronchial epithelial cells-the role of SMAD2/3.
%B Journal of cellular physiology
%D 2010
%C United States
%I John Wiley & Sons, Inc.
%V 225
%N 3
%P 846-54
%@ 1097-4652
%X 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) ??1, all of which are elevated in asthmatic airways. This study examines the signaling pathways leading to TGF??1 induced IL-6 and IL-8 in primary HBE cells from asthmatic and non-asthmatic volunteers. HBE cells were stimulated with TGF??1 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. TGF??1 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 TGF??1 induced IL-6 in both cell groups. TGF??1 induced Smad2 phosphorylation, and blockade of Smad2/3 prevented both the TGF??1 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 TGF??1 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.
%Z FOR Codes: 60103


%0 Journal Article
%~ PubMed
%A Krimmer, D I
%A Loseli, M
%A Hughes, J M
%A Oliver, B G G
%A Moir, L M
%A Hunt, N H
%A Black, J L
%A Burgess, J K
%T CD40 and OX40 ligand are differentially regulated on asthmatic airway smooth muscle.
%B Allergy
%D 2009
%C United Kingdom, Swit
%I Wiley-Blackwell Publishing Ltd.
%V 64
%N 7
%P 1074-82
%@ 0105-4538
%X 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-alpha) and interferon-gamma (IFN-gamma) on ASM CD40 and OX40L expression.
%Z FOR Codes: 110701


%0 Journal Article
%~ Isi
%A Seidel, P.
%A Merfort, I.
%A Hughes, J. M.
%A Oliver, B. G. G.
%A Tamm, M.
%A Roth, M.
%T Dimethylfumarate inhibits NF-kappa B function at multiple levels to limit airway smooth muscle cell cytokine secretion
%B American Journal of Physiology-Lung Cellular and Molecular Physiology
%D 2009
%C United States
%I American Physiological Society
%V 297
%N 0
%P L326-L339
%@ 1040-0605
%X 
%Z FOR Codes: 111504


%0 Journal Article
%~ PubMed
%A Stelzer-Braid, Sacha
%A Oliver, Brian G
%A Blazey, Angus J
%A Argent, Elizabeth
%A Newsome, Timothy P
%A Rawlinson, William D
%A Tovey, Euan R
%T Exhalation of respiratory viruses by breathing, coughing, and talking.
%B Journal of medical virology
%D 2009
%C United States
%I John Wiley & Sons, Inc.
%V 81
%N 9
%P 1674-9
%@ 0146-6615
%X 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 respiratory viruses. The exhaled samples from a subset of 10 subjects who were PCR positive for rhinovirus were also examined by cell culture for this virus. Of the 50 subjects, among the 33 with symptoms of upper respiratory tract infections, 21 had at least one virus detected by PCR, while amongst the 17 asymptomatic subjects, 4 had a virus detected by PCR. Overall, rhinovirus was detected in 19 subjects, influenza in 4 subjects, parainfluenza in 2 subjects, and human metapneumovirus in 1 subject. Two subjects were co-infected. Of the 25 subjects who had virus-positive nasal mucus, the same virus type was detected in 12 breathing samples, 8 talking samples, and in 2 coughing samples. In the subset of exhaled samples from 10 subjects examined by culture, infective rhinovirus was detected in 2. These data provide further evidence that breathing may be a source of respirable particles carrying infectious virus.
%Z FOR Codes: 110203


%0 Journal Article
%~ PubMed
%A Black, Judith L
%A Oliver, Brian G G
%A Roth, Michael
%T Molecular mechanisms of combination therapy with inhaled corticosteroids and long-acting beta-agonists.
%B Chest
%D 2009
%C United States
%I American College of Chest Physicians
%V 136
%N 4
%P 1095-1100
%@ 0012-3692
%X 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 delivered either separately or through one device has provided some clear and important clinical advantages. The mechanisms underlying these interactions have emerged as novel and provocative. beta(2)-Agonists can stimulate the glucocorticoid receptor (GR) and promote its translocation to the nucleus, resulting in increased CS-mediated gene transcription. In structural airway cells, such as fibroblasts and smooth muscle, this gene transcription is associated with the formation of a complex between the GR and another transcription factor, CCAAT enhancer-binding protein (C/EBP)-alpha. Airway smooth muscle cells from persons with asthma are deficient in C/EBP-alpha, which may explain the finding that CSs do not inhibit the proliferation of these cells in vitro. Whether this deficiency can explain the increased bulk of muscle in the asthmatic airway remains to be established. beta(2)-Agonists can inhibit mast cell mediator release, but this response is susceptible to desensitization, a process that CSs can inhibit. CSs also can increase the transcription of the beta(2)-receptor gene in the lung and the nasal mucosa. These effects of CSs mitigate against the reduced transcription of beta(2)-receptors, which occurs as a consequence of long-term beta(2)-agonist administration. Delineation of the exact mechanisms underlying these effects will ensure rational, direct therapy.
%Z FOR Codes: 111501


