120 results found
Nilsson M, Rhedin M, Hendrickx R, et al., 2022, Characterization of Selective and Potent JAK1 Inhibitors Intended for the Inhaled Treatment of Asthma, DRUG DESIGN DEVELOPMENT AND THERAPY, Vol: 16, Pages: 2901-2917, ISSN: 1177-8881
Smith JA, Harle A, Dockry R, et al., 2021, Aprepitant for cough in lung cancer: a randomised placebo-controlled trial and mechanistic insights, American Journal of Respiratory and Critical Care Medicine, Vol: 203, Pages: 737-745, ISSN: 1073-449X
RATIONALE: Effective cough treatments are a significant unmet need in lung cancer patients. Aprepitant is a licensed treatment for nausea and vomiting, which blocks substance P activation of Neurokinin 1 (NK-1) receptors, a mechanism also implicated in cough. OBJECTIVE: To assess aprepitant in lung cancer patients with cough and evaluate mechanisms in vagal nerve tissue. METHODS: Randomised double-blind crossover trial of lung cancer patients with bothersome cough. They received three days of aprepitant or matched placebo; following a three day wash out, patients crossed to the alternative treatment. The primary endpoint was awake cough frequency measured at screening and day 3 of each treatment; secondary endpoints included patient-reported outcomes. In vitro, the depolarization of isolated guinea pig and human vagus nerve sections in grease gap recording chambers, indicative of sensory nerve activation, was measured to evaluate mechanism. MEASUREMENTS AND MAIN RESULTS: Twenty lung cancer patients enrolled, mean age 66years (±7.7), 60% female, 80% non-small cell cancer, 50% advanced stage and 55% WHO performance status 1. Cough frequency improved with aprepitant, reducing by 22.2%(95%CI 2.8-37.7%) over placebo whilst awake (p=0.03), 30.3%(95%CI 12.7-44.3) over 24hours (p=0.002) and 59.8%(95%CI 15.1-86.0) during sleep (p=0.081). Patient-reported outcomes all significantly improved. Substance P depolarised both guinea pig and human vagus nerve. Aprepitant significantly inhibited substance P induced depolarisation by 78% in guinea pig (p=0.0145) and 94% in human vagus (p=0.0145). DISCUSSION: Substance P activation of NK-1 receptors appears to be an important mechanism driving cough in lung cancer, and NK-1 antagonists show promise as anti-tussive therapies. Clinical trial registration available at www.http://www.isrctn.com/, ID: ISRCTN16200035.
Doherty DF, Nath S, Poon J, et al., 2019, Protein Phosphatase 2A Reduces Cigarette Smoke-induced Cathepsin S and Loss of Lung Function, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 200, Pages: 51-62, ISSN: 1073-449X
Chen X, Bonvini SJ, Dubuis ED, et al., 2019, Cromoglycate Inhibits Oxidative Stress Triggered Airway Sensory Nerves Through Its Actions on the Ion Channel TRPV2: A New Insight into Biological Mechanism of Action, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Wortley M, Bonvini SJ, Flajolet PLM, et al., 2018, The anti-tussive effects of an inhaled LABA are maintained after chronic treatment, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Belvisi MG, Baker K, Malloy N, et al., 2018, Modelling the asthma phenotype: impact of cigarette smoke exposure, Respiratory Research, Vol: 19, ISSN: 1465-9921
BackgroundAsthmatics that are exposed to inhaled pollutants such as cigarette smoke (CS) have increased symptom severity. Approximately 25% of adult asthmatics are thought to be active smokers and many sufferers, especially in the third world, are exposed to high levels of inhaled pollutants. The mechanism by which CS or other airborne pollutants alter the disease phenotype and the effectiveness of treatment in asthma is not known. The aim of this study was to determine the impact of CS exposure on the phenotype and treatment sensitivity of rodent models of allergic asthma.MethodsModels of allergic asthma were configured that mimicked aspects of the asthma phenotype and the effect of CS exposure investigated. In some experiments, treatment with gold standard asthma therapies was investigated and end-points such as airway cellular burden, late asthmatic response (LAR) and airway hyper-Reactivity (AHR) assessed.ResultsCS co-exposure caused an increase in the LAR but interestingly attenuated the AHR. The effectiveness of LABA, LAMA and glucocorticoid treatment on LAR appeared to be retained in the CS-exposed model system. The eosinophilia or lymphocyte burden was not altered by CS co-exposure, nor did CS appear to alter the effectiveness of glucocorticoid treatment. Steroids, however failed to reduce the neutrophilic inflammation in sensitized mice exposed to CS.ConclusionsThese model data have certain parallels with clinical findings in asthmatics, where CS exposure did not impact the anti-inflammatory efficacy of steroids but attenuated AHR and enhanced symptoms such as the bronchospasm associated with the LAR. These model systems may be utilised to investigate how CS and other airborne pollutants impact the asthma phenotype; providing the opportunity to identify novel targets.
