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Dr Maria Sukkar


Dr Maria Sukkar completed her PhD in Pharmacy at The University of Sydney in 2002. Dr Sukkar’s research expertise is focussed on understanding the cellular and molecular pathways that lead to chronic airway inflammation and airflow obstruction in asthma and chronic obstructive pulmonary disease. Dr Sukkar was a post doctoral research scientist at the National Heart and Lung Institute, Imperial College London for seven years (2001 – 2007) and has held a position as Lecturer in Pharmacy Practice at the Faculty of Pharmacy, The University of Sydney for the past four years (2008 – 2011). Dr Sukkar has principally been involved in developing, teaching and co-ordinating pharmacotherapeutics and professional practice courses for final year Pharmacy students in the Bachelor of Pharmacy at the University of Sydney. Dr Sukkar continues to pursue her research interests in airways disease and currently has several PhD students under her supervision. Dr Sukkar joined the UTS School of Pharmacy as Senior Lecturer in November 2011, and is also an Honorary Associate of the Woolcock Institute of Respiratory Medicine.

Dr Sukkar is an experienced doctoral supervisor and welcomes research degree enquiries via a formal expression of interest (please do not email directly).

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Senior Lecturer, Pharmacy
PhD Pharmacy
+61 2 9514 8302

Research Interests

Dr Sukkar is an experienced doctoral supervisor and welcomes research degree enquiries via a formal expression of interest (please do not email directly).

Can supervise: Yes


Sukkar, M.B. & Chung, K.F. 2008, 'The Airway Smooth Muscle in Chronic Obstructive Pulmonary Disease (COPD)' in Airway Smooth Muscle in Asthma and COPD: Biology and Pharmacology, pp. 201-233.
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Ullah, A.M., Pharm, M., Revez, J., Loh, Z., Simpson, J., Zhang, V., Bain, L., Varelias, A., Rose-John, S., Blumenthal, A., Smyth, M., Hill, G., Sukkar, M., Ferreira, M. & Phipps, S. 2015, 'IL-6R BLOCKADE ATTENUATES EXPERIMENTAL ALLERGIC ASTHMA ASSOCIATED WITH ACTIVATION OF THE IL-6 TRANS-SIGNALLING PATHWAY', RESPIROLOGY, pp. 32-32.
Ullah, M.A., Revez, J., Loh, Z., Simpson, J., Zhang, V., Bain, L., Varelias, A., Rose-John, S., Blumenthal, A., Smyth, M., Hill, G., Sukkar, M., Ferreira, M.A. & Phipps, S. 2015, 'IL-6R blockade attenuates experimental allergic asthma associated with activation of the IL-6 trans-signalling pathway', ALLERGY, pp. 43-44.
Ullah, M.A., Sukkar, M., Ferreira, M. & Phipps, S. 2014, 'IL-6R blockade: A new personalised treatment for asthma?', CYTOKINE, pp. 40-40.
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Ullah, M.A., Loh, Z., Gan, W.J., Zhang, V., Lynch, J., Eacharath, J., Hughes, J.M., Armour, C.L., Phipps, S. & Sukkar, M.B. 2013, 'HMGB1-RAGE AXIS MEDIATES HOUSE DUST MITE INDUCED ALLERGIC SENSITIZATION AND AIRWAY INFLAMMATION', RESPIROLOGY, pp. 25-25.
Manetsch, M., Seidel, P., Che, W., Ge, Q., Sukkar, M. & Ammit, A.J. 2011, 'Effect Of H202 On The Synergistic Upregulation Of TnfAlpha-Induced Cytokines By TLR2 Ligand Engagement', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE.
Sukkar, M.B., Wood, L.G., Tooze, M., Simpson, J.L., McDonald, V.M., Gibson, P. & Wark, P.A. 2011, 'Deficiency Of Srage In Asthma And COPD Is Selectively Associated With Neutrophilic Airway Inflammation', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE.
Sukkar, M.B., Yeo, C.Y., Ge, Q., Armour, C.L., Michaeloudes, C. & Chung, K.F. 2009, 'Is Oxidative Stress an Important Determinant of Airway Smooth Muscle Cytokine and Chemokin Production?', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE.
Michaeloudes, C., Sukkar, M.B., Johnson, M. & Chung, K.F. 2009, 'Regulation of Oxidant and Antioxidant Enzyme Expression by TGF-beta in Human Airway Smooth Muscle Cells', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE.
Sukkar, M.B. & Hughes, J.M. 2001, 'Flow-cytometr1c detection of intracellular gm-csf in human airway smooth muscle cells (asmc)', Respirology.
Rationale: ASMC synthesise many inflammatory mediators and so may be imolved in the regulation of airway inflammation in asthma. Recently, we reported that IL-l and TNF-a prime ASMC to release GM-CSF in response to human serum (Sukkar et al., Med Inflamm 2000;9:173180). ASMC in culture represent a heterogenous population of cells \vith regard to their contractile, proliferative and synthetic functions. The purpose of this study was to develop a methodology for flow-cytometric detection of intracellular GM-CSF in ASMC in order to determine whether cytokine synthesis is a function of all or only a distinct phenotypic subset of cells. Methods: Induction of GM-CSF synthesis: ASMC were pre-treated with IL-l and TNF-a (5-25ng/tnl each) for 24hrs before being incubated in 10% human serum for 24hrs. Brefeldin A ( 10(ig/ml), an inhibitor of intracellular protein transport, was added to the cells for the final 20hrs of the incubation period with human serum. GM-CSF staining: ASMC were fixed in 4% formalin and then incubated with a GM-CSF antibody (Ab) conjugated to R-phycoerythrin (0.2mg/ml) or its isotype control diluted (1;2-1;80) in a solution containing 0.5% saponin (permeabilizing agent). ASMC were w-ashed thoroughly prior to flow-cytometric analysis. Results and Conclusions: Preliminary results indicate that 50% of ASMC synthesise GM-CSF. In ASMC obtained from any given donor, the proportion of cells staining for GM-CSF was dependent on the Ab concentration as well as the amount of GM-CSF production. This is the first study to utilise flott-cytometric techniques for intracellular cytokine detection in ASMC. This methodology will be invaluable for further phenotypic characterisation of synthetic ASMC in culture.
