373 results found
Barnes PJ, Anderson GP, Fageras M, et al., 2021, Chronic lung diseases: prospects for regeneration and repair, EUROPEAN RESPIRATORY REVIEW, Vol: 30, ISSN: 0905-9180
Dhindsa RS, Mattsson J, Nag A, et al., 2021, Identification of a missense variant in SPDL1 associated with idiopathic pulmonary fibrosis, Communications Biology, Vol: 4, ISSN: 2399-3642
Idiopathic pulmonary fibrosis (IPF) is a fatal disorder characterised by progressive, destructive lung scarring. Despite substantial progress, the genetic determinants of this disease remain incompletely defined. Using whole genome and whole exome sequencing data from 752 individuals with sporadic IPF and 119,055 UK Biobank controls, we performed a variant-level exome-wide association study (ExWAS) and gene-level collapsing analyses. Our variant-level analysis revealed a novel association between a rare missense variant in SPDL1 and IPF (NM_017785.5:g.169588475 G > A p.Arg20Gln; p = 2.4 × 10−7, odds ratio = 2.87, 95% confidence interval: 2.03–4.07). This signal was independently replicated in the FinnGen cohort, which contains 1028 cases and 196,986 controls (combined p = 2.2 × 10−20), firmly associating this variant as an IPF risk allele. SPDL1 encodes Spindly, a protein involved in mitotic checkpoint signalling during cell division that has not been previously described in fibrosis. To the best of our knowledge, these results highlight a novel mechanism underlying IPF, providing the potential for new therapeutic discoveries in a disease of great unmet need.
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.
Bonvini SJ, Birrell MA, Dubuis E, et al., 2020, Novel airway smooth muscle-mast cell interactions and a role for the TRPV4-ATP axis in non-atopic asthma, EUROPEAN RESPIRATORY JOURNAL, Vol: 56, ISSN: 0903-1936
Adner M, Canning BJ, Meurs H, et al., 2020, Back to the future: re-establishing guinea pig in vivo asthma models., Clin Sci (Lond), Vol: 134, Pages: 1219-1242
Research using animal models of asthma is currently dominated by mouse models. This has been driven by the comprehensive knowledge on inflammatory and immune reactions in mice, as well as tools to produce genetically modified mice. Many of the identified therapeutic targets influencing airway hyper-responsiveness and inflammation in mouse models, have however been disappointing when tested clinically in asthma. It is therefore a great need for new animal models that more closely resemble human asthma. The guinea pig has for decades been used in asthma research and a comprehensive table of different protocols for asthma models is presented. The studies have primarily been focused on the pharmacological aspects of the disease, where the guinea pig undoubtedly is superior to mice. Further reasons are the anatomical and physiological similarities between human and guinea pig airways compared with that of the mouse, especially with respect to airway branching, neurophysiology, pulmonary circulation and smooth muscle distribution, as well as mast cell localization and mediator secretion. Lack of reagents and specific molecular tools to study inflammatory and immunological reactions in the guinea pig has however greatly diminished its use in asthma research. The aim in this position paper is to review and summarize what we know about different aspects of the use of guinea pig in vivo models for asthma research. The associated aim is to highlight the unmet needs that have to be addressed in the future.
Smith JA, Wortley MA, Bonvini S, et al., 2020, "Truth is ever to be found in simplicity, and not in the multiplicity and confusion of things" - Sir Isaac Newton, EUROPEAN RESPIRATORY JOURNAL, Vol: 55, ISSN: 0903-1936
Mattsson J, Ibanez KG, Wigmore E, et al., 2020, Genetic Analysis Identifies a Novel Missense Variant in SPDL1 Associated with Idiopathic Pulmonary Fibrosis, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Bonvini SJ, Adcock JJ, Kobold N, et al., 2019, A novel role for TRPM3 in Airway Smooth Muscle Contraction, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Flajolet P, Bonvini SJ, Dekkak B, et al., 2019, Investigating Transient Receptor Potential V4 channel induced bronchospasm, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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
Miles JHA, Dubuis E, Bonvini SJ, et al., 2019, Monitoring Cough in a Preclinical Guinea Pig Model of Idiopathic Pulmonary Fibrosis, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Wortley MA, Bonvini SJ, Adcock JJ, et al., 2019, Agonism of EP4 Receptors Expressed on Airway Sensory Nerves Inhibits Cough, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Almeida-Oliveira AR, Aquino JCJ, Abbasi A, et al., 2019, Effects of Aerobic Exercise on Molecular Aspects of Asthma: Involvement of SOCS-JAK-STAT, EXERCISE IMMUNOLOGY REVIEW, Vol: 25, Pages: 98-110, ISSN: 1077-5552
Almeida-Oliveira AR, Aquino-Junior J, Abbasi A, et al., 2019, Effects of aerobic exercise on molecular aspects of asthma: involvement of SOCS-JAK-STAT., Exerc Immunol Rev, Vol: 25, Pages: 50-62, ISSN: 1077-5552
BACKGROUND: Aerobic training (AT) decreases airway inflammation in asthma, but the underlying cellular and molecular mechanisms are not completely understood. Thus, this study evaluated the participation of SOCS-JAK-STAT signaling in the effects of AT on airway inflammation, remodeling and hyperresponsiveness in a model of allergic airway inflammation. METHODS: C57Bl/6 mice were divided into Control (Co), Exercise (Ex), HDM (HDM), and HDM+Exercise (HDM+ Ex). Dermatophagoides pteronyssinus (100ug/mouse) were administered oro-tracheally on days 0, 7, 14, 21, 28, 35, 42 and 49. AT was performed in a treadmill during 4 weeks in moderate intensity, from day 24 until day 52. RESULTS: AT inhibited HDM-induced total cells (p<0.001), eosinophils (p<0.01), neutrophils (p<0.01) and lymphocytes (p<0.01) in BAL, and eosinophils (p<0.01), neutrophils (p<0.01) and lymphocytes (p<0.01) in peribronchial space. AT also reduced BAL levels of IL-4 (p<0.001), IL-5 (p<0.001), IL-13 (p<0.001), CXCL1 (p<0.01), IL-17 (p<0.01), IL-23 (p<0.05), IL-33 (p<0.05), while increased IL- 10 (p<0.05). Airway collagen fibers (p<0.01), elastic fibers p<0.01) and mucin (p<0.01) were also reduced by AT. AT also inhibited HDM-induced airway hyperresponsiveness (AHR) to methacholine 6,25mg/ml (p<0.01), 12,5mg/mL (p<0.01), 25mg/mL (p<0.01) and 50mg/mL (p<0.01). Mechanistically, AT reduced the expression of STAT6 (p<0.05), STAT3 (p<0.001), STAT5 (p<0.01) and JAK2 (p<0.001), similarly by peribronchial leukocytes and by airway epithelial cells. SOCS1 expression (p<0.001) was upregulated in leukocytes and in epithelial cells, SOCS2 (p<0.01) was upregulated in leukocytes and SOCS3 down-regulated in leukocytes (p<0.05) and in epithelial cells (p<0.001). CONCLUSIONS: AT reduces asthma phenotype involving SOCSJAK- STAT signaling.