Peiró T, Patel DF, Akthar S, et al., 2017, Neutrophils drive alveolar macrophage IL-1β release during respiratory viral infection, Thorax, Vol: 73, Pages: 546-556, ISSN: 1468-3296
Background Alveolar macrophages are sentinels of the airways that must exhibit immune restraint to innocuous antigens but elicit a robust inflammatory response to pathogenic threats. How distinction between these dichotomous functions is controlled is poorly defined.Neutrophils are the first responders to infection, and we hypothesised that they may free alveolar macrophages from their hyporesponsive state, promoting their activation. Activation of the inflammasome and interleukin (IL)-1β release is a key early inflammatory event that must be tightly regulated. Thus, the role of neutrophils in defining inflammasome activation in the alveolar macrophage was assessed.Methods Mice were infected with the X31 strain of influenza virus and the role of neutrophils in alveolar macrophage activation established through administration of a neutrophil-depleting (1A8) antibody.Results Influenza elicited a robust IL-1β release that correlated (r=0.6849; p<0.001) with neutrophil infiltrate and was ablated by neutrophil depletion. Alveolar macrophages were shown to be the prominent source of IL-1β during influenza infection, and virus triggered the expression of Nod-like receptor protein 3 (NLRP3) inflammasome and pro-IL-1β in these cells. However, subsequent activation of the inflammasome complex and release of mature IL-1β from alveolar macrophages were critically dependent on the provision of a secondary signal, in the form of antimicrobial peptide mCRAMP, from infiltrating neutrophils.Conclusions Neutrophils are critical for the activation of the NLRP3 inflammasome in alveolar macrophages during respiratory viral infection. Accordingly, we rationalise that neutrophils are recruited to the lung to confront a viable pathogenic threat and subsequently commit alveolar macrophages to a pro-inflammatory phenotype to combat infection.
Smyth E, Solomon A, Birrell MA, et al., 2017, Effects of diesel exhaust particles on coagulation., British Journal of Pharmacology, Vol: 174, Pages: 4200-4200, ISSN: 1476-5381
Wortley MA, Adcock JJ, Dubuis ED, et al., 2017, Targeting fatty acid amide hydrolase as a therapeutic strategy for antitussive therapy, European Respiratory Journal, Vol: 50, Pages: 1-11, ISSN: 0903-1936
Cough is the most common reason to visit a primary care physician, yet it remains an unmet medical need. Fatty acid amide hydrolase (FAAH) is an enzyme that breaks down endocannabinoids, and inhibition of FAAH produces analgesic and anti-inflammatory effects. Cannabinoids inhibit vagal sensory nerve activation and the cough reflex, so it was hypothesised that FAAH inhibition would produce antitussive activity via elevation of endocannabinoids.Primary vagal ganglia neurons, tissue bioassay, in vivo electrophysiology and a conscious guinea pig cough model were utilised to investigate a role for fatty acid amides in modulating sensory nerve activation in vagal afferents.FAAH inhibition produced antitussive activity in guinea pigs with concomitant plasma elevation of the fatty acid amides N-arachidonoylethanolamide (anandamide), palmitoylethanolamide, N-oleoylethanolamide and linoleoylethanolamide. Palmitoylethanolamide inhibited tussive stimulus-induced activation of guinea pig airway innervating vagal ganglia neurons, depolarisation of guinea pig and human vagus, and firing of C-fibre afferents. These effects were mediated via a cannabinoid CB2/Gi/o-coupled pathway and activation of protein phosphatase 2A, resulting in increased calcium sensitivity of calcium-activated potassium channels.These findings identify FAAH inhibition as a target for the development of novel, antitussive agents without the undesirable side-effects of direct cannabinoid receptor agonists.