%0 Journal Article
%~ PubMed
%A Fukuyama, Satoru
%A Nakano, Takako
%A Matsumoto, Takafumi
%A Oliver, Brian G G
%A Burgess, Janette K
%A Moriwaki, Atsushi
%A Tanaka, Kentaro
%A Kubo, Masato
%A Hoshino, Tomoaki
%A Tanaka, Hiroyuki
%A McKenzie, Andrew N J
%A Matsumoto, Koichiro
%A Aizawa, Hisamichi
%A Nakanishi, Yoichi
%A Yoshimura, Akihiko
%A Black, Judith L
%A Inoue, Hiromasa
%T Pulmonary suppressor of cytokine signaling-1 induced by IL-13 regulates allergic asthma phenotype.
%B American Journal of Respiratory and Critical Care Medicine
%D 2009
%C United States
%I American Thoracic Society
%V 179
%N 11
%P 992-998
%@ 1073-449X
%X 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 signaling (SOCS) family protein, a negative regulator of the Janus kinase/STAT signaling pathway, contributes to helper T cell differentiation during immune responses, the role of SOCS proteins within the structural cells of a target organ has not been clarified in allergy. OBJECTIVES: To study the local function of SOCS in the development of asthma. METHODS: We used mouse models of IL-13- and ovalbumin (OVA)-induced allergic airway disease. Airway smooth muscle cells were cultured from patients with asthma. MEASUREMENTS AND MAIN RESULTS: The administration of IL-13 induced not only airway responses but also SOCS1 expression at the local inflammatory site. The up-regulated SOCS1 markedly suppressed IL-13-dependent STAT6 activation and eotaxin expression and subsequently down-regulated IL-13-induced airway inflammatory responses. The inactivation of SOCS1 induced airway hyperresponsiveness after IL-13 treatment even in hyporesponsive C57BL/6 background mice. In an OVA-induced model of allergic airway disease, allergen exposure up-regulated local SOCS1 expression, and the induction of SOCS1 in the airways attenuated allergen-induced airway responses. Inactivation of IL-13 inhibited SOCS1 induction in a model of allergic airway disease. Interestingly, airway smooth muscle cells from individuals with asthma had impaired up-regulation of SOCS1 after IL-13 stimulation. CONCLUSIONS: SOCS1 induction by IL-13 in airway structural cells is critical to negatively control allergic airway disease.
%Z FOR Codes: 110203


%0 Journal Article
%~ PubMed
%A Weckmann, Markus
%A Trian, Thomas
%A Oliver, Brian Gg
%T Reconstruction is not renovation - the role of remodeling in asthma.
%B Journal of Asthma and Allergy
%D 2009
%C United Kingdom
%I Dove Medical Press Ltd.
%V 2
%N 
%P 33-42
%@ 1178-6965
%X 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.
%Z FOR Codes: 110203


%0 Journal Article
%~ PubMed
%A Burgess, Janette K
%A Ceresa, Claudia
%A Johnson, Simon R
%A Kanabar, Varsha
%A Moir, Lyn M
%A Nguyen, Trang T B
%A Oliver, Brian G G
%A Schuliga, Michael
%A Ward, Jane
%T Tissue and matrix influences on airway smooth muscle function.
%B Pulmonary pharmacology & therapeutics
%D 2009
%C United Kingdom
%I Academic Press
%V 22
%N 0
%P 379-87
%@ 1094-5539
%X 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. The mechanisms leading to airway remodelling are not well understood. ASM cells have the potential to play a key role in these processes through the production and release of ECM proteins. The ASM cells and ECM proteins are each able to influence the behaviour and characteristics of the other. The modified ECM profile in the asthmatic airway may contribute to the altered behaviour of the ASM cells, such responses to ECM proteins are modulated through the cell surface expression of integrin receptors. ASM cells from asthmatic individuals express different levels of some integrin subunits compared to nonasthmatic ASM cells, which have the potential to further influence their responses to the ECM proteins in the airways. ECM homeostasis requires the presence and activation of matrix metalloproteinases and their tissue inhibitors, which in turn modulate the interaction of the ASM cells and the ECM proteins. Furthermore, the complex interactions of the ASM cells and the ECM in the asthmatic airways and the role played by external stimuli, such as viral infections, to modulate airway remodelling are currently unknown. This review summarises our current understanding of the influence of the ECM on ASM function.
%Z FOR Codes: 110203


