Publications
29 results found
Pinkerton J, Preite S, Piras A, et al., 2023, PI3Kγd inhibition suppresses key disease features in a rat model of asthma, ERS International Congress 2023 abstracts, Publisher: European Respiratory Society
Pinkerton J, Kim R, Brown A, et al., 2022, Interaction between type 2 cytokine and inflammasome responses in the pathogenesis of obesity-associated asthma, 2022 ERS International Congress, Publisher: European Respiratory Society, ISSN: 0903-1936
Carroll O, Brown A, Mayall J, et al., 2022, Female sex hormones affect asthma severity by altering cellular metabolism in the airways, 2022 ERS International Congress, Publisher: European Respiratory Society, ISSN: 0903-1936
Pinkerton JW, Kim RY, Brown AC, et al., 2022, Relationship between type 2 cytokine and inflammasome responses in obesity-associated asthma, Journal of Allergy and Clinical Immunology, Vol: 149, Pages: 1270-1280, ISSN: 0091-6749
BACKGROUND: Obesity is a risk factor for asthma, and obese asthmatic individuals are more likely to have severe, steroid-insensitive disease. How obesity affects the pathogenesis and severity of asthma is poorly understood. Roles for increased inflammasome-mediated neutrophilic responses, type 2 immunity, and eosinophilic inflammation have been described. OBJECTIVE: We investigated how obesity affects the pathogenesis and severity of asthma and identified effective therapies for obesity-associated disease. METHODS: We assessed associations between body mass index and inflammasome responses with type 2 (T2) immune responses in the sputum of 25 subjects with asthma. Functional roles for NLR family, pyrin domain-containing (NLRP) 3 inflammasome and T2 cytokine responses in driving key features of disease were examined in experimental high-fat diet-induced obesity and asthma. RESULTS: Body mass index and inflammasome responses positively correlated with increased IL-5 and IL-13 expression as well as C-C chemokine receptor type 3 expression in the sputum of subjects with asthma. High-fat diet-induced obesity resulted in steroid-insensitive airway hyperresponsiveness in both the presence and absence of experimental asthma. High-fat diet-induced obesity was also associated with increased NLRP3 inflammasome responses and eosinophilic inflammation in airway tissue, but not lumen, in experimental asthma. Inhibition of NLRP3 inflammasome responses reduced steroid-insensitive airway hyperresponsiveness but had no effect on IL-5 or IL-13 responses in experimental asthma. Depletion of IL-5 and IL-13 reduced obesity-induced NLRP3 inflammasome responses and steroid-insensitive airway hyperresponsiveness in experimental asthma. CONCLUSION: We found a relationship between T2 cytokine and NLRP3 inflammasome responses in obesity-associated asthma, highlighting the potential utility of T2 cytokine-targeted biologics and inflammasome inhibitors.
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
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- Citations: 3
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
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- Citations: 1
Pinkerton JW, Adcock JJ, Zervas D, et al., 2021, PI3Kγd 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
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- Citations: 1
Pinkerton JW, Kim RY, Koeninger L, et al., 2021, Human β-defensin-2 suppresses key features of asthma in murine models of allergic airways disease, CLINICAL AND EXPERIMENTAL ALLERGY, Vol: 51, Pages: 120-131, ISSN: 0954-7894
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- Citations: 15
Miles J, Pinkerton JW, Bonvini SJ, et al., 2020, Modelling IPF-associated chronic cough: role for oxidative stress?, The 2020 ERS International Congress, Publisher: European Respiratory Society, Pages: 1-2, ISSN: 0903-1936
Introduction: Chronic cough is a key symptom that plagues the lives of IPF patients, indeed, it is often the reason the disease is initially diagnosed. The aim of this project was to develop a pre-clinical model of IPF-associated cough and compare the mediator profiles with clinical samples, to aid in the search for effective treatments.Methods: Male guinea pigs (around 325g) were intratracheally dosed with vehicle (saline) or bleomycin (6 USP/kg) and coughs were quantified through manual observation of in-cage video footage, by watching 4.5 hours a day, for 3 weeks. Lung tissue, bronchoalveolar lavage fluid (BALF) and blood was harvested from a parallel group of animals. These were used to assess the extent of fibrosis and measure mediator production (e.g. a marker of oxidative stress: 8-isoprostane). Human BALF was obtained from IPF patients and healthy controls.Results: Spontaneous coughing was recorded in guinea pigs given bleomycin, which was associated with an increase in lung fibrosis and BALF 8-isoprostane (a marker of oxidative stress). We noted similar increases in BALF 8-isoprostane levels in the clinical samples.Conclusions: We have developed a preclinical model to aid in the search for a treatment for IPF-associated coughing. Furthermore, initial data suggests that an increase in oxidative burden (a known trigger of coughing) could be an attractive target.