Belvisi MG, Birrell MA, 2017, The emerging role of transient receptor potential channels in chronic lung disease, EUROPEAN RESPIRATORY JOURNAL, Vol: 50, ISSN: 0903-1936
Paschalaki KE, Zampetaki A, Baker JR, et al., 2017, Downregulation of MicroRNA-126 Augments DNA Damage Response in Cigarette Smokers and COPD Patients., Am J Respir Crit Care Med
Belvisi MG, Smith JA, 2017, ATP and cough reflex hypersensitivity: a confusion of goals?, European Respiratory Journal, Vol: 50, ISSN: 0903-1936
Bonvini SJ, Belvisi MG, 2017, Cough and airway disease: the role of ion channels, Pulmonary Pharmacology and Therapeutics, Vol: 47, Pages: 21-28, ISSN: 1094-5539
Cough is the most common reason for patients to visit a primary care physician, yet it remains an unmet medical need. It can be idiopathic in nature but can also be a troublesome symptom across chronic lung diseases such as asthma, COPD and idiopathic pulmonary fibrosis (IPF). Chronic cough affects up to 12% of the population and yet there are no safe and effective therapies. The cough reflex is regulated by vagal, sensory afferent nerves which innervate the airway. The Transient Receptor Potential (TRP) family of ion channels are expressed on sensory nerve terminals, and when activated can evoke cough. This review focuses on the role of 4 TRP channels; TRP Vannilloid 1 (TRPV1), TRP Ankyrin 1 (TRPA1), TRP Vannilloid 4 (TRPV4) and TRP Melastatin 8 (TRPM8) and the purinergic P2X3 receptor and their possible role in chronic cough. We conclude that these ion channels, given their expression profile and their role in the activation of sensory afferents and the cough reflex, may represent excellent therapeutic targets for the treatment of respiratory symptoms in chronic lung disease.
Belvisi MG, Birrell MA, Wortley MA, et al., 2017, XEN-D0501, a novel TRPV1 antagonist, does not reduce cough in refractory cough patients, American Journal of Respiratory and Critical Care Medicine, Vol: 196, Pages: 1255-1263, ISSN: 1073-449X
RATIONALE: Heightened cough responses to inhaled capsaicin, a TRPV1 agonist, are characteristic of patients with chronic cough. However, previously a TRPV1 antagonist (SB-705498) failed to improve spontaneous cough frequency in these patients despite small reductions in capsaicin-evoked cough. OBJECTIVES: XEN-D0501 (potent TRPV1 antagonist) was compared with SB-705498 in pre-clinical studies to establish whether an improved efficacy profile would support a further clinical trial of XEN-D0501 in refractory chronic cough. METHODS: XEN-D0501 and SB-705498 were profiled against capsaicin in a sensory nerve activation assay and in vivo potency established against capsaicin-induced cough in the guinea pig. Twenty patients with refractory chronic cough participated in a double-blind, randomised, placebo-controlled, crossover study evaluating the effect of 14 days XEN-D0501 (oral, 4mg bd) versus placebo on awake cough frequency (primary outcome), capsaicin-evoked cough and patient reported outcomes. MEASUREMENTS AND MAIN RESULTS: XEN-D0501 was more efficacious and 1000-fold more potent than SB-705498 at inhibiting capsaicin-induced depolarization of guinea pig and human isolated vagus. In vivo, XEN-D0501 completely inhibited capsaicin-induced cough whereas 100-times more SB-705498 was required to achieve the same effect. In patients, XEN-D0501 substantially reduced maximal cough responses to capsaicin (mean change from baseline XEN-D0501 -19.3(±16.4) coughs vs. placebo -1.8(±5.8), p<0.0001), but not spontaneous awake cough frequency (mean change from baseline XEN-D0501 6.7c/h(±16.9) vs. placebo 0.4c/h(±13.7), p =0.41). CONCLUSIONS: XEN-D0501 demonstrated superior efficacy and potency in pre-clinical and clinical capsaicin challenge studies; despite this improved pharmacodynamic profile, spontaneous cough frequency did not improve, ruling out TRPV1 as an effective therapeutic target for refractory cough. Clinical trial registration available ww