%0 Journal Article
%~ PubMed
%A Huynh, Kerrianne N
%A Oliver, Brian G
%A Stelzer, Sacha
%A Rawlinson, William D
%A Tovey, Euan R
%T A new method for sampling and detection of exhaled respiratory virus aerosols.
%B Clinical Infectious Diseases
%D 2008
%C United States
%I University of Chicago Press
%V 46
%N 1
%P 93-95
%@ 1058-4838
%X 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 after coughing (20 times), talking (20 min), or breathing (20 min) from 6, 5, and 3 patients, respectively.
%Z FOR Codes: 110399


%0 Book Section
%A Black, Judith
%A Burgess, Janette
%A Oliver, Brian
%A Moir, Lyn
%T Altered properties of airway smooth muscle in asthma
%B Airway Smooth Muscle in Asthma and COPD: Biology and Pharmacology
%D 2008
%C United Kingdom
%I John Wiley & Sons Ltd
%V 
%N 
%P 181-199
%@ 978-0-470-06066-7
%E Chung, Kian Fan
%X 
%Z FOR Codes: 110203


%0 Journal Article
%~ PubMed
%A Oliver, Brian G
%A Lim, Sam
%A Wark, Peter
%A Laza-Stanca, Vasile
%A King, Nicholas J C
%A Black, Judith L
%A Burgess, Janette K
%A Roth, Michael
%A Johnston, Sebastian L
%T Rhinovirus exposure impairs immune responses to bacterial products in human alveolar macrophages.
%B Thorax
%D 2008
%C London
%I British Medical Journal Publishing Group
%V 63
%N 6
%P 519-25
%@ 1468-3296
%X 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.
%Z FOR Codes: 110804


%0 Journal Article
%~ PubMed
%A Matsumoto, Hisako
%A Moir, Lyn M
%A Oliver, Brian Gg
%A Burgess, Janette K
%A Roth, Michael
%A Black, Judith L
%A McParland, Brent E
%T Comparison of gel contraction mediated by asthmatic and non-asthmatic airway smooth muscle cells.
%B Thorax
%D 2007
%C London
%I British Medical Journal Publishing Group
%V 62
%N 10
%P 848-54
%@ 1468-3296
%X 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 purpose of this study was to establish a method to measure contraction of ASM cells by embedding them into a collagen gel, and to compare the contraction between subjects with and without asthma.
%Z FOR Codes: 110502 111601


%0 Journal Article
%~ PubMed
%A Burgess, Janette K
%A Oliver, Brian G G
%A Poniris, Maree H
%A Ge, Qi
%A Boustany, Sarah
%A Cox, Natalie
%A Moir, Lyn M
%A Johnson, Peter R A
%A Black, Judith L
%T A phosphodiesterase 4 inhibitor inhibits matrix protein deposition in airways in vitro.
%B The Journal of allergy and clinical immunology
%D 2006
%C US
%I Mosby, Inc
%V 118
%N 3
%P 649-57
%@ 0091-6749
%X 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 examined the effect of corticosteroids, long-acting beta(2)-agonists, and a phosphodiesterase 4 (PDE4) inhibitor on ASM-released connective tissue growth factor (CTGF), collagen I, fibronectin, versican, and IL-6. METHODS: Airway smooth muscle cells from individuals with and without asthma were stimulated with TGF-beta with or without the drugs and CTGF and ECM protein expression measured by real-time PCR, cell surface, or matrix-associated ELISA. IL-6 release was measured by ELISA. Bronchial rings from individuals without asthma were incubated with TGF-beta with or without the drugs. RESULTS: Neither corticosteroids nor long-acting beta(2)-agonists reduced TGF-beta-induced CTGF, collagen I, or fibronectin in either cell type, whereas corticosteroids alone induced the expression of CTGF, collagen I, and fibronectin. These drugs did not prevent the accumulation of TGF-beta-induced proteins in bronchial rings, whereas the PDE4 inhibitor roflumilast inhibited TGF-beta-induced CTGF, collagen I, and fibronectin. CONCLUSION: In our model, current asthma therapies are not able to inhibit matrix protein deposition from ASM cells. The results of this study suggest that the PDE4 inhibitor roflumilast may have a role in regulating the ECM and therefore aspects of airway remodeling in asthma. CLINICAL IMPLICATIONS: Although current asthma therapies are effective in reducing inflammation and symptoms, reversal or prevention of structural changes contributing to remodeling may require additional therapy, which could include PDE4 inhibitors.
%Z FOR Codes: 110502 111601