Sukkar, M., Johnson, P., Hughes, J.M. & Armour, C. 1999, 'Responsiveness of human airways in vitro is increased by IL-1 beta and TNF alpha.', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, pp. A124-A124.
Sukkar, M.B., Hughes, J.M., Johnson, P.R.A. & Armour, C.L. 1999, 'Human serum increases human airway smooth muscle cell (ASMC) cytokine synthesis', Respirology.
Chronic inflammation of the airways is a major factor contributing to abnormal airway function in asthma. We have demonstrated that the inflammatory cytokines IL-1 and TNF- induce human ASMC to synthesize GM-CSF, a cytokine involved in the survival and activation of airway inflammatory cells, such as the eosinophil. It was recently demonstrated that IL-1 and TNF- induce the expression of the IgE receptor on human ASMC (Allakhverdiet ai, Am J Respir Crit Care Med 157;A658 1998). These observations prompted us to investigate whether allergen challenge of passively sensitized human ASMC that had been previously treated with IL-1 and TNF-, would result in GM-CSF production by ASMC. Methods: ASMC were stimulated with IL-1 and TNF- in combination (5,10,25ng/ml each) for 24h followed by medium with 10% serum from either an atopic asthmatic allergic to house dust mite (HDM) or a non-atopic non-asthmatic or Monomed A (defined serum substitute), for a further 24h. Following this, ASMC were challenged with HDM for 24h. GM-CSF was measured in supernatants collected after each treatment step by ELISA. Results: HDM challenge did not induce GM-CSF release from human ASMC. However, stimulation of ASMC with atopic asthmatic serum (AAS) or non-atopic non-asthmatic serum (NAS) significantly increased GM-CSF release from ASMC that had been previously exposed to IL-1 and TNF-, but not from those that had not been exposed to cytokines (see table). GM-CSF (pg/ml) (±SEM) IL-1/TNF- (ng/ml) AAS (n=5) NAS (n=5) Monomed A (n=3) 0 4.6 (±3.2) 6.44 (±4.2) 0 (±O) 5 268.8 (±81.1) 331.2 (±54.2) 75.8 (±28.8) 10 407.2 (±99.0) 410 (±40.3) 145.1 (±48.6) 25 603.8(±118.3) 665.2 (±55.0)~~ 244.3 (±111.5) Conclusions: These findings suggest that ASMC, in addition to their contractile function, may play an active role in airway inflammation, particularly during periods of vascular leakage. However, the role of IgE in this is minimal.

Journal articles

Wong, S.L.I. & Sukkar, M.B. 2017, 'The SPARC protein: an overview of its role in lung cancer and pulmonary fibrosis and its potential role in chronic airways disease.', Br J Pharmacol, vol. 174, no. 1, pp. 3-14.
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The SPARC (secreted protein acidic and rich in cysteine) protein is matricellular molecule regulating interactions between cells and their surrounding extracellular matrix (ECM). This protein thus governs fundamental cellular functions such as cell adhesion, proliferation and differentiation. SPARC also regulates the expression and activity of numerous growth factors and matrix metalloproteinases essential for ECM degradation and turnover. Studies in SPARC-null mice have revealed a critical role for SPARC in tissue development, injury and repair and in the regulation of the immune response. In the lung, SPARC drives pathological responses in non-small cell lung cancer and idiopathic pulmonary fibrosis by promoting microvascular remodelling and excessive deposition of ECM proteins. Remarkably, although chronic airway conditions such as asthma and chronic obstructive pulmonary disease (COPD) involve significant remodelling in both the airway and vascular compartments, the role of SPARC in these conditions has thus far been overlooked. In this review, we discuss the role of SPARC in lung cancer and pulmonary fibrosis, as well as potential mechanisms by which it may contribute to the disease process in asthma and COPD.
Arikkatt, J., Ullah, M.A., Short, K.R., Zhang, V., Gan, W.J., Loh, Z., Werder, R.B., Simpson, J., Sly, P.D., Mazzone, S.B., Spann, K.M., Ferreira, M.A.R., Upham, J.W., Sukkar, M.B. & Phipps, S. 2017, 'RAGE deficiency predisposes mice to virus-induced paucigranulocytic asthma', eLife, vol. 6.
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© 2017, eLife Sciences Publications Ltd. All rights reserved.Asthma is a chronic inflammatory disease. Although many patients with asthma develop type-2 dominated eosinophilic inflammation, a number of individuals develop paucigranulocytic asthma, which occurs in the absence of eosinophilia or neutrophilia. The aetiology of paucigranulocytic asthma is unknown. However, both respiratory syncytial virus (RSV) infection and mutations in the receptor for advanced glycation endproducts (RAGE) are risk factors for asthma development. Here, we show that RAGE deficiency impairs anti-viral immunity during an early-life infection with pneumonia virus of mice (PVM; a murine analogue of RSV). The elevated viral load was associated with the release of high mobility group box-1 (HMGB1) which triggered airway smooth muscle remodelling in early-life. Re-infection with PVM in later-life induced many of the cardinal features of asthma in the absence of eosinophilic or neutrophilic inflammation. Anti-HMGB1 mitigated both early-life viral disease and asthma-like features, highlighting HMGB1 as a possible novel therapeutic target.
Harris, J., Lang, T., Thomas, J.P.W., Sukkar, M.B., Nabar, N.R. & Kehrl, J.H. 2017, 'Autophagy and inflammasomes', Molecular Immunology.
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© 2017 Elsevier Ltd.Autophagy is a ubiquitous cellular mechanism for the targeted lysosomal degradation of various cytosolic constituents, from proteins to organelles. As an essential homeostatic mechanism, autophagy is upregulated in response to numerous environmental and pharmacological stimuli, including starvation, where it facilitates the recycling of essential amino acids. In addition, autophagy plays specific roles within the immune system; it serves as a source of peptides for antigen presentation, a mechanism for the engulfment and degradation of intracellular pathogens and as a key regulator of inflammatory cytokines. In particular, autophagy has been shown to play a number of roles in regulating inflammasome activation, from the removal of inflammasome-activating endogenous signals, to the sequestration and degradation of inflammasome components. Autophagy also plays a role in determining the fate of IL-1, which is concentrated in autophagosomes. This review discusses a growing body of literature that suggests autophagy is a critical regulator of inflammasome activation and the subsequent release of IL-1 family cytokines.