Smyth E, Solomon A, Birrell MA, et al., 2017, Influence of inflammation and nitric oxide upon platelet aggregation following deposition of diesel exhaust particles in the airways., British Journal of Pharmacology, Vol: 174, Pages: 2130-2139, ISSN: 0007-1188
Background and Purpose: Exposure to nanoparticulate pollution has been implicated in platelet-driven thrombotic events such as myocardial infarction. Inflammation and impairment of NO bioavailability have been proposed as potential causative mechanisms. It is unclear, however, whether airways exposure to combustion-derived nanoparticles such as diesel exhaust particles (DEP) or carbon black (CB) can augment platelet aggregation in vivo and the underlying mechanisms remain undefined. We aimed to investigate the effects of acute lung exposure to DEP and CB on platelet activation and the associated role of inflammation and endothelial-derived NO.Experimental Approach: DEP and CB were intratracheally instilled into wild-type (WT) and eNOS−/− mice and platelet aggregation was assessed in vivo using an established model of radio-labelled platelet thromboembolism. The underlying mechanisms were investigated by measuring inflammatory markers, NO metabolites and light transmission aggregometry.Key Results: Platelet aggregation in vivo was significantly enhanced in WT and eNOS−/− mice following acute airways exposure to DEP but not CB. CB exposure, but not DEP, was associated with significant increases in pulmonary neutrophils and IL-6 levels in the bronchoalveolar lavage fluid and plasma of WT mice. Neither DEP nor CB affected plasma nitrate/nitrite concentration and DEP-induced human platelet aggregation was inhibited by an NO donor.Conclusions and Implications: Pulmonary exposure to DEP and subsequent platelet activation may contribute to the reports of increased cardiovascular risk, associated with exposure to airborne pollution, independent of its effects on inflammation or NO bioavailability.
Robinson RK, Birrell MA, Adcock JJ, et al., 2017, Mechanistic link between diesel exhaust particles and respiratory reflexes, Journal of Allergy and Clinical Immunology, Vol: 141, Pages: 1074-1084.e9, ISSN: 1097-6825
BackgroundDiesel exhaust particles (DEPs) are a major component of particulate matter in Europe's largest cities, and epidemiologic evidence links exposure with respiratory symptoms and asthma exacerbations. Respiratory reflexes are responsible for symptoms and are regulated by vagal afferent nerves, which innervate the airway. It is not known how DEP exposure activates airway afferents to elicit symptoms, such as cough and bronchospasm.ObjectiveWe sought to identify the mechanisms involved in activation of airway sensory afferents by DEPs.MethodsIn this study we use in vitro and in vivo electrophysiologic techniques, including a unique model that assesses depolarization (a marker of sensory nerve activation) of human vagus.ResultsWe demonstrate a direct interaction between DEP and airway C-fiber afferents. In anesthetized guinea pigs intratracheal administration of DEPs activated airway C-fibers. The organic extract (DEP-OE) and not the cleaned particles evoked depolarization of guinea pig and human vagus, and this was inhibited by a transient receptor potential ankyrin-1 antagonist and the antioxidant N-acetyl cysteine. Polycyclic aromatic hydrocarbons, major constituents of DEPs, were implicated in this process through activation of the aryl hydrocarbon receptor and subsequent mitochondrial reactive oxygen species production, which is known to activate transient receptor potential ankyrin-1 on nociceptive C-fibers.ConclusionsThis study provides the first mechanistic insights into how exposure to urban air pollution leads to activation of guinea pig and human sensory nerves, which are responsible for respiratory symptoms. Mechanistic information will enable the development of appropriate therapeutic interventions and mitigation strategies for those susceptible subjects who are most at risk.