Pinkerton J, Dekkak B, Zervas D, et al., 2020, Profiling the impact of two JAK inhibitors in a pre-clinical model of allergic asthma, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Ali MK, Kim RY, Brown AC, et al., 2020, Critical role for iron accumulation in the pathogenesis of fibrotic lung disease, JOURNAL OF PATHOLOGY, Vol: 251, Pages: 49-62, ISSN: 0022-3417
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- Citations: 57
Ali MK, Kim RY, Brown AC, et al., 2020, Crucial role for lung iron level and regulation in the pathogenesis and severity of asthma., European Respiratory Journal, Vol: 55, Pages: 1-14, ISSN: 0903-1936
Accumulating evidence highlights links between iron regulation and respiratory disease. Here, we assessed the relationship between iron levels and regulatory responses in clinical and experimental asthma.We show that cell-free iron levels are reduced in the bronchoalveolar lavage (BAL) supernatant of severe or mild-moderate asthma patients and correlate with lower forced expiratory volume in 1 s (FEV1). Conversely, iron-loaded cell numbers were increased in BAL in these patients and with lower FEV1/forced vital capacity (FEV1/FVC). The airway tissue expression of the iron sequestration molecules divalent metal transporter 1 (DMT1) and transferrin receptor 1 (TFR1) are increased in asthma with TFR1 expression correlating with reduced lung function and increased type 2 (T2) inflammatory responses in the airways. Furthermore, pulmonary iron levels are increased in a house dust mite (HDM)-induced model of experimental asthma in association with augmented Tfr1 expression in airway tissue, similar to human disease. We show that macrophages are the predominant source of increased Tfr1 and Tfr1+ macrophages have increased Il13 expression. We also show that increased iron levels induce increased pro-inflammatory cytokine and/or extracellular matrix (ECM) responses in human airway smooth muscle (ASM) cells and fibroblasts ex vivo and induce key features of asthma, including airway hyper-responsiveness and fibrosis and T2 inflammatory responses, in vivoTogether these complementary clinical and experimental data highlight the importance of altered pulmonary iron levels and regulation in asthma, and the need for a greater focus on the role and potential therapeutic targeting of iron in the pathogenesis and severity of disease.