Pozzoli, M., Traini, D., Young, P.M., Sukkar, M.B. & Sonvico, F. 2017, 'Development of a Soluplus budesonide freeze-dried powder for nasal drug delivery.', Drug Dev Ind Pharm, pp. 1-9.
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OBJECTIVE: The aim of this work was to develop an amorphous solid dispersions/solutions (ASD) of a poorly soluble drug, budesonide (BUD) with a novel polymer Soluplus(®) (BASF, Germany) using a freeze-drying technique, in order to improve dissolution and absorption through the nasal route. SIGNIFICANCE: The small volume of fluid present in the nasal cavity limits the absorption of a poorly soluble drug. Budesonide is a corticosteroid, practically insoluble and normally administered as a suspension-based nasal spray. METHODS: The formulation was prepared through freeze-drying of polymer-drug solution. The formulation was assessed for its physicochemical (specific surface area, calorimetric analysis and X-ray powder diffraction), release properties and aerodynamic properties as well as transport in vitro using RPMI 2650 nasal cells, in order to elucidate the efficacy of the Soluplus-BUD formulation. RESULTS: The freeze-dried Soluplus-BUD formulation (LYO) showed a porous structure with a specific surface area of 1.4334±0.0178 m(2)/g. The calorimetric analysis confirmed an interaction between BUD and Soluplus and X-ray powder diffraction the amorphous status of the drug. The freeze-dried formulation (LYO) showed faster release compared to both water-based suspension and dry powder commercial products. Furthermore, a LYO formulation, bulked with calcium carbonate (LYO-Ca), showed suitable aerodynamic characteristics for nasal drug delivery. The permeation across RPMI 2650 nasal cell model was higher compared to a commercial water-based BUD suspension. CONCLUSIONS: Soluplus has been shown to be a promising polymer for the formulation of BUD amorphous solid suspension/solution. This opens up opportunities to develop new formulations of poorly soluble drug for nasal delivery.
Gold, M.J., Hiebert, P.R., Park, H.Y., Stefanowicz, D., Le, A., Starkey, M.R., Deane, A., Brown, A.C., Liu, G., Horvat, J.C., Ibrahim, Z.A., Sukkar, M.B., Hansbro, P.M., Carlsten, C., VanEeden, S., Sin, D.D., McNagny, K.M., Knight, D.A. & Hirota, J.A. 2016, 'Mucosal production of uric acid by airway epithelial cells contributes to particulate matter-induced allergic sensitization.', Mucosal immunology, vol. 9, no. 3, pp. 809-820.
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Exposure to particulate matter (PM), a major component of air pollution, contributes to increased morbidity and mortality worldwide. PM induces innate immune responses and contributes to allergic sensitization, although the mechanisms governing this process remain unclear. Lung mucosal uric acid has also been linked to allergic sensitization. The links among PM exposure, uric acid, and allergic sensitization remain unexplored. We therefore investigated the mechanisms behind PM-induced allergic sensitization in the context of lung mucosal uric acid. PM10 and house dust mite exposure selectively induced lung mucosal uric acid production and secretion in vivo, which did not occur with other challenges (lipopolysaccharide, virus, bacteria, or inflammatory/fibrotic stimuli). PM10-induced uric acid mediates allergic sensitization and augments antigen-specific T-cell proliferation, which is inhibited by uricase. We then demonstrate that human airway epithelial cells secrete uric acid basally and after stimulation through a previously unidentified mucosal secretion system. Our work discovers a previously unknown mechanism of air pollution-induced, uric acid-mediated, allergic sensitization that may be important in the pathogenesis of asthma.
Pozzoli, M., Ong, H.X., Morgan, L., Sukkar, M., Traini, D., Young, P.M. & Sonvico, F. 2016, 'Application of RPMI 2650 Nasal Cell Model to a 3D Printed Apparatus for the Testing of Drug Deposition and Permeation of Nasal Products.', European Journal of Pharmaceutics and Biopharmaceutics, vol. 107, pp. 223-233.
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The aim of this study was to incorporate an optimized RPMI2650 nasal cell model into a 3D printed model of the nose to test deposition and permeation of drugs intended for use in the nose. The nasal cell model was optimized for barrier properties in terms of permeation marker and mucus production. RT-qPCR was used to determine the xenobiotic transporter gene expression of RPMI 2650 cells in comparison with primary nasal cells. After 14 days in culture, the cells were shown to produce mucus, and to express TEER (define) values and sodium fluorescein permeability consistent with values reported for excised human nasal mucosa. In addition, good correlation was found between RPMI 2650 and primary nasal cells transporters expression values. The purpose built 3D printed model of the nose takes the form of an expansion chamber with inserts for cells and an orifice for insertion of a spray drug delivery device. This model was validated against the FDA glass chamber with cascade impactors that is currently approved for studies of nasal products. No differences were found between the two apparatus. The apparatus including the nasal cell model was used to test a commercial nasal product containing budesonide (Rhinocort, AstraZeneca, Australia). Drug deposition and transport studies on RPMI 2650 were successfully performed. The new 3D printed apparatus that incorporate cells can be used as valid in vitro model to test nasal products in conditions that mimic the delivery from nasal devices in real life conditions.
Clementino, A., Batger, M., Garrastazu, G., Pozzoli, M., Del Favero, E., Rondelli, V., Gutfilen, B., Barboza, T., Sukkar, M.B., Souza, S.A.L., Cantu, L. & Sonvico, F. 2016, 'The nasal delivery of nanoencapsulated statins - an approach for brain delivery', International Journal of Nanomedicine, vol. 11, pp. 6575-6590.
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Ullah, M.A., Revez, J.A., Loh, Z., Simpson, J., Zhang, V., Bain, L., Varelias, A., Rose-John, S., Blumenthal, A., Smyth, M.J., Hill, G.R., Sukkar, M.B., Ferreira, M.A. & Phipps, S. 2015, 'Allergen-induced IL-6 trans-signaling activates T cells to promote type 2 and type 17 airway inflammation.', The Journal of allergy and clinical immunology, vol. 136, no. 4, pp. 1065-1073.