Baker K, Raemdonck K, Snelgrove RJ, et al., 2017, Characterisation of a murine model of the late asthmatic response, Respiratory Research, Vol: 18, ISSN: 1465-9921
Background: The incidence of asthma is increasing at an alarming rate. While the current available therapies areeffective, there are associated side effects and they fail to adequately control symptoms in all patient subsets. In thesearch to understand disease pathogenesis and find effective therapies hypotheses are often tested in animalmodels before progressing into clinical studies. However, current dogma is that animal model data is often notpredictive of clinical outcome. One possible reason for this is the end points measured such as antigen-challengeinduced late asthmatic response (LAR) is often used in early clinical development, but seldom in animal modelsystems. As the mouse is typically selected as preferred species for pre-clinical models, we wanted to characteriseand probe the validity of a murine model exhibiting an allergen induced LAR.Methods: C57BL/6 mice were sensitised with antigen and subsequently topically challenged with the sameantigen. The role of AlumTM adjuvant, glucocorticoid, long acting muscarinic receptor antagonist (LAMA), TRPA1,CD4+ and CD8+ T cells, B cells, Mast cells and IgE were determined in the LAR using genetically modified mice anda range of pharmacological tools.Results: Our data showed that unlike other features of asthma (e.g. cellular inflammation, elevated IgE levels andairway hyper-reactivity (AHR) the LAR required AlumTMadjuvant. Furthermore, the LAR appeared to be sensitive toglucocorticoid and required CD4+ T cells. Unlike in other species studied, the LAR was not sensitive to LAMAtreatment nor required the TRPA1 ion channel, suggesting that airway sensory nerves are not involved in the LARin this species. Furthermore, the data suggested that CD8+ T cells and the mast cell—B-cell - IgE axis appear to beprotective in this murine model.Conclusion: Together we can conclude that this model does feature steroid sensitive, CD4+ T cell dependent,allergen induced LAR. However, collectively our data questions the validit
Wortley MA, Birrell MA, Belvisi MG, 2017, Drugs Affecting TRP Channels., Pages: 213-241
Chronic obstructive pulmonary disease (COPD) and asthma are both common respiratory diseases that are associated with airflow reduction/obstruction and pulmonary inflammation. Whilst drug therapies offer adequate symptom control for many mild to moderate asthmatic patients, severe asthmatics and COPD patients symptoms are often not controlled, and in these cases, irreversible structural damage occurs with disease progression over time. Transient receptor potential (TRP) channels, in particular TRPV1, TRPA1, TRPV4 and TRPM8, have been implicated with roles in the regulation of inflammation and autonomic nervous control of the lungs. Evidence suggests that inflammation elevates levels of activators and sensitisers of TRP channels and additionally that TRP channel expression may be increased, resulting in excessive channel activation. The enhanced activity of these channels is thought to then play a key role in the propagation and maintenance of the inflammatory disease state and neuronal symptoms such as bronchoconstriction and cough. For TRPM8 the evidence is less clear, but as with TRPV1, TRPA1 and TRPV4, antagonists are being developed by multiple companies for indications including asthma and COPD, which will help in elucidating their role in respiratory disease.
Thurston T, Matthews S, Jennings E, et al., 2016, Growth inhibition of cytosolic Salmonella by caspase-1 and caspase-11 precedes host cell death, Nature Communications, Vol: 7, ISSN: 2041-1723
Sensing bacterial products in the cytosol of mammalian cells by NOD-like receptors leads to the activation of caspase-1 inflammasomes, and the production of the pro-inflammatory cytokines interleukin (IL)-18 and IL-1β. In addition, mouse caspase-11 (represented in humans by its orthologs, caspase-4 and caspase-5) detects cytosolic bacterial LPS directly. Activation of caspase-1 and caspase-11 initiates pyroptotic host cell death that releases potentially harmful bacteria from the nutrient-rich host cell cytosol into the extracellular environment. Here we use single cell analysis and time-lapse microscopy to identify a subpopulation of host cells, in which growth of cytosolic Salmonella Typhimurium is inhibited independently or prior to the onset of cell death. The enzymatic activities of caspase-1 and caspase-11 are required for growth inhibition in different cell types. Our results reveal that these proteases have important functions beyond the direct induction of pyroptosis and proinflammatory cytokine secretion in the control of growth and elimination of cytosolic bacteria.