Pinkerton J, Kim R, Brown A, et al., 2019, IL-5/IL-13 drive NLRP3 inflammasome-mediated, steroid-resistant AHR in a model of obesity-associated asthma, ERS International Congress 2019 abstracts, Publisher: European Respiratory Society
Kim R, Horvat J, Pinkerton J, et al., 2019, INTERRELATIONSHIP BETWEEN MICRORNA-21, IL-1β AND SLC26A4 RESPONSES IN SEVERE ASTHMA, Publisher: WILEY, Pages: 77-77, ISSN: 1323-7799
Pinkerton J, Kim R, Robertson A, et al., 2019, Inflammasomes in the lung, Molecular Immunology, ISSN: 0161-5890
Kim RY, Pinkerton JW, Essilfie AT, et al., 2017, Role for NLRP3 Inflammasome-mediated, IL-1β-Dependent Responses in Severe, Steroid-Resistant Asthma, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 196, Pages: 283-297, ISSN: 1073-449X
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- Citations: 250
Horvat J, Kim R, Pinkerton J, et al., 2016, NLRP3 inflammasome-mediated, IL-1β-dependent inflammatory responses drive steroid-resistant asthma, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Pinkerton J, Kim R, Essilfie A-T, et al., 2016, Investigating antioxidant therapy for steroid-resistant asthma, ERS International Congress 2016 abstracts, Publisher: European Respiratory Society
Kim R, Pinkerton J, Essilfie A-T, et al., 2016, NLRP3 inflammasome-mediated, IL-1β-dependent inflammatory responses drive severe, steroid-resistant asthma, International Congress of Immunology (ICI), Publisher: WILEY-BLACKWELL, Pages: 569-570, ISSN: 0014-2980
Kim RY, Rae B, Neal R, et al., 2016, Elucidating novel disease mechanisms in severe asthma, Clinical & Translational Immunology, Vol: 5, ISSN: 2050-0068
<jats:p>Corticosteroids are broadly active and potent anti‐inflammatory agents that, despite the introduction of biologics, remain as the mainstay therapy for many chronic inflammatory diseases, including inflammatory bowel diseases, nephrotic syndrome, rheumatoid arthritis, chronic obstructive pulmonary disease and asthma. Significantly, there are cohorts of these patients with poor sensitivity to steroid treatment even with high doses, which can lead to many iatrogenic side effects. The dose‐limiting toxicity of corticosteroids, and the lack of effective therapeutic alternatives, leads to substantial excess morbidity and healthcare expenditure. We have developed novel murine models of respiratory infection‐induced, severe, steroid‐resistant asthma that recapitulate the hallmark features of the human disease. These models can be used to elucidate novel disease mechanisms and identify new therapeutic targets in severe asthma. Hypothesis‐driven studies can elucidate the roles of specific factors and pathways. Alternatively, 'Omics approaches can be used to rapidly generate new targets. Similar approaches can be used in other diseases.</jats:p>
Kim RY, Horvat JC, Pinkerton JW, et al., 2016, MicroRNA-21 drives severe, steroid-insensitive experimental asthma by amplifying phosphoinositide 3-kinase–mediated suppression of histone deacetylase 2, Journal of Allergy and Clinical Immunology, Vol: 139, Pages: 519-532, ISSN: 1097-6825
BACKGROUND: Severe steroid-insensitive asthma is a substantial clinical problem. Effective treatments are urgently required, however, their development is hampered by a lack of understanding of the mechanisms of disease pathogenesis. Steroid-insensitive asthma is associated with respiratory tract infections and noneosinophilic endotypes, including neutrophilic forms of disease. However, steroid-insensitive patients with eosinophil-enriched inflammation have also been described. The mechanisms that underpin infection-induced, severe steroid-insensitive asthma can be elucidated by using mouse models of disease. OBJECTIVE: We sought to develop representative mouse models of severe, steroid-insensitive asthma and to use them to identify pathogenic mechanisms and investigate new treatment approaches. METHODS: Novel mouse models of Chlamydia, Haemophilus influenzae, influenza, and respiratory syncytial virus respiratory tract infections and ovalbumin-induced, severe, steroid-insensitive allergic airway disease (SSIAAD) in BALB/c mice were developed and interrogated. RESULTS: Infection induced increases in the levels of microRNA (miRNA)-21 (miR-21) expression in the lung during SSIAAD, whereas expression of the miR-21 target phosphatase and tensin homolog was reduced. This was associated with an increase in levels of phosphorylated Akt, an indicator of phosphoinositide 3-kinase (PI3K) activity, and decreased nuclear histone deacetylase (HDAC)2 levels. Treatment with an miR-21-specific antagomir (Ant-21) increased phosphatase and tensin homolog levels. Treatment with Ant-21, or the pan-PI3K inhibitor LY294002, reduced PI3K activity and restored HDAC2 levels. This led to suppression of airway hyperresponsiveness and restored steroid sensitivity to allergic airway disease. These observations were replicated with SSIAAD associated with 4 different pathogens. CONCLUSION: We identify a previously unrecognized role for an miR-21/PI3K/HDAC2 axis in SSIAAD. Our data
