384 results found
Singh D, Beier J, Astbury C, et al., 2022, The novel bronchodilator navafenterol: a phase 2a, multicentre, randomised, double-blind, placebo-controlled crossover trial in COPD, EUROPEAN RESPIRATORY JOURNAL, Vol: 59, ISSN: 0903-1936
Nilsson M, Rhedin M, Hendrickx R, et al., 2022, Characterization of Selective and Potent JAK1 Inhibitors Intended for the Inhaled Treatment of Asthma., Drug Des Devel Ther, Vol: 16, Pages: 2901-2917
Purpose: Janus kinase 1 (JAK1) is implicated in multiple inflammatory pathways that are critical for the pathogenesis of asthma, including the interleukin (IL)-4, IL-5, IL-13, and thymic stromal lymphopoietin cytokine signaling pathways, which have previously been targeted to treat allergic asthma. Here, we describe the development of AZD0449 and AZD4604, two novel and highly selective JAK1 inhibitors with promising properties for inhalation. Methods: The effects of AZD0449 and AZD4604 in JAK1 signaling pathways were assessed by measuring phosphorylation of signal transducer and activator of transcription (STAT) proteins and chemokine release using immunoassays of whole blood from healthy human volunteers and rats. Pharmacokinetic studies performed on rats evaluated AZD0449 at a lung deposited dose of 52 μg/kg and AZD4604 at 30 µg/kg. The efficacy of AZD0449 and AZD4604 was assessed by evaluating lung inflammation (cell count and cytokine levels) and the late asthmatic response (average enhanced pause [Penh]). Results: Both compounds inhibited JAK1-dependent cytokine signaling pathways in a dose-dependent manner in human and rat leukocytes. After intratracheal administration in rats, both compounds exhibited low systemic exposures and medium-to-long terminal lung half-lives (AZD0449, 34 hours; AZD4604, 5 hours). Both compounds inhibited STAT3 and STAT5 phosphorylation in lung tissue from ovalbumin (OVA)-challenged rats. AZD0449 and AZD4604 also inhibited eosinophilia in the lung and reduced the late asthmatic response, measured as Penh in the OVA rat model. Conclusion: AZD0449 and AZD4604 show potential as inhibitors of signaling pathways involved in asthmatic immune responses, with target engagement demonstrated locally in the lung. These findings support the clinical development of AZD0449 and AZD4604 for the treatment of patients with asthma.
Ptasinski VA, Stegmayr J, Belvisi MG, et al., 2021, Targeting Alveolar Repair in Idiopathic Pulmonary Fibrosis, AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, Vol: 65, Pages: 347-365, ISSN: 1044-1549
Koivisto A-P, Belvisi MG, Gaudet R, et al., 2021, Advances in TRP channel drug discovery: from target validation to clinical studies, NATURE REVIEWS DRUG DISCOVERY, Vol: 21, Pages: 41-59, ISSN: 1474-1776
Sadiq MW, Asimus S, Belvisi MG, et al., 2021, Characterisation of pharmacokinetics, safety and tolerability in a first-in-human study for AZD8154, a novel inhaled selective PI3K gamma delta dual inhibitor targeting airway inflammatory disease, BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Vol: 88, Pages: 260-270, ISSN: 0306-5251
Chen X, Bonvini SJ, Adcock J, et al., 2021, Activation of GPR35 Inhibits Airway Sensory Nerves and the Late Asthmatic Response in Preclinical Model Systems, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Pinkerton JW, Dekkak B, Zervas D, et al., 2021, Velsecorat (AZD7594), a Selective Glucocorticoid Receptor Modulator (SGRM) Demonstrates Favorable Pre-Clinical Efficacy vs Safety Profile Compared to Current Clinical Inhaled Steroid, Fluticasone Furoate, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Pinkerton JW, Adcock JJ, Zervas D, et al., 2021, PI3K gamma d Inhibitor, AZD8154, Demonstrates Improved Efficacious Profile Over PI3Kd Selective Inhibitor, GSK2269557, in a Rat Model of Asthma, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Bonvini SJ, Miles JH, Flajolet P, et al., 2021, A Novel Mechanism of Action for the NK1 Receptor in Airway Sensory Nerves, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
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.
Williams TC, Jackson DJ, Maltby S, et al., 2020, Rhinovirus-induced CCL17 and CCL22 in asthma exacerbations and differential regulation by STAT6., American Journal of Respiratory Cell and Molecular Biology, Vol: 64, Pages: 344-356, ISSN: 1044-1549
The interplay of type-2 inflammation and anti-viral immunity underpins asthma exacerbation pathogenesis. Virus infection induces type-2 inflammation-promoting chemokines CCL17 and CCL22 in asthma, however mechanisms regulating induction are poorly understood. By using a human rhinovirus (RV) challenge model in human airway epithelial cells in vitro and mice in vivo, we assessed mechanisms regulating CCL17 and CCL22 expression. Subjects with mild-to-moderate asthma and healthy volunteers were experimentally infected with RV and airway CCL17 and CCL22 protein quantified. In vitro airway epithelial cell- and mouse-RV infection models were then employed to define STAT6- and NF-κB-mediated regulation of CCL17 and CCL22 expression. Following RV infection, CCL17 and CCL22 expression was higher in asthma, which differentially correlated with clinical and immunological parameters. Air-liquid interface (ALI) differentiated primary epithelial cells from donors with asthma also expressed higher levels of RV-induced CCL22. RV infection boosted type-2 cytokine-induced STAT6 activation. In epithelial cells, type-2 cytokines and STAT6 activation had differential effects on chemokine expression: increasing CCL17 and suppressing CCL22, whereas NF-κB promoted expression of both chemokines. In mice, RV infection activated pulmonary STAT6 which was required for CCL17, but not CCL22 expression. STAT6-knockout mice infected with RV expressed increased levels of NF-kB-regulated chemokines, which was associated with rapid viral clearance. Therefore, RV-induced upregulation of CCL17 and CCL22 was mediated by NF-κB activation, whereas expression was differentially regulated by STAT6. Together, findings suggest therapeutic targeting of type-2-STAT6 activation alone will not block all inflammatory pathways during RV infection in asthma.
Wortley MA, Bonvini SJ, Adcock JJ, et al., 2020, EPAC drives the anti-tussive effect of EP4 receptors on airway sensory nerves, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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, Virtual 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, International Congress of the European-Respiratory-Society (ERS), 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, International Congress of the European-Respiratory-Society (ERS), 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
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