Bonvini S, Arshad M, Wortley MA, et al., 2016, TRPM3: A regulator of airway sensory nerves and respiratory reflexes, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Mesnil C, Raulier S, Paulissen G, et al., 2016, Lung-resident eosinophils represent a distinct regulatory eosinophil subset, Journal of Clinical Investigation, Vol: 126, Pages: 3279-3295, ISSN: 1558-8238
Increases in eosinophil numbers are associated with infection and allergic diseases, including asthma, but there is also evidence that eosinophils contribute to homeostatic immune processes. In mice, the normal lung contains resident eosinophils (rEos), but their function has not been characterized. Here, we have reported that steady-state pulmonary rEos are IL-5-independent parenchymal Siglec-FintCD62L+CD101lo cells with a ring-shaped nucleus. During house dust mite-induced airway allergy, rEos features remained unchanged, and rEos were accompanied by recruited inflammatory eosinophils (iEos), which were defined as IL-5-dependent peribronchial Siglec-FhiCD62L-CD101hi cells with a segmented nucleus. Gene expression analyses revealed a more regulatory profile for rEos than for iEos, and correspondingly, mice lacking lung rEos showed an increase in Th2 cell responses to inhaled allergens. Such elevation of Th2 responses was linked to the ability of rEos, but not iEos, to inhibit the maturation, and therefore the pro-Th2 function, of allergen-loaded DCs. Finally, we determined that the parenchymal rEos found in nonasthmatic human lungs (Siglec-8+CD62L+IL-3Rlo cells) were phenotypically distinct from the iEos isolated from the sputa of eosinophilic asthmatic patients (Siglec-8+CD62LloIL-3Rhi cells), suggesting that our findings in mice are relevant to humans. In conclusion, our data define lung rEos as a distinct eosinophil subset with key homeostatic functions.
Belvisi MG, 2016, Transient receptor potential cation channel, subfamily V, member 4 and airway, sensory afferent activation: role of adenosine triphosphate, Journal of Allergy and Clinical Immunology, Vol: 138, Pages: 249-261.e12, ISSN: 1097-6825
BackgroundSensory nerves innervating the airways play an important role in regulating various cardiopulmonary functions, maintaining homeostasis under healthy conditions and contributing to pathophysiology in disease states. Hypo-osmotic solutions elicit sensory reflexes, including cough, and are a potent stimulus for airway narrowing in asthmatic patients, but the mechanisms involved are not known. Transient receptor potential cation channel, subfamily V, member 4 (TRPV4) is widely expressed in the respiratory tract, but its role as a peripheral nociceptor has not been explored.ObjectiveWe hypothesized that TRPV4 is expressed on airway afferents and is a key osmosensor initiating reflex events in the lung.MethodsWe used guinea pig primary cells, tissue bioassay, in vivo electrophysiology, and a guinea pig conscious cough model to investigate a role for TRPV4 in mediating sensory nerve activation in vagal afferents and the possible downstream signaling mechanisms. Human vagus nerve was used to confirm key observations in animal tissues.ResultsHere we show TRPV4-induced activation of guinea pig airway–specific primary nodose ganglion cells. TRPV4 ligands and hypo-osmotic solutions caused depolarization of murine, guinea pig, and human vagus and firing of Aδ-fibers (not C-fibers), which was inhibited by TRPV4 and P2X3 receptor antagonists. Both antagonists blocked TRPV4-induced cough.ConclusionThis study identifies the TRPV4-ATP-P2X3 interaction as a key osmosensing pathway involved in airway sensory nerve reflexes. The absence of TRPV4-ATP–mediated effects on C-fibers indicates a distinct neurobiology for this ion channel and implicates TRPV4 as a novel therapeutic target for neuronal hyperresponsiveness in the airways and symptoms, such as cough.