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A variant in the IL-6 receptor (IL-6R) gene increases asthma risk and is predicted to decrease IL-6 classic signaling and increase IL-6 trans-signaling. This suggests that inhibition of IL-6 trans-signaling, but not classic signaling, might suppress allergic airway inflammation.We sought to determine whether IL-6 signaling contributes to (1) acute experimental asthma induced by clinically relevant allergens and (2) variation in asthma clinical phenotypes in asthmatic patients.Mice were sensitized to house dust mite (HDM) or cockroach at day 0, treated with IL-6R inhibitors at day 13, and challenged with the same allergen at days 14 to 17. End points were measured 3 hours after the final challenge. IL-6 and soluble IL-6 receptor (sIL-6R) expression in induced sputum of asthmatic patients was correlated with asthma clinical phenotypes.Both HDM and cockroach induced a type 2/type 17 cytokine profile and mixed granulocytic inflammation in the airways. Both allergens increased IL-6 expression in the airways, but only cockroach induced sIL-6R expression. Therefore HDM challenge promoted IL-6 classic signaling but not trans-signaling; in this model treatment with anti-IL-6R did not suppress airway inflammation. In contrast, cockroach-induced inflammation involved activation of IL-6 trans-signaling and production of IL-17A by T cells. Anti-IL-6R, selective blockade of sIL-6R, or T-cell deficiency significantly attenuated cockroach-induced inflammation. Asthmatic patients with high airway IL-6 and sIL-6R levels were enriched for the neutrophilic and mixed granulocytic subtypes.Experimental asthma associated with both high IL-6 and high sIL-6R levels in the airways is attenuated by treatment with IL-6R inhibitors.
Ullah, M.A., Loh, Z., Gan, W.J., Zhang, V., Yang, H., Li, J.H., Yamamoto, Y., Schmidt, A.M., Armour, C.L., Hughes, J.M., Phipps, S. & Sukkar, M.B. 2014, 'Receptor for advanced glycation end products and its ligand high-mobility group box-1 mediate allergic airway sensitization and airway inflammation.', The Journal of allergy and clinical immunology, vol. 134, no. 2, pp. 440-450.
BACKGROUND: The receptor for advanced glycation end products (RAGE) shares common ligands and signaling pathways with TLR4, a key mediator of house dust mite (Dermatophagoides pteronyssinus) (HDM) sensitization. We hypothesized that RAGE and its ligand high-mobility group box-1 (HMGB1) cooperate with TLR4 to mediate HDM sensitization. OBJECTIVES: To determine the requirement for HMGB1 and RAGE, and their relationship with TLR4, in airway sensitization. METHODS: TLR4(-/-), RAGE(-/-), and RAGE-TLR4(-/-) mice were intranasally exposed to HDM or cockroach (Blatella germanica) extracts, and features of allergic inflammation were measured during the sensitization or challenge phase. Anti-HMGB1 antibody and the IL-1 receptor antagonist Anakinra were used to inhibit HMGB1 and the IL-1 receptor, respectively. RESULTS: The magnitude of allergic airway inflammation in response to either HDM or cockroach sensitization and/or challenge was significantly reduced in the absence of RAGE but not further diminished in the absence of both RAGE and TLR4. HDM sensitization induced the release of HMGB1 from the airway epithelium in a biphasic manner, which corresponded to the sequential activation of TLR4 then RAGE. Release of HMGB1 in response to cockroach sensitization also was RAGE dependent. Significantly, HMGB1 release occurred downstream of TLR4-induced IL-1, and upstream of IL-25 and IL-33 production. Adoptive transfer of HDM-pulsed RAGE(+/+)dendritic cells to RAGE(-/-) mice recapitulated the allergic responses after HDM challenge. Immunoneutralization of HMGB1 attenuated HDM-induced allergic airway inflammation. CONCLUSION: The HMGB1-RAGE axis mediates allergic airway sensitization and airway inflammation. Activation of this axis in response to different allergens acts to amplify the allergic inflammatory response, which exposes it as an attractive target for therapeutic intervention.
Sukkar, M. & Postma, D.S. 2013, 'Receptor for advanced glycation end products and soluble receptor for advanced glycation end products: A balancing act in chronic obstructive pulmonary disease?', American Journal of Respiratory and Critical Care Medicine, vol. 188, no. 8, pp. 893-894.
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The receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor implicated in immune/inflammatory and tissue remodeling responses in numerous pathological states. RAGE plays an important role in lung development during embryogenesis and homeostatic maintenance of the adult lung, where its expression is high relative to other organ tissues (1, 2). RAGE exists primarily in two forms, a transmembrane protein consisting of a cytoplasmic signaling domain and an extracellular ligand-binding domain, and a soluble protein that lacks the transmembrane and cytoplasmic domains. Soluble RAGE (sRAGE) circulates in blood under physiological conditions and is an endogenous inhibitor of RAGE signaling. Although sRAGE is primarily generated through alternative RNA splicing, soluble isoforms are also produced via proteolytic ectodomain shedding of the cell-bound receptor (1). Recent evidence suggests that levels of RAGE expression and sRAGE isoforms are altered in chronic obstructive pulmonary disease (COPD) (1). Higher RAGE expression is observed in epithelial and smooth muscle layers of the airway wall in subjects with COPD than in smokers and never-smokers without COPD (1). In addition, RAGE expression is higher in alveolar walls of resection tissue samples of subjects with than without COPD (3). On the other hand, we and others have demonstrated reduced airway and systemic levels of sRAGE in subjects with COPD, and shown this to be associated with the degree of lung function impairment, predominance of neutrophilic lung inflammation, and both the presence and progression of emphysema (1, 4-6). Boschetto and colleagues did not observe reduced plasma sRAGE in subjects with mild-to-moderate COPD, further suggesting that sRAGE deficiency is associated with more severe disease and/ or disease progression (7).
Ibrahim, Z.A., Armour, C.L., Phipps, S. & Sukkar, M. 2013, 'RAGE and TLRs: relatives, friends or neighbours?', Molecular Immunology, vol. 56, no. 4, pp. 739-744.