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
Chen X, Bonvini SJ, Dubuis E, et al., 2018, Characterisation of TRPA1 activation on sensory nerves, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Bolaji JA, Adcock JJ, Sandstrom T, et al., 2018, Biodiesel: is it any safer to use?, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Flajolet P, De Alba J, Raemdonck K, et al., 2018, Characterisation of a chronic preclinical model of allergic asthma, 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.
Saunders P, Czyzyk P, Sen S, et al., 2018, Measuring Cough and Its Impact on Quality of Life in Fibrotic Lung Disease, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Bolaji J, Bonvini SJ, Adcock JJ, et al., 2018, Cleaning Agent Surfactant, 4-Octylphenol, Activates Airway Sensory Nerves and Triggers Respiratory Symptoms: Role in Occupational Asthma?, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Bonvini SJ, Wortley MA, Adcock JJ, et al., 2018, Oestradiol Triggers Airway Sensory Nerve Activation Via The TRPM3-P2X2/3 Ion Channel Axis, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Wortley MA, Adcock JJ, Dubuis ED, et al., 2018, Key Role for TLR2 in Bacterial Activation of Airway Sensory Nerves, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Chen X, Bonvini SJ, Dubuis E, et al., 2018, Cromoglycate Inhibits Airway Sensory Nerves Through an Impact on NADPHase: A Novel Understanding of Its Biological Activity?, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Ma J, Bonvini SJ, Dubuis E, et al., 2018, Investigation into the Mechanisms Driving Hypo-Osmotic Stress-Triggered Activation of Airway Sensory Nerves, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Bonvini SJ, Wortley MA, Adcock JJ, et al., 2017, OESTROGEN: AN ENDOGENOUS AGONIST FOR TRPM3 TRIGGERED SENSORY NERVE ACTIVATION IN THE AIRWAY?, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A1-A1, ISSN: 0040-6376
Wortley MA, Dubuis ED, Bonvini SJ, et al., 2017, BACTERIA CAN TRIGGER AIRWAY SENSORY NERVES VIA THE ACTIVATION OF TLR2, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A1-A1, ISSN: 0040-6376
Rodrigues Brandao-Rangel MA, Lacerda Bachi AL, Oliveira-Junior MC, et al., 2017, Exercise inhibits the effects of smoke-induced COPD involving modulation of STAT3, Oxidative Medicine and Cellular Longevity, Vol: 2017, ISSN: 1942-0900
Purpose. Evaluate the participation of STAT3 in the effects of aerobic exercise (AE) in a model of smoke-induced COPD.Methods.C57Bl/6 male mice were divided into control, Exe, COPD, and COPD+Exe groups. Smoke were administered during 90 days.Treadmill aerobic training begun on day 61 until day 90. Pulmonary inflammation, systemic inflammation, the level of lungemphysema, and the airway remodeling were evaluated. Analysis of integral and phosphorylated expression of STAT3 by airwayepithelial cells, peribronchial leukocytes, and parenchymal leukocytes was performed.Results. AE inhibited smoke-inducedaccumulation of total cells (p<0001), lymphocytes (p<0001), and neutrophils (p<0001) in BAL, as well as BAL levels of IL-1β(p<0001), CXCL1 (p<0001), IL-17 (p<0001), and TNF-α(p<005), while increased the levels of IL-10 (p<0001). AEalso inhibited smoke-induced increases in total leukocytes (p<0001), neutrophils (p<005), lymphocytes (p<0001), andmonocytes (p<001) in blood, as well as serum levels of IL-1β(p<001), CXCL1 (p<001), IL-17 (p<005), and TNF-α(p<001), while increased the levels of IL-10 (p<0001). AE reduced smoke-induced emphysema (p<0001) and collagenfiber accumulation in the airways (p<0001). AE reduced smoke-induced STAT3 and phospho-STAT3 expression in airwayepithelial cells (p<0001), peribronchial leukocytes (p<0001), and parenchymal leukocytes (p<0001).Conclusions.AEreduces smoke-induced COPD phenotype involving STAT3.
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.
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