Belvisi MG, Birrell MA, Khalid S, et al., 2016, Neurophenotypes in airway diseases: insights from translational cough studies, American Journal of Respiratory and Critical Care Medicine, Vol: 193, Pages: 1364-1372, ISSN: 1535-4970
Rationale: Most airway diseases, including chronic obstructive pulmonary disease (COPD), are associated with excessive coughing. The extent to which this may be a consequence of increased activation of vagal afferents by pathology in the airways (e.g. inflammatory mediators, excessive mucus) or an altered neuronal phenotype is unknown. Understanding whether respiratory diseases are associated with dysfunction of airway sensory nerves has the potential to identify novel therapeutic targets. Objectives: To assess the changes in cough responses to a range of inhaled irritants in COPD, and model these in animals to investigate the underlying mechanisms. Methods: Cough responses to inhaled stimuli in patients with COPD, healthy smokers, refractory chronic cough, asthma and healthy volunteers were assessed and compared with vagus/airway nerve and cough responses in a cigarette smoke (CS) exposure guinea-pig model. Measurements and Main Results: Patients with COPD had heightened cough responses to capsaicin but reduced responses to PGE2 compared with healthy volunteers. Furthermore, the different patient groups all exhibited different patterns of modulation of cough responses. Consistent with these findings, capsaicin caused a greater number of coughs in CS-exposed guinea-pigs than in controls; similar increased responses were observed in ex-vivo vagus nerve and neuron cell bodies in the vagal ganglia. However, responses to PGE2 were decreased by CS-exposure. Conclusions: CS exposure is capable of inducing responses consistent with phenotypic switching in airway sensory nerves comparable to the cough responses observed in patients with COPD. Moreover, the differing profiles of cough responses support the concept of disease-specific neuro-phenotypes in airway disease.
Baker K, Raemdonck K, Dekkak B, et al., 2016, Role of the ion channel, transient receptor potential cation channel subfamily V member 1 (TRPV1), in allergic asthma, Respiratory Research, Vol: 17, ISSN: 1465-993X
BACKGROUND: Asthma prevalence has increased world-wide especially in children; thus there is a need to develop new therapies that are safe and effective especially for patients with severe/refractory asthma. CD4(+) T cells are thought to play a central role in disease pathogenesis and associated symptoms. Recently, TRPV1 has been demonstrated to regulate the activation and inflammatory properties of CD4(+) cells. The aim of these experiments was to demonstrate the importance of CD4(+) T cells and the role of TRPV1 in an asthma model using a clinically ready TRPV1 inhibitor (XEN-D0501) and genetically modified (GM) animals. METHODS: Mice (wild type, CD4 (-/-) or TRPV1 (-/-)) and rats were sensitised with antigen (HDM or OVA) and subsequently topically challenged with the same antigen. Key features associated with an allergic asthma type phenotype were measured: lung function (airway hyperreactivity [AHR] and late asthmatic response [LAR]), allergic status (IgE levels) and airway inflammation. RESULTS: CD4(+) T cells play a central role in both disease model systems with all the asthma-like features attenuated. Targeting TRPV1 using either GM mice or a pharmacological inhibitor tended to decrease IgE levels, airway inflammation and lung function changes. CONCLUSION: Our data suggests the involvement of TRPV1 in allergic asthma and thus we feel this target merits further investigation.
Raemdonck K, Baker K, Dale N, et al., 2016, CD4(+) and CD8(+) T cells play a central role in a HDM driven model of allergic asthma., Respiratory Research, Vol: 17, ISSN: 1465-993X
BACKGROUND: The incidence of asthma is increasing at an alarming rate and while the current available therapies are effective in the majority of patients they fail to adequately control symptoms at the more severe end of the disease spectrum. In the search to understand disease pathogenesis and find effective therapies animal models are often employed. As exposure to house dust mite (HDM) has a causative link, it is thought of as the allergen of choice for modelling asthma. The objective was to develop a HDM driven model of asthmatic sensitisation and characterise the role of key allergic effector cells/mediators. METHODS: Mice were sensitised with low doses of HDM and then subsequently challenged. Cellular inflammation, IgE and airway responsiveness (AHR) was assessed in wild type mice or CD4(+)/CD8(+) T cells, B cells or IgE knock out mice. RESULTS: Only those mice sensitised with HDM responded to subsequent low dose topical challenge. Similar to the classical ovalbumin model, there was no requirement for systemic alum sensitisation. Characterisation of the role of effector cells demonstrated that the allergic cellular inflammation and AHR was dependent on CD4(+) and CD8(+) T cells but not B cells or IgE. Finally, we show that this model, unlike the classic OVA model, appears to be resistant to developing tolerance. CONCLUSIONS: This CD4(+)/CD8(+) T cell dependent, HDM driven model of allergic asthma exhibits key features of asthma. Furthermore, we suggest that the ability to repeat challenge with HDM means this model is amenable to studies exploring the effect of therapeutic dosing in chronic, established disease.