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The innate immune system forms the first line of protection against infectious and non-infectious tissue injury. Cells of the innate immune system detect pathogen-associated molecular patterns or endogenous molecules released as a result of tissue injury or inflammation through various innate immune receptors, collectively termed pattern-recognition receptors. Members of the Toll-like receptor (TLR) family of pattern-recognition receptors have well established roles in the host immune response to infection, while the receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor predominantly involved in the recognition of endogenous molecules released in the context of infection, physiological stress or chronic inflammation. RAGE and TLRs share common ligands and signaling pathways, and accumulating evidence points towards their co-operative interaction in the host immune response. At present however, little is known about the mechanisms that result in TLR versus RAGE signalling or RAGETLR cross-talk in response to their shared ligands. Here we review what is known in relation to the physicochemical basis of ligand interactions between TLRs and RAGE, focusing on three shared ligands of these receptors: HMGB1, S100A8/A9 and LPS. Our aim is to discuss what is known about differential ligand interactions with RAGE and TLRs and to highlight important areas for further investigation so that we may better understand the role of these receptors and their relationship in host defense.
Sukkar, M., Wood, L., Tooze, M., Simpson, J., McDonald, V., Gibson, P. & Wark, P. 2012, 'Soluble RAGE is deficient in neutrophilic asthma and COPD', European Respiratory Journal, vol. 39, pp. 721-729.
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The receptor for advanced glycation end-products (RAGE) is a pattern-recognition receptor involved in the host response to injury, infection and inflammation. It is a membrane receptor, but also has soluble forms (sRAGE). Deficiencies in sRAGE are linked to heightened inflammation in various chronic conditions. We determined whether airway and systemic levels of sRAGE and the RAGE ligands HMGB1 (high-mobility group box-1) and serum amyloid A (SAA) are related to neutrophilic inflammation in asthma and chronic obstructive pulmonary disease (COPD).
Sukkar, M., Ullah, M.A., Gan, W.J., Wark, P.A., Chung, K.F., Hughes, M.J., Armour, C.L. & Phipps, S. 2012, 'RAGE: a new frontier in chronic airways disease', British Journal of Pharmacology, vol. 167, no. 6, pp. 1161-1176.
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Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous inflammatory disorders of the respiratory tract characterized by airflow obstruction. It is now clear that the environmental factors that drive airway pathology in asthma and COPD, including allergens, viruses, ozone and cigarette smoke, activate innate immune receptors known as pattern-recognition receptors, either directly or indirectly by causing the release of endogenous ligands. Thus, there is now intense research activity focused around understanding the mechanisms by which pattern-recognition receptors sustain the airway inflammatory response, and how these mechanisms might be targeted therapeutically. One pattern-recognition receptor that has recently come to attention in chronic airways disease is the receptor for advanced glycation end products (RAGE). RAGE is a member of the immunoglobulin superfamily of cell surface receptors that recognizes pathogen- and host-derived endogenous ligands to initiate the immune response to tissue injury, infection and inflammation. Although the role of RAGE in lung physiology and pathophysiology is not well understood, recent genome-wide association studies have linked RAGE gene polymorphisms with airflow obstruction. In addition, accumulating data from animal and clinical investigations reveal increased expression of RAGE and its ligands, together with reduced expression of soluble RAGE, an endogenous inhibitor of RAGE signalling, in chronic airways disease. In this review, we discuss recent studies of the ligandRAGE axis in asthma and COPD, highlight important areas for future research and discuss how this axis might potentially be harnessed for therapeutic benefit in these conditions.
Manetsch, M., Seidel, P., Heintz, U., Che, W., Hughes, J.M., Ge, Q., Sukkar, M.B. & Ammit, A.J. 2012, 'TLR2 ligand engagement upregulates airway smooth muscle TNF-induced cytokine production.', American journal of physiology. Lung cellular and molecular physiology, vol. 302, no. 9, pp. L838-L845.
Airway inflammation and respiratory infections are important factors contributing to disease exacerbation in chronic airway diseases such as asthma and chronic obstructive pulmonary disease. Airway smooth muscle (ASM) cells express Toll-like receptors (TLRs) and may be involved in the amplification of airway inflammatory responses during infectious exacerbations. We determined whether infectious stimuli (mimicked using Pam3CSK4, a synthetic bacterial lipopeptide that binds to TLR2/TLR1) further enhance ASM cell inflammatory responses to TNF in vitro and the signaling pathways involved. Human ASM cells were pretreated for 1 h with Pam3CSK4 (1 g/ml) in the absence or presence of TNF (10 ng/ml), and IL-6 and IL-8 release was measured after 24 h. As expected, stimulation with Pam3CSK4 or TNF alone induced significant IL-6 and IL-8 release. Furthermore, Pam3CSK4 significantly increased TNF-induced IL-6 and IL-8 mRNA expression and protein release and neutrophil chemotactic activity. The potentiating effect of Pam3CSK4 on TNF-induced inflammatory responses was not due to enhanced TLR2 expression nor did it involve augmentation of NF-B or MAPK signaling pathways. Rather, Pam3CSK4 induced cAMP response element (CRE) binding protein phosphorylation and induced CRE-mediated transcriptional regulation, suggesting that Pam3CSK4 and TNF are acting in concert to enhance ASM cytokine secretion via parallel transcriptional pathways. Our findings suggest that ASM cells may be involved in the amplification of airway inflammatory responses during infectious exacerbations in chronic airway disease.
Michaeloudes, C., Sukkar, M., Khorasani, N.M. & Bhavsar, P.K. 2011, 'TGF-B regulates Nox4, MnSOD and catalase expression, and IL-6 release in airway smooth muscle cells', American Journal of Physiology: Lung Cellular and Molecular Physiology, vol. 300, pp. 295-304.
