Publications
42 results found
Ombredane HCJ, Fenwick PS, Barnes PJ, et al., 2023, Temporal Release of IL-1 Family Members from Virally Infected Airway Epithelial Cells Suggests IL-36γ Is the Early Responder., Am J Respir Cell Mol Biol, Vol: 68, Pages: 339-341
Fawzy A, Baker JR, Keller TL, et al., 2022, Selected Bibliography of Recent Research in Chronic Obstructive Pulmonary Disease, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 206, Pages: 1408-1417, ISSN: 1073-449X
Baker JR, Fenwick PS, Koss CK, et al., 2022, Imbalance between IL-36 receptor agonist and antagonist drives neutrophilic inflammation in COPD, JCI Insight, Vol: 7, ISSN: 2379-3708
Current treatments fail to modify the underlying pathophysiology and disease progression of chronic obstructive pulmonary disease (COPD), necessitating alternative therapies. Here, we show that COPD subjects have increased IL-36γ and decreased IL-36 receptor antagonist (IL-36Ra) in bronchoalveolar and nasal fluid compared to control subjects. IL-36γ is derived from small airway epithelial cells (SAEC) and further induced by a viral mimetic, whereas IL-36RA is derived from macrophages. IL-36γ stimulates release of the neutrophil chemoattractants CXCL1 and CXCL8, as well as elastolytic matrix metalloproteinases (MMPs) from small airway fibroblasts (SAF). Proteases released from COPD neutrophils cleave and activate IL-36γ thereby perpetuating IL-36 inflammation. Transfer of culture media from SAEC to SAF stimulated release of CXCL1, that was inhibited by exogenous IL-36RA. The use of a therapeutic antibody that inhibits binding to the IL-36 receptor (IL-36R) attenuated IL-36γ driven inflammation and cellular cross talk. We have demonstrated a mechanism for the amplification and propagation of neutrophilic inflammation in COPD and that blocking this cytokine family via a IL-36R neutralizing antibody could be a promising new therapeutic strategy in the treatment of COPD.
Fenwick P, Baker JR, Koss CK, et al., 2022, TRPV4 Identifies Phagocytic Macrophages and May Promote Phagocytosis in Both Healthy and COPD Cells, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Hassibi S, Baker JR, Barnes PJ, et al., 2022, COPD Macrophages Show Reduced Clearance of Senescent Airway Epithelial Cells, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Wysoczanski R, Baker JR, Fenwick P, et al., 2022, Defective Phagocytosis in COPD Macrophages Is Improved by Mitochondrial Antioxidants Without Alteration in Mitochondrial Function, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Ho V, Baker JR, Willison KR, et al., 2022, Novel Single Cell Analysis of microRNA Levels in Response to Oxidative Stress and in COPD Using Microfluidic Technology, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Baker JR, Fenwick PS, Koss CK, et al., 2022, Inhibition of the IL-36 Receptor Reduces Viral Induced Cross-Talk Between Small Airway Epithelial Cells and Fibroblast in COPD, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Devulder J, Baker JR, Odqvist L, et al., 2022, Transfer of microRNA Through Extracellular Vesicles Propagate Airway Epithelial Cells Senescence in COPD, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Barnes PJ, Baker J, Donnelly LE, 2022, Autophagy in asthma and chronic obstructive pulmonary disease, CLINICAL SCIENCE, Vol: 136, Pages: 733-746, ISSN: 0143-5221
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- Citations: 5
Baker JR, Mahdi M, Nicolau DV, et al., 2022, Early Th2 inflammation in the upper respiratory mucosa as a predictor of severe COVID-19 and modulation by early treatment with inhaled corticosteroids: a mechanistic analysis., The Lancet Respiratory Medicine, ISSN: 2213-2600
BACKGROUND: Community-based clinical trials of the inhaled corticosteroid budesonide in early COVID-19 have shown improved patient outcomes. We aimed to understand the inflammatory mechanism of budesonide in the treatment of early COVID-19. METHODS: The STOIC trial was a randomised, open label, parallel group, phase 2 clinical intervention trial where patients were randomly assigned (1:1) to receive usual care (as needed antipyretics were only available treatment) or inhaled budesonide at a dose of 800 μg twice a day plus usual care. For this experimental analysis, we investigated the nasal mucosal inflammatory response in patients recruited to the STOIC trial and in a cohort of SARS-CoV-2-negative healthy controls, recruited from a long-term observational data collection study at the University of Oxford. In patients with SARS-CoV-2 who entered the STOIC study, nasal epithelial