Publications
120 results found
Birrell MA, Maher SA, Dekkak B, et al., 2015, Anti-inflammatory effects of PGE(2) in the lung: role of the EP4 receptor subtype, Thorax, Vol: 70, Pages: 740-747, ISSN: 0040-6376
Background Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory diseases of the airway. Current treatment options (long acting β-adrenoceptor agonists and glucocorticosteroids) are not optimal as they are only effective in certain patient groups and safety concerns exist regarding both compound classes. Therefore, novel bronchodilator and anti-inflammatory strategies are being pursued. Prostaglandin E2 (PGE2) is an arachidonic acid-derived eicosanoid produced by the lung which acts on four different G-protein coupled receptors (EP1–4) to cause an array of beneficial and deleterious effects. The aim of this study was to identify the EP receptor mediating the anti-inflammatory actions of PGE2 in the lung using a range of cell-based assays and in vivo models.Methods and results It was demonstrated in three distinct model systems (innate stimulus, lipopolysaccharide (LPS); allergic response, ovalbumin (OVA); inhaled pollutant, cigarette smoke) that mice missing functional EP4 (Ptger4−/−) receptors had higher levels of airway inflammation, suggesting that endogenous PGE2 was suppressing inflammation via EP4 receptor activation. Cell-based assay systems (murine and human monocytes/alveolar macrophages) demonstrated that PGE2 inhibited cytokine release from LPS-stimulated cells and that this was mimicked by an EP4 (but not EP1–3) receptor agonist and inhibited by an EP4 receptor antagonist. The anti-inflammatory effect occurred at the transcriptional level and was via the adenylyl cyclase/cAMP/ cAMP-dependent protein kinase (PKA) axis.Conclusion This study demonstrates that EP4 receptor activation is responsible for the anti-inflammatory activity of PGE2 in a range of disease relevant models and, as such, could represent a novel therapeutic target for chronic airway inflammatory conditions.
Buckley SMK, Delhove JMKM, Perocheau DP, et al., 2015, In vivo bioimaging with tissue-specific transcription factor activated luciferase reporters, Scientific Reports, Vol: 5, ISSN: 2045-2322
The application of transcription factor activated luciferase reporter cassettes in vitro is widespread but potential for in vivo application has not yet been realized. Bioluminescence imaging enables non-invasive tracking of gene expression in transfected tissues of living rodents. However the mature immune response limits luciferase expression when delivered in adulthood. We present a novel approach of tissue-targeted delivery of transcription factor activated luciferase reporter lentiviruses to neonatal rodents as an alternative to the existing technology of generating germline transgenic light producing rodents. At this age, neonates acquire immune tolerance to the conditionally responsive luciferase reporter. This simple and transferrable procedure permits surrogate quantitation of transcription factor activity over the lifetime of the animal. We show principal efficacy by temporally quantifying NFκB activity in the brain, liver and lungs of somatotransgenic reporter mice subjected to lipopolysaccharide (LPS)-induced inflammation. This response is ablated in Tlr4−/− mice or when co-administered with the anti-inflammatory glucocorticoid analogue dexamethasone. Furthermore, we show the malleability of this technology by quantifying NFκB-mediated luciferase expression in outbred rats. Finally, we use somatotransgenic bioimaging to longitudinally quantify LPS- and ActivinA-induced upregulation of liver specific glucocorticoid receptor and Smad2/3 reporter constructs in somatotransgenic mice, respectively.
Lilburn DML, Lesbats C, Six JS, et al., 2015, Hyperpolarized Kr-83 magnetic resonance imaging of alveolar degradation in a rat model of emphysema, Journal of the Royal Society Interface, Vol: 12, ISSN: 1742-5689
Hyperpolarized ⁸³Kr surface quadrupolar relaxation (SQUARE) generates MRI contrast that was previously shown to correlate with surface-to-volume ratios in porous model surface systems. The underlying physics of SQUARE contrast is conceptually different from any other current MRI methodology as the method uses the nuclear electric properties of the spin I = 9/2 isotope 83Kr. To explore the usage of this non-radioactive isotope for pulmonary pathophysiology, MRI SQUARE contrast was acquired in excised rat lungs obtained from an elastase-induced model of emphysema. A significant ⁸³Kr T₁ relaxation time increase in the SQUARE contrast was found in the elastase-treated lungs compared with the baseline data from control lungs. The SQUARE contrast suggests a reduction in pulmonary surface-to-volume ratio in the emphysema model that was validated by histology. The finding supports usage of 83Kr SQUARE as a new biomarker for surface-to-volume ratio changes in emphysema.