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Reactive oxygen species (ROS) are generated as a result of normal cellular metabolism, mainly through the mitochondria and peroxisomes, but their release is enhanced by the activation of oxidant enzymes such as NADPH oxidases or downregulation of endogenous antioxidant enzymes such as manganese-superoxide dismutase (MnSOD) and catalase. Transforming growth factor-B (TGF-B), found to be overexpressed in airway smooth muscle (ASM) from asthmatic and chronic obstructive pulmonary disease patients, may be a pivotal regulator of abnormal ASM cell (ASMC) function in these diseases. An important effect of TGF-B on ASMC inflammatory responses is the induction of IL-6 release. TGF-B also triggers intracellular ROS release in ASMCs by upregulation of NADPH oxidase 4 (Nox4). However, the effect of TGF-B on the expression of key antioxidant enzymes and subsequently on oxidant/antioxidant balance is unknown. Moreover, the role of redoxdependent pathways in the mediation of the proinflammatory effects of TGF-B in ASMCs is unclear. In this study, we show that TGF-B induced the expression of Nox4 while at the same time inhibiting the expression of MnSOD and catalase. This change in oxidant/antioxidant enzymes was accompanied by elevated ROS levels and IL-6 release. Further studies revealed a role for Smad3 and phosphatidylinositol kinase-mediated pathways in the induction of oxidant/antioxidant imbalance and IL-6 release. The changes in oxidant/antioxidant enzymes and IL-6 release were reversed by the antioxidants N-acetylcysteine (NAC) and ebselen through inhibition of Smad3 phosphorylation, indicating redox-dependent activation of Smad3 by TGF-B. Moreover, these findings suggest a potential role for NAC in preventing TGF-B-mediated pro-oxidant and proinflammatory responses in ASMCs. Knockdown of Nox4 using small interfering RNA partially prevented the inhibition of MnSOD but had no effect on catalase and IL-6 expression. These findings provide novel insights into redo regul...
Kritikos, V.S., Woulfe, J., Sukkar, M.B. & Saini, B. 2011, 'Intergroup peer assessment in problem-based learning tutorials for undergraduate Pharmacy students', American Journal of Pharmaceutical Education, vol. 75, no. 4.
Objective. To develop, implement, and evaluate a process of intergroup peer assessment and feedback using problem-based learning (PBL) tutorials. Methods. A peer-assessment process was used in a PBL tutorial setting for an integrated pharmacy practice course in which small groups of students graded each others' PBL case presentations and provided feedback in conjunction with facilitator assessment. Assessment. Students' quantitative and qualitative perceptions of the peer assessment process were triangulated with facilitator feedback. Students became more engaged, confident, and motivated, and developed a range of self-directed, life-long learning skills. Students had mixed views regarding the fairness of the process and grade descriptors. Facilitators strongly supported the peer assessment process. Conclusions. Peer assessment is an appropriate method to assess PBL skills and is endorsed by students as appropriate and useful.
Clarke, D., Damera, G., Sukkar, M. & Tliba, O. 2009, 'Transcriptional regulation of cytokine function in airway smooth muscle cells', Pulmonary Pharmacology and Therapeutics, vol. 22, no. 5, pp. 436-445.
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Despite numerous studies of the cellular effects of cytokines on cultured ASM, few have identified intracellular signaling pathways by which cytokines modulate or induce these cellular responses. In this review we provide an overview of the transcriptional mechanisms as well as intracellular signaling pathways regulating cytokine functions in ASM cells. The recent discovery of toll-like receptors in ASM cells represents a significant development in our understanding of the immuno-modulatory capabilities of ASM cells. Thus, we also review emerging evidence of the inflammatory response to toll-like receptor activation in ASM cells.
Issa, R., Sorrentino, R., Sukkar, M., Sriskandan, S., Chung, K.F. & Mitchell, J. 2008, 'Differential regulation of CCL-11/eotaxin-1 and CXCL-8/IL-8 by Gram-positive and Gram-negative bacteria in human airway smooth muscle cells', Respiratory Research, vol. 9, no. 30, pp. 1-8.
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Bacterial infections are a cause of exacerbation of airway disease. Airway smooth muscle cells (ASMC) are a source of inflammatory cytokines/chemokines that may propagate local airway inflammatory responses. We hypothesize that bacteria and bacterial products could induce cytokine/chemokine release from ASMC. Our findings that ASMC can respond directly to Gram-negative and Gram-positive bacteria by releasing the neutrophil selective chemokine, CXCL-8, is consistent with what we know about the role of neutrophil recruitment in bacterial infections in the lung. Our findings that bacteria inhibit the release of the eosinophil selective chemokine, eotaxin-1 may help to explain the mechanisms by which bacterial immunotherapy reduces allergic inflammation in the lung.
Oltmanns, U., Walters, M., Sukkar, M., Xie, S., Issa, R., Mitchell, J., Johnson, M. & Chung, K. 2008, 'Fluticasone, But Not Salmeterol, Reduces Cigarette Smoke-induced Production Of Interleukin-8 In Human Airway Smooth Muscle', Pulmonary Pharmacology & Therapeutics, vol. 21, no. 2, pp. 292-297.
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Cigarette smoke is the leading risk factor for the development of chronic obstructive pulmonary disease. We have recently shown that cigarette smoke extract synergises with tumour necrosis factor alpha (TNF alpha) in the induction of interleukin-8 (IL-8)
Zuyderduyn, S., Sukkar, M., Fust, A., Dhaliwal, S. & Burgess, J.K. 2008, 'Treating asthma means treating airway smooth muscle cells', European Respiratory Journal, vol. 32, no. 2, pp. 265-274.
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Asthma is characterised by airway hyperresponsiveness, airway inflammation and airway remodelling. Airway smooth muscle cells are known to be the main effector cells of airway narrowing. In the present paper, studies will be discussed that have led to a novel view of the role of airway smooth muscle in the pathogenesis of asthma in which airway hyperresponsiveness, remodelling and inflammation are, at least in part, attributable to airway smooth muscle. Furthermore, how this new view may lead to a change in the phenotyping and treatment of patients with asthma will be discussed.
Bhavsar, P.K., Sukkar, M., Khorasani, N.M., Lee, K. & Chung, K.F. 2008, 'Glucocorticoid suppression of CX3CL1 (fractalkine) by reduced gene promoter recruitment of NF-kB', The Journal of the Federation of American Societies for Experimental Biology, vol. 22, pp. 1807-1816.