Jones VC, Birrell MA, Maher SA, et al., 2016, Role of EP2 and EP4 receptors in airway microvascular leak induced by prostaglandin E2, British Journal of Pharmacology, Vol: 173, Pages: 992-1004, ISSN: 1476-5381
Barnett-Vanes A, Sharrock A, Birrell MA, et al., 2016, A single 9-colour flow cytometric method to characterise major leukocyte populations in the rat: validation in a model of LPS-induced pulmonary inflammation, PLOS One, Vol: 11, ISSN: 1932-6203
Birch J, Anderson RK, Correia-Melo C, et al., 2015, DNA damage response at telomeres contributes to lung aging and chronic obstructive pulmonary disease., American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol: 309, Pages: L1124-L1137, ISSN: 1522-1504
Cellular senescence has been associated with the structural and functional decline observed during physiological lung aging and in chronic obstructive pulmonary disease (COPD). Airway epithelial cells are the first line of defense in the lungs and are important to COPD pathogenesis. However, the mechanisms underlying airway epithelial cell senescence, and particularly the role of telomere dysfunction in this process, are poorly understood. We aimed to investigate telomere dysfunction in airway epithelial cells from patients with COPD, in the aging murine lung and following cigarette smoke exposure. We evaluated colocalization of γ-histone protein 2A.X and telomeres and telomere length in small airway epithelial cells from patients with COPD, during murine lung aging, and following cigarette smoke exposure in vivo and in vitro. We found that telomere-associated DNA damage foci increase in small airway epithelial cells from patients with COPD, without significant telomere shortening detected. With age, telomere-associated foci increase in small airway epithelial cells of the murine lung, which is accelerated by cigarette smoke exposure. Moreover, telomere-associated foci predict age-dependent emphysema, and late-generation Terc null mice, which harbor dysfunctional telomeres, show early-onset emphysema. We found that cigarette smoke accelerates telomere dysfunction via reactive oxygen species in vitro and may be associated with ataxia telangiectasia mutated-dependent secretion of inflammatory cytokines interleukin-6 and -8. We propose that telomeres are highly sensitive to cigarette smoke-induced damage, and telomere dysfunction may underlie decline of lung function observed during aging and in COPD.
Asthma is increasing globally and current treatments only manage a proportion of patients. There is an urgent need to develop new therapies. Lymphocytes are thought to play a central role in the pathophysiology of asthma through the production of inflammatory mediators. This is thought to be via the transcription factor NFAT which in turn can be activated through Ca2+ release-activated Ca2+ (CRAC) channels. The aim of this work was to investigate the role of CRAC in clinical and pre-clinical models of allergic asthma.Initial data demonstrated that the NFAT pathway is increased in stimulated lymphocytes from asthmatics. To confirm a role for the channel we showed that a selective inhibitor, Synta 66, blocked mediator production from lymphocytes. Synta 66 inhibited CD2/3/28 induced IL-2, IL-7, IL-13 & IFNΥ in a concentration-dependent manner in healthy and severe asthma donors, with over 60% inhibition observed for all cytokines. NFAT pathway was also increased in a pre-clinical asthma model. In this model we have demonstrated that CRAC played a central role in the airway inflammation and late asthmatic response (LAR). In conclusion, our data provides evidence that suggests targeting CRAC channels could be of therapeutic benefit for asthma sufferers.
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