Maher SA, Birrell MA, Adcock JJ, et al., 2015, Prostaglandin D-2 and the role of the DP1, DP2 and TP receptors in the control of airway reflex events, European Respiratory Journal, Vol: 45, Pages: 1108-1118, ISSN: 0903-1936
Prostaglandin D2 (PGD2) causes cough and levels are increased in asthma suggesting that it may contribute to symptoms. Although the prostaglandin D2 receptor 2 (DP2) is a target for numerous drug discovery programmes little is known about the actions of PGD2 on sensory nerves and cough.We used human and guinea pig bioassays, in vivo electrophysiology and a guinea pig conscious cough model to assess the effect of prostaglandin D2 receptor (DP1), DP2 and thromboxane receptor antagonism on PGD2 responses.PGD2 caused cough in a conscious guinea pig model and an increase in calcium in airway jugular ganglia. Using pharmacology and receptor-deficient mice we showed that the DP1 receptor mediates sensory nerve activation in mouse, guinea pig and human vagal afferents. In vivo, PGD2 and a DP1 receptor agonist, but not a DP2 receptor agonist, activated single airway C-fibres. Interestingly, activation of DP2 inhibited sensory nerve firing to capsaicin in vitro and in vivo.The DP1 receptor could be a therapeutic target for symptoms associated with asthma. Where endogenous PGD2 levels are elevated, loss of DP2 receptor-mediated inhibition of sensory nerves may lead to an increase in vagally associated symptoms and the potential for such adverse effects should be investigated in clinical studies with DP2 antagonists.
Bonvini SJ, Birrell MA, Smith JA, et al., 2015, Targeting TRP channels for chronic cough: from bench to bedside, NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, Vol: 388, Pages: 401-420, ISSN: 0028-1298
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- Citations: 50
Belvisi MG, 2015, Therapeutic advances for treatment-resistant cough, LANCET, Vol: 385, Pages: 1160-1162, ISSN: 0140-6736
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- Citations: 2
Herbst S, Shah A, Moya MM, et al., 2015, Phagocytosis-dependent activation of a TLR9-BTK-calcineurin-NFAT pathway co-ordinates innate immunity to Aspergillus fumigatus, EMBO Molecular Medicine, Vol: 7, Pages: 240-258, ISSN: 1757-4676
Transplant recipients on calcineurin inhibitors are at high risk of invasive fungal infection. Understanding how calcineurin inhibitors impair fungal immunity is a key priority for defining risk of infection. Here, we show that the calcineurin inhibitor tacrolimus impairs clearance of the major mould pathogen Aspergillus fumigatus from the airway, by inhibiting macrophage inflammatory responses. This leads to defective early neutrophil recruitment and fungal clearance. We confirm these findings in zebrafish, showing an evolutionarily conserved role for calcineurin signalling in neutrophil recruitment during inflammation. We find that calcineurin–NFAT activation is phagocytosis dependent and collaborates with NF‐κB for TNF‐α production. For yeast zymosan particles, activation of macrophage calcineurin–NFAT occurs via the phagocytic Dectin‐1–spleen tyrosine kinase pathway, but for A. fumigatus, activation occurs via a phagosomal TLR9‐dependent and Bruton's tyrosine kinase‐dependent signalling pathway that is independent of MyD88. We confirm the collaboration between NFAT and NF‐κB for TNF‐α production in primary alveolar macrophages. These observations identify inhibition of a newly discovered macrophage TLR9–BTK–calcineurin–NFAT signalling pathway as a key immune defect that leads to organ transplant‐related invasive aspergillosis.