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Respiratory epithelial cells are a source of CX3CL1 (fractalkine), which mediates cell adhesion and acts as a chemoattractant for monocytes, T cells, and mast cells. We show, in lung A549 epithelial cells, that the tumor necrosis factor-α (TNF-α) and IFNγ synergistically induced protein release and mRNA expression of CX3CL1 is inhibited by dexamethasone, without interfering with cytokine-induced nuclear translocation of NF-κB, and by an inhibitor of IκB kinase 2, AS602868. DNA binding assays confirmed the ability of NF-κB to bind to the proximal CX3CL1 promoter. Chromatin immunoprecipitation assays showed a 5-fold increase in the recruitment of NF-κB to the CX3CL1 gene promoter in response to IFNγ/TNF-α; this too was reversed by dexamethasone. In contrast, dexamethasone did not displace NF-κB from the granulocyte-macrophage colony-stimulating factor gene promoter. We conclude that CX3CL1 expression is regulated through the NF-κB pathway and that dexamethasone inhibits CX3CL1 expression through a glucocorticoid receptor-dependent (RU486 sensitive) mechanism. This study also provides support for the action of glucocorticoids mediating their suppressive effects on expression by interfering with the binding of transcriptional activators at native gene promoters.
Kaur, M., Holden, N.S., Wilson, S.M., Sukkar, M.B., Chung, K.F., Barnes, P.J., Newton, R. & Giembycz, M.A. 2008, 'Effect of beta2-adrenoceptor agonists and other cAMP-elevating agents on inflammatory gene expression in human ASM cells: a role for protein kinase A.', American journal of physiology. Lung cellular and molecular physiology, vol. 295, no. 3, pp. L505-L514.
In diseases such as asthma, airway smooth muscle (ASM) cells play a synthetic role by secreting inflammatory mediators such as granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, or IL-8 and by expressing surface adhesion molecules, including ICAM-1. In the present study, PGE(2), forskolin, and short-acting (salbutamol) and long-acting (salmeterol and formoterol) beta(2)-adrenoceptor agonists reduced the expression of ICAM-1 and the release of GM-CSF evoked by IL-1beta in ASM cells. IL-1beta-induced IL-8 release was also repressed by PGE(2) and forskolin, whereas the beta(2)-adrenoceptor agonists were ineffective. In each case, repression of these inflammatory indexes was prevented by adenoviral overexpression of PKIalpha, a highly selective PKA inhibitor. These data indicate a PKA-dependent mechanism of repression and suggest that agents that elevate intracellular cAMP, and thereby activate PKA, may have a widespread anti-inflammatory effect in ASM cells. Since ICAM-1 and GM-CSF are highly NF-kappaB-dependent genes, we used an adenoviral-delivered NF-kappaB-dependent luciferase reporter to examine the effects of forskolin and the beta(2)-adrenoceptor agonists on NF-kappaB activation. There was no effect on luciferase activity measured in the presence of forskolin or beta(2)-adrenoceptor agonists. This finding is consistent with the observation that IL-1beta-induced expression of IL-6, a known NF-kappaB-dependent gene in ASM, was also unaffected by beta(2)-adrenoceptor agonists, forskolin, PGE(2), 8-bromo-cAMP, or rolipram. Collectively, these results indicate that repression of IL-1beta-induced ICAM-1 expression and GM-CSF release by cAMP-elevating agents, including beta(2)-adrenoceptor agonists, may not occur through a generic effect on NF-kappaB.
Issa, R., Xie, S., Khorasani, N., Sukkar, M., Adcock, I., Lee, K. & Chung, K. 2007, 'Corticosteroid Inhibition Of Growth-related Oncogene Protein-alpha Via Mitogen-activated Kinase Phosphatase-1 In Airway Smooth Muscle Cells', Journal Of Immunology, vol. 178, no. 11, pp. 7366-7375.
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Expression of the inflammatory chemokine, growth-related oncogene protein-alpha (GRO-alpha), from airway smooth muscle cells (ASMC) is regulated by pathways involving NF-kappa B and MAPK activation. We determined the effects of dexamethasone on GRO-alpha
Torrego, A., Hew, M., Oates, T., Sukkar, M. & Chung, K.F. 2007, 'Expression and activation of TGF-b isoforms in acute allergen-induced remodelling in asthma', Thorax, vol. 62, no. 4, pp. 307-313.
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Aim: To determine the effect of allergen challenge on airway inflammation and remodelling and whether TGF-b isoforms and the Smad signalling pathways are involved. Thirteen patients with atopic asthma underwent inhalational challenge with 0.9% saline, followed by allergen 3-4 weeks later. After both challenges, fibreoptic bronchoscopy was undertaken to obtain bronchial biopsies and tissue samples were processed for immunohistochemistry and examined by microscopy. Conclusions: TGF-b2 may contribute to the remodelling changes in allergic asthma following single allergen exposure.
Lu, D., Xie, S., Sukkar, M., Lu, X., Scully, M. & Chung, K.F. 2007, 'Inhibition of Airway Smooth Muscle Adhesion and Migration by the Disintegrin Domain of ADAM-15', American Journal of Respiratory Cell and Molecular Biology, vol. 37, no. 4, pp. 494-500.
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Disintegrin and metalloprotease proteins (ADAMs) are membrane anchored glycoproteins involved in cell adhesion, cell fusion, protein ecto-domain shedding, and intracellular signaling. We examined whether the disintegrin domain of ADAM-15 (named ddADAM-15) containing an Asp-Gly Asp (RGD) integrin-binding motif could interfere with airway smooth muscle cell (ASMC) adhesion and migration.
Xie, S., Sukkar, M.B., Issa, R., Khorasani, N.M. & Chung, K.F. 2007, 'Mechanisms of induction of airway smooth muscle hyperplasia by transforming growth factor-beta.', American journal of physiology. Lung cellular and molecular physiology, vol. 293, no. 1, pp. L245-L253.