%0 Journal Article
%~ PubMed
%A Oliver, Brian G
%A Black, Judith L
%T Airway smooth muscle and asthma.
%B Allergology International
%D 2006
%C Japan
%I Japanese Society of Allergology
%V 55
%N 3
%P 215-23
%@ 1323-8930
%X 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-alpha, the influence of an altered extracellular matrix and/or a decrease in release of factors such as PGE(2) 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.
%Z FOR Codes: 111601 110502


%0 Journal Article
%~ PubMed
%A Oliver, Brian G G
%A Johnston, Sebastian L
%A Baraket, Melissa
%A Burgess, Janette K
%A King, Nicholas J C
%A Roth, Michael
%A Lim, Sam
%A Black, Judith L
%T Increased proinflammatory responses from asthmatic human airway smooth muscle cells in response to rhinovirus infection.
%B Respiratory research
%D 2006
%C United Kingdom
%I BioMed Central Ltd.
%V 7
%N 
%P 71
%@ 1465-993X
%X 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 interaction of RV and human airway smooth muscle cells (HASM). We hypothesised that rhinovirus induction of inflammatory cytokine release from airway smooth muscle is augmented and differentially regulated in asthmatic compared to normal HASM cells. METHODS: HASM cells, isolated from either asthmatic or non-asthmatic subjects, were infected with rhinovirus. Cytokine production was assayed by ELISA, ICAM-1 cell surface expression was assessed by FACS, and the transcription regulation of IL-6 was measured by luciferase activity. RESULTS: RV-induced IL-6 release was significantly greater in HASM cells derived from asthmatic subjects compared to non-asthmatic subjects. This response was RV specific, as 5% serum- induced IL-6 release was not different in the two cell types. Whilst serum stimulated IL-8 production in cells from both subject groups, RV induced IL-8 production in only asthmatic derived HASM cells. The transcriptional induction of IL-6 was differentially regulated via C/EBP in the asthmatic and NF-kappaB + AP-1 in the non-asthmatic HASM cells. CONCLUSION: This study demonstrates augmentation and differential transcriptional regulation of RV specific innate immune response in HASM cells derived from asthmatic and non-asthmatics, and may give valuable insight into the mechanisms of RV-induced asthma exacerbations.
%Z FOR Codes: 110701 110804


%0 Journal Article
%~ PubMed
%A Ammit, Alaina J
%A Moir, Lyn M
%A Oliver, Brian
%A Hughes, J Margaret
%A Alkhouri, Hatem
%A Ge, Qi
%A Burgess, Janette K
%A Black, Judith L
%A Roth, M
%T The effect of IL-6 trans-signaling on the pro-remodeling phenotype of airway smooth muscle.
%B American journal of physiology. Lung cellular and molecular physiology
%D 2006
%C United States
%I American Physiological Society
%V 292
%N 
%P L199-206
%@ 1040-0605
%X Increased levels of IL-6 are documented in asthma, but its contribution to the pathology is unknown. Asthma is characterized by airway wall thickening due to increased extracellular matrix deposition, inflammation, angiogenesis, and airway smooth muscle (ASM) mass. IL-6 binds to a specific membrane-bound receptor, IL-6 receptor-alpha (mIL-6Ralpha), and subsequently to the signaling protein gp130. Alternatively, IL-6 can bind to soluble IL-6 recpetor-alpha (sIL-6Ralpha) to stimulate membrane receptor-deficient cells, a process called trans-signaling. We discovered that primary human ASM cells do not express mIL-6Ralpha and, therefore, investigated the effect of IL-6 trans-signaling on the pro-remodeling phenotype of ASM. ASM required sIL-6Ralpha to activate signal transducer and activator 3, with no differences observed between cells from asthmatic subjects compared with controls. Further analysis revealed that IL-6 alone or with sIL-6Ralpha did not induce release of matrix-stimulating factors (including connective tissue growth factor, fibronectin, or integrins) and had no effect on mast cell adhesion to ASM or ASM proliferation. However, in the presence of sIL-6Ralpha, IL-6 increased eotaxin and VEGF release and may thereby contribute to local inflammation and vessel expansion in airway walls of asthmatic subjects. As levels of sIL-6Ralpha are increased in asthma, this demonstration of IL-6 trans-signaling in ASM has relevance to the development of airway remodeling.
%Z FOR Codes: 111601 110203