Birrell MA, Bonvini SJ, Wortley MA, et al., 2015, The role of adenylyl cyclase isoform 6 in β-adrenoceptor signalling in murine airways, BRITISH JOURNAL OF PHARMACOLOGY, Vol: 172, Pages: 131-141, ISSN: 0007-1188
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- Citations: 6
Maher SA, Birrell MA, Bonvini SJ, et al., 2014, MENTHOL HAS BENEFICIAL EFFECTS IN THE AIRWAYS THROUGH A TRPM8-INDEPENDENT MECHANISM, Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A79-A80, ISSN: 0040-6376
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- Citations: 3
Baxter M, Eltom S, Dekkak B, et al., 2014, Role of transient receptor potential and pannexin channels in cigarette smoke-triggered ATP release in the lung, THORAX, Vol: 69, Pages: 1080-1089, ISSN: 0040-6376
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- Citations: 61
Adcock JJ, Birrell MA, Maher SA, et al., 2014, CHARACTERISATION OF A delta- AND C-FIBRES INNERVATING GUINEA-PIG AIRWAYS, Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A77-A77, ISSN: 0040-6376
Wortley MA, Maher SA, Bonvini SJ, et al., 2014, ESTABLISHING A ROLE FOR TRPV1 ON SENSORY NERVES IN COPD ASSOCIATED CHRONIC COUGH, Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A78-A79, ISSN: 0040-6376
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- Citations: 1
Eltom S, Belvisi MG, Stevenson CS, et al., 2014, Role of the Inflammasome-Caspase1/11-IL-1/18 Axis in Cigarette Smoke Driven Airway Inflammation: An Insight into the Pathogenesis of COPD, PLOS One, Vol: 9, ISSN: 1932-6203
BackgroundChronic Obstructive Pulmonary Disease (COPD) is an inflammatory airway disease often associated with cigarette smoke (CS) exposure. The disease is increasing in global prevalence and there is no effective therapy. A major step forward would be to understand the disease pathogenesis. The ATP-P2X7 pathway plays a dominant role in murine models of CS induced airway inflammation, and markers of activation of this axis are upregulated in patients with COPD. This strongly suggests that the axis could be important in the pathogenesis of COPD. The aim of this study was to perform a detailed characterisation of the signalling pathway components involved in the CS-driven, P2X7 dependent airway inflammation.MethodsWe used a murine model system, bioassays and a range of genetically modified mice to better understand this complex signalling pathway.ResultsThe inflammasome-associated proteins NALP3 and ASC, but not IPAF and AIM2, are required for CS-induced IL-1β/IL-18 release, but not IL-1α. This was associated with a partial decrease in lung tissue caspase 1 activity and BALF neutrophilia. Mice missing caspase 1/11 or caspase 11 had markedly attenuated levels of all three cytokines and neutrophilia. Finally the mechanism by which these inflammatory proteins are involved in the CS-induced neutrophilia appeared to be via the induction of proteins involved in neutrophil transmigration e.g. E-Selectin.ConclusionThis data indicates a key role for the P2X7-NALP3/ASC-caspase1/11-IL-1β/IL-18 axis in CS induced airway inflammation, highlighting this pathway as a possible therapeutic target for the treatment of COPD.
Singh RK, Furze RC, Birrell MA, et al., 2014, A role for Rab27 in neutrophil chemotaxis and lung recruitment, BMC CELL BIOLOGY, Vol: 15, ISSN: 1471-2121
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- Citations: 21
Eltom S, Belvisi MG, Yew-Booth L, et al., 2014, TLR4 activation induces IL-1β release via an IPAF dependent but caspase 1/11/8 independent pathway in the lung, RESPIRATORY RESEARCH, Vol: 15
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- Citations: 16
Eltom S, Dale N, Raemdonck KRG, et al., 2014, Respiratory Infections Cause the Release of Extracellular Vesicles: Implications in Exacerbation of Asthma/COPD, PLOS One, Vol: 9, ISSN: 1932-6203
BackgroundInfection-related exacerbations of respiratory diseases are a major health concern; thus understanding the mechanisms driving them is of paramount importance. Despite distinct inflammatory profiles and pathological differences, asthma and COPD share a common clinical facet: raised airway ATP levels. Furthermore, evidence is growing to suggest that infective agents can cause the release of extracellular vesicle (EVs) in vitro and in bodily fluids. ATP can evoke the P2X7/caspase 1 dependent release of IL-1β/IL-18 from EVs; these cytokines are associated with neutrophilia and are increased during exacerbations. Thus we hypothesized that respiratory infections causes the release of EVs in the airway and that the raised ATP levels, present in respiratory disease, triggers the release of IL-1β/IL-18, neutrophilia and subsequent disease exacerbations.MethodsTo begin to test this hypothesis we utilised human cell-based assays, ex vivo murine BALF, in vivo pre-clinical models and human samples to test this hypothesis.ResultsData showed that in a murine model of COPD, known to have increased airway ATP levels, infective challenge causes exacerbated inflammation. Using cell-based systems, murine models and samples collected from challenged healthy subjects, we showed that infection can trigger the release of EVs. When exposed to ATP the EVs release IL-1β/IL-18 via a P2X7/caspase-dependent mechanism. Furthermore ATP challenge can cause a P2X7 dependent increase in LPS-driven neutrophilia.ConclusionsThis preliminary data suggests a possible mechanism for how infections could exacerbate respiratory diseases and may highlight a possible signalling pathway for drug discovery efforts in this area.