Airway smooth muscle (ASM) hyperplasia is a characteristic feature of the asthmatic airway, but the underlying mechanisms that induce ASM hyperplasia remain unknown. Because transforming growth factor (TGF)-beta is a potent regulator of ASM cell proliferation, we determined its expression and mitogenic signaling pathways in ASM cells. We obtained ASM cells by laser capture microdissection of bronchial biopsies and found that ASM cells from asthmatic patients expressed TGF-beta1 mRNA and protein to a greater extent than nonasthmatic individuals using real-time RT-PCR and immunohistochemistry, respectively. TGF-beta1 stimulated the growth of nonconfluent and confluent ASM cells either in the presence or absence of serum in a time- and concentration-dependent manner. The mitogenic activity of TGF-beta1 on ASM cells was inhibited by selective inhibitors of TGF-beta receptor I kinase (SD-208), phosphatidylinositol 3-kinase (PI3K, LY-294002), ERK (PD-98059), JNK (SP-600125), and NF-kappaB (AS-602868). On the other hand, p38 MAPK inhibitor (SB-203580) augmented TGF-beta1-induced proliferation. To study role of the Smads, we transduced ASM cells with an adenovirus vector-expressing Smad4, Smad7, or dominant-negative Smad3 and found no involvement of these Smads in TGF-beta1-induced proliferation. Dexamethasone caused a dose-dependent inhibition in TGF-beta1-induced proliferation. Our findings suggest that TGF-beta1 may act in an autocrine fashion to induce ASM hyperplasia, mediated by its receptor and several kinases including PI3K, ERK, and JNK, whereas p38 MAPK is a negative regulator. NF-kappaB is also involved in the TGF-beta1 mitogenic signaling, but Smad pathway does not appear important.
Catley, M.C., Sukkar, M., Chung, K., Jaffee, B.D., Liao, S.M., Coyle, A.J., Haddad, E., Barnes, P.J. & Newton, R. 2006, 'Validation of the anti-inflammatory properties of small molecule I kappa B kinase (IKK)-2 inhibitors by comparison with adenoviral-mediated delivery of dominant-negative IKK1 and IKK2 in human airways smooth muscle', Molecular Pharmacology, vol. 70, no. 2, pp. 697-705.
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Bayram, H., Ito, K., Issa, R., Ito, M., Sukkar, M. & Chung, K.F. 2006, 'Regulation of human lung epithelial cell numbers by diesel exhaust particles', European Respiratory Journal, vol. 27, no. 4, pp. 705-713.
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Issa, R., Xie, S., Lee, K., Standbridge, R.D., Bhavsar, P., Sukkar, M. & Chung, K. 2006, 'GRO-alpha regulation in airway smooth muscle by IL-1 beta and TNF-alpha: role of NF-kappa B and MAP kinases', American Journal of Physiology: Lung Cellular and Molecular Physiology, vol. 291, no. 1, pp. 66-74.
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growth-related oncogene protein-alpha; extracellular signal kinase; NH2-regulated kinase; Jun NH2; terminal kinase; nuclear factor-kappaB
Sukkar, M., Xie, S., Khorasani, N.M., Kon, O.M., Stanbridge, R.D., Issa, R. & Chung, K. 2006, 'Toll-like receptor 2, 3, and 4 expression and function in human airway smooth muscle', Journal of Allergy and Clinical Immunology, vol. 118, no. 3, pp. 641-648.
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oltmanns, U., Sukkar, M., Xie, S., John, M. & Chung, K.F. 2005, 'Induction of Human Airway Smooth Muscle Apoptosis by Neutrophils and Neutrophil Elastase', American Journal of Respiratory Cell and Molecular Biology, vol. 32, pp. 334-341.
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Xie, S., Sukkar, M., Issa, R., Oltmanns, U., Nicholson, A.G. & Chung, K. 2005, 'Regulation of TGF-beta 1-induced connective tissue growth factor expression in airway smooth muscle cells', American Journal of Physiology: Lung Cellular and Molecular Physiology, vol. 288, no. 1, pp. 68-76.
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Xie, S., Issa, R., Sukkar, M., Oltmanns, U., Bhavsar, P.K., Papi, A., Caramori, G., Adcock, I. & Chung, K.F. 2005, 'Induction and regulation of matrix metalloproteinase-12 in human airway smooth muscle cells', Respiratory Research, vol. 6, no. 148, pp. 1-11.
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Jarai, G., Sukkar, M., Garrett, S., Duroudier, N., Westwick, J., Adcock, I. & Chung, K. 2004, 'Effects Of Interleukin-1 Beta, Interleukin-13 And Transforming Growth Factor-beta On Gene Expression In Human Airway Smooth Muscle Using Gene Microarrays', European Journal Of Pharmacology, vol. 497, no. 3, pp. 255-265.
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Inflammatory gene expression in airway smooth muscle may be influenced by its inflammatory milieu. We analysed the gene expression profile of airway smooth muscle cells cultured from human airways exposed to a pro-inflammatory cytokine, interleukin-1beta
Sukkar, M., Stanley, A.J., Blake, A.E., Hodgkin, P.D., Johnson, P.R., Armour, C.L. & Hughes, M.J. 2004, ''Proliferative' and 'synthetic' airway smooth muscle cells are overlapping populations', Immunology And Cell Biology, vol. 82, no. 5, pp. 471-478.
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Sukkar, M., Issa, R., Xie, S., Oltmanns, U., Newton, R. & Chung, K. 2004, 'Fractalkine/CX(3)CL1 production by human airway smooth muscle cells: induction by IFN-gamma and TNF-alpha and regulation by TGF-beta and corticosteroids', American Journal of Physiology: Lung Cellular and Molecular Physiology, vol. 287, no. 6, pp. 1230-1240.
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Oltmanns, U., Issa, R., Sukkar, M., John, M. & Chung, K. 2003, 'Role of c-jun N-terminal kinase in the induced release of GM-CSF, RANTES and IL-8 from human airway smooth muscle cells', British Journal Of Pharmacology, vol. 139, no. 6, pp. 1228-1234.
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Sukkar, M., Hughes, M.J., Armour, C.L. & Johnson, P.R. 2001, 'Tumour necrosis factor-a potentiates contraction of human bronchus in vitro', Respirology, vol. 6, no. 3, pp. 199-203.
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Sukkar, M., Hughes, J.M., Johnson, P.R. & Armour, C.L. 2000, 'GM-CSF production from human airway smooth muscle cells is potentiated by human serum', Mediators of Inflammation, vol. 9, no. 3-4, pp. 161-168.
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Sukkar, M. 2008, 'The toll on the road to allergic airways disease', pp. 71-73.
The discovery of human toll-like receptors that help defend against microbial infection has led to significant advances in our understanding of the interplay between microbial exposure, immune system development and allergic disease at multiple levels.