Kim R, Pinkerton J, Essilfie A, et al., 2016, NLRP3 INFLAMMASOME- MEDIATED, IL-1β-DEPENDENT INFLAMMATORY RESPONSES DRIVE SEVERE, STEROID-INSENSITIVE ASTHMA, Publisher: WILEY-BLACKWELL, Pages: 46-46, ISSN: 1323-7799
Horvat J, Kim R, Pinkerton J, et al., 2016, Identification of novel therapeutic targets for steroid-insensitive asthma using models that represent different clinical subtypes of disease, Respirology, Vol: 21, Pages: 55-55, ISSN: 1440-1843
Kim RY, Pinkerton JW, Essilfie A-T, et al., 2016, Nlrp3 Inflammasome-Mediated, Il-1β-Dependent Inflammatory Responses Drive Severe, Steroid-Insensitive Asthma, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Kim RY, Pinkerton JW, Gibson PG, et al., 2015, Inflammasomes in COPD and neutrophilic asthma, Thorax, Vol: 70, Pages: 1199-1201, ISSN: 0040-6376
Singanayagam A, Glanville N, Walton RP, et al., 2015, A short-term mouse model that reproduces the immunopathological features of rhinovirus-induced exacerbation of COPD, Clinical Science, Vol: 129, Pages: 245-258, ISSN: 1470-8736
Viral exacerbations of chronic obstructive pulmonary disease (COPD), commonly caused by rhinovirus (RV) infections, are poorly controlled by current therapies. This is due to a lack of understanding of the underlying immunopathological mechanisms. Human studies have identified a number of key immune responses that are associated with RV-induced exacerbations including neutrophilic inflammation, expression of inflammatory cytokines and deficiencies in innate anti-viral interferon. Animal models of COPD exacerbation are required to determine the contribution of these responses to disease pathogenesis. We aimed to develop a short-term mouse model that reproduced the hallmark features of RV-induced exacerbation of COPD. Evaluation of complex protocols involving multiple dose elastase and lipopolysaccharide (LPS) administration combined with RV1B infection showed suppression rather than enhancement of inflammatory parameters compared with control mice infected with RV1B alone. Therefore, these approaches did not accurately model the enhanced inflammation associated with RV infection in patients with COPD compared with healthy subjects. In contrast, a single elastase treatment followed by RV infection led to heightened airway neutrophilic and lymphocytic inflammation, increased expression of tumour necrosis factor (TNF)-α, C-X-C motif chemokine 10 (CXCL10)/IP-10 (interferon γ-induced protein 10) and CCL5 [chemokine (C-C motif) ligand 5]/RANTES (regulated on activation, normal T-cell expressed and secreted), mucus hypersecretion and preliminary evidence for increased airway hyper-responsiveness compared with mice treated with elastase or RV infection alone. In summary, we have developed a new mouse model of RV-induced COPD exacerbation that mimics many of the inflammatory features of human disease. This model, in conjunction with human models of disease, will provide an essential tool for studying disease mechanisms and allow testing of novel therapies with pot
Hansbro P, Kim R, Pinkerton J, et al., 2015, MicroRNA-21 drives severe, steroid-insensitive experimental asthma by amplifying PI3K-mediated suppression of HDAC2, Annual Meeting of the American-Association-of-Immunologists (IMMUNOLOGY), Publisher: AMER ASSOC IMMUNOLOGISTS, ISSN: 0022-1767
Essilfie A-T, Horvat JC, Kim RY, et al., 2015, Macrolide therapy suppresses key features of experimental steroid-sensitive and steroid-insensitive asthma, Thorax, Vol: 70, Pages: 458-467, ISSN: 0040-6376
Hansbro PM, Kim RY, Pinkerton JW, et al., 2015, Infection-Induced Microrna-21 Drives Severe, Steroid-Insensitive Experimental Asthma By Amplifying PhosphoINOSitide-3-Kinase (pi3k)-Mediated Suppression Of Histone Deacetylase (hdac)2, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
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