Dubuis E, Wortley MA, Grace MS, et al., 2014, Theophylline inhibits the cough reflex through a novel mechanism of action, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 133, Pages: 1588-1598, ISSN: 0091-6749
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- Citations: 25
Grace MS, Baxter M, Dubuis E, et al., 2014, Transient receptor potential ( TRP) channels in the airway: role in airway disease, BRITISH JOURNAL OF PHARMACOLOGY, Vol: 171, Pages: 2593-2607, ISSN: 0007-1188
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- Citations: 129
Birrell MA, Bonvini SJ, Dubuis E, et al., 2014, Tiotropium modulates transient receptor potential V1 (TRPV1) in airway sensory nerves: A beneficial off-target effect?, Journal of Allergy and Clinical Immunology, Vol: 133, Pages: 679-687.e9, ISSN: 0091-6749
BackgroundRecent studies have suggested that the long-acting muscarinic receptor antagonist tiotropium, a drug widely prescribed for its bronchodilator activity in patients with chronic obstructive pulmonary disease and asthma, improves symptoms and attenuates cough in preclinical and clinical tussive agent challenge studies. The mechanism by which tiotropium modifies tussive responses is not clear, but an inhibition of vagal tone and a consequent reduction in mucus production from submucosal glands and bronchodilation have been proposed.ObjectiveThe aim of this study was to investigate whether tiotropium can directly modulate airway sensory nerve activity and thereby the cough reflex.MethodsWe used a conscious cough model in guinea pigs, isolated vagal sensory nerve and isolated airway neuron tissue– and cell-based assays, and in vivo single-fiber recording electrophysiologic techniques.ResultsInhaled tiotropium blocked cough and single C-fiber firing in the guinea pig to the transient receptor potential (TRP) V1 agonist capsaicin, a clinically relevant tussive stimulant. Tiotropium and ipratropium, a structurally similar muscarinic antagonist, inhibited capsaicin responses in isolated guinea pig vagal tissue, but glycopyrrolate and atropine did not. Tiotropium failed to modulate other TRP channel–mediated responses. Complementary data were generated in airway-specific primary ganglion neurons, demonstrating that tiotropium inhibited capsaicin-induced, but not TRPA1-induced, calcium movement and voltage changes.ConclusionFor the first time, we have shown that tiotropium inhibits neuronal TRPV1-mediated effects through a mechanism unrelated to its anticholinergic activity. We speculate that some of the clinical benefit associated with taking tiotropium (eg, in symptom control) could be explained through this proposed mechanism of action.
Dubuis E, Grace M, Wortley MA, et al., 2013, Harvesting, isolation, and functional assessment of primary vagal ganglia cells., Curr Protoc Pharmacol, Vol: 62, Pages: 12.15.1-12.15.27
Airway sensory nerves play an important defensive role in the lungs, being central in mediating protective responses like cough and bronchoconstriction. In some cases, these responses become excessive, hypersensitive, and deleterious. Understanding the normal function of airway nerves and phenotype changes associated with disease will help in developing new therapeutics for treating chronic obstructive pulmonary disease and chronic cough. Guinea pigs, and to a lesser extent ferrets, are commonly employed for studying the cough reflex because they have a cough response similar to humans. While rats and mice do not exhibit a cough response, they do possess sensory nerves that respond to the same range of tussive stimuli as guinea pigs and humans. Described in this unit are protocols for harvesting guinea pig, mouse, and rat sensory nerve cell bodies to assess molecular and functional changes associated with pulmonary disease, and to identify new targets for therapeutic intervention.
Grace MS, Dubuis E, Birrell MA, et al., 2013, Pre-clinical studies in cough research: Role of Transient Receptor Potential (TRP) channels, PULMONARY PHARMACOLOGY & THERAPEUTICS, Vol: 26, Pages: 498-507, ISSN: 1094-5539
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- Citations: 46
Bonvini SJ, Adcock JJ, Grace MS, et al., 2013, Activation of TRPV4 causes bronchoconstriction: A possible role in respiratory disease?, EUROPEAN RESPIRATORY JOURNAL, Vol: 42, ISSN: 0903-1936
Shenker NS, Polidoro S, van Veldhoven K, et al., 2013, Epigenome-wide association study in the European Prospective Investigation into Cancer and Nutrition (EPIC-Turin) identifies novel genetic loci associated with smoking, HUMAN MOLECULAR GENETICS, Vol: 22, Pages: 843-851, ISSN: 0964-6906
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- Citations: 304
Eltom S, Stevenson C, Birrell MA, 2013, Cigarette smoke exposure as a model of inflammation associated with COPD., Curr Protoc Pharmacol, Vol: Chapter 5
Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation resulting from inflammation-driven pathologies in the lungs that are a consequence of smoking over many years. Given that the disease is increasing globally, understanding the mechanism by which cigarette smoke (CS) causes lung inflammation and exploiting that knowledge to develop effective treatments is urgently required. Animal models of CS exposure are commonly used to examine the inflammatory processes that may be involved in the development of COPD. The protocols described in this unit detail the development of preclinical models of CS-driven lung inflammation. These systems can be utilized to investigate the role of various biological pathways in CS-mediated inflammation and to assess the efficacy of new therapeutic strategies for treating COPD.
Rastrick JMD, Stevenson CS, Eltom S, et al., 2013, Cigarette smoke induced airway inflammation is independent of NF-kappa B signalling, PLOS One, Vol: 8, ISSN: 1932-6203
Dubuis E, Grace M, Wortley MA, et al., 2013, Harvesting, isolation, and functional assessment of primary vagal ganglia cells, Current Protocols in Pharmacology, Vol: 1, ISSN: 1934-8282
Airway sensory nerves play an important defensive role in the lungs, being central in mediating protective responses like cough and bronchoconstriction. In some cases, these responses become excessive, hypersensitive, and deleterious. Understanding the normal function of airway nerves and phenotype changes associated with disease will help in developing new therapeutics for treating chronic obstructive pulmonary disease and chronic cough. Guinea pigs, and to a lesser extent ferrets, are commonly employed for studying the cough reflex because they have a cough response similar to humans. While rats and mice do not exhibit a cough response, they do possess sensory nerves that respond to the same range of tussive stimuli as guinea pigs and humans. Described in this unit are protocols for harvesting guinea pig, mouse, and rat sensory nerve cell bodies to assess molecular and functional changes associated with pulmonary disease, and to identify new targets for therapeutic intervention. © 2013 by John Wiley & Sons, Inc.
Birrell MA, Maher SA, Buckley J, et al., 2013, Selectivity profiling of the novel EP2 receptor antagonist, PF-04418948, in functional bioassay systems: atypical affinity at the guinea pig EP2 receptor, BRITISH JOURNAL OF PHARMACOLOGY, Vol: 168, Pages: 129-138, ISSN: 0007-1188
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- Citations: 24
Rastrick JM, Stevenson CS, Eltom S, et al., 2013, Correction: Cigarette Smoke Induced Airway Inflammation Is Independent of NF-κB Signalling., PLoS One, Vol: 8
[This corrects the article on p. e54128 in vol. 8.].
Grace M, Birrell MA, Dubuis E, et al., 2012, Transient receptor potential channels mediate the tussive response to prostaglandin E<sub>2</sub> and bradykinin, THORAX, Vol: 67, Pages: 891-900, ISSN: 0040-6376
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- Citations: 111
Grace MS, Dubuis E, Birrell MA, et al., 2012, TRP Channel Antagonists as Potential Antitussives, LUNG, Vol: 190, Pages: 11-15, ISSN: 0341-2040
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- Citations: 14
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