lining fluid was sampled at day of randomisation (day 0) and at day 14 following randomisation, blood samples were also collected at day 28 after randomisation. Nasal epithelial lining fluid and blood samples were collected from the SARS-CoV-2 negative control cohort. Inflammatory mediators in the nasal epithelial lining fluid and blood were assessed for a range of viral response proteins, and innate and adaptive response markers using Meso Scale Discovery enzyme linked immunoassay panels. These samples were used to investigate the evolution of inflammation in the early COVID-19 disease course and assess the effect of budesonide on inflammation. FINDINGS: 146 participants were recruited in the STOIC trial (n=73 in the usual care group; n=73 in the budesonide group). 140 nasal mucosal samples were available at day 0 (randomisation) and 122 samples at day 14. At day 28, whole blood was collected from 123 participants (62 in the budesonide group and 61 in the usual care group). 20 blood or nasal samples were collected from healthy controls. In early COVID-19 disease, there was an enhanced in
Koss CK, Wohnhaas CT, Baker JR, et al., 2021, IL36 is a critical upstream amplifier of neutrophilic lung inflammation in mice, Communications Biology, Vol: 4, Pages: 1-15, ISSN: 2399-3642
IL-36, which belongs to the IL-1 superfamily, is increasingly linked to neutrophilic inflammation. Here, we combined in vivo and in vitro approaches using primary mouse and human cells, as well as, acute and chronic mouse models of lung inflammation to provide mechanistic insight into the intercellular signaling pathways and mechanisms through which IL-36 promotes lung inflammation. IL-36 receptor deficient mice exposed to cigarette smoke or cigarette smoke and H1N1 influenza virus had attenuated lung inflammation compared with wild-type controls. We identified neutrophils as a source of IL-36 and show that IL-36 is a key upstream amplifier of lung inflammation by promoting activation of neutrophils, macrophages and fibroblasts through cooperation with GM-CSF and the viral mimic poly(I:C). Our data implicate IL-36, independent of other IL-1 family members, as a key upstream amplifier of neutrophilic lung inflammation, providing a rationale for targeting IL-36 to improve treatment of a variety of neutrophilic lung diseases.
Baker JR, Fenwick PS, Owles HB, et al., 2021, IL-36? - a key mediator of neutrophilic inflammation in chronic obstructive pulmonary disease, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Devulder J, Baker JR, Donnelly LE, et al., 2021, Extracellular vesicles produced by airway epithelial cells in response to oxidative stress contain microRNAs associated with cellular senescence, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Baker JR, Donnelly LE, 2021, Leukocyte function in COPD: clinical relevance and potential for drug therapy., The International Journal of Chronic Obstructive Pulmonary Disease, Vol: 16, Pages: 2227-2242, ISSN: 1176-9106
Chronic obstructive pulmonary disease (COPD) is a progressive lung condition affecting 10% of the global population over 45 years. Currently, there are no disease-modifying treatments, with current therapies treating only the symptoms of the disease. COPD is an inflammatory disease, with a high infiltration of leukocytes being found within the lung of COPD patients. These leukocytes, if not kept in check, damage the lung, leading to the pathophysiology associated with the disease. In this review, we focus on the main leukocytes found within the COPD lung, describing how the release of chemokines from the damaged epithelial lining recruits these cells into the lung. Once present, these cells become active and may be driven towards a more pro-inflammatory phenotype. These cells release their own subtypes of inflammatory mediators, growth factors and proteases which can all lead to airway remodeling, mucus hypersecretion and emphysema. Finally, we describe some of the current therapies and potential new targets that could be utilized to target aberrant leukocyte function in the COPD lung. Here, we focus on old therapies such as statins and corticosteroids, but also look at the emerging field of biologics describing those which have been tested in COPD already and potential new monoclonal antibodies which are under review.
Ritchie AI, Baker JR, Parekh TM, et al., 2021, Update in Chronic Obstructive Pulmonary Disease 2020, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 204, Pages: 14-22, ISSN: 1073-449X
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- Citations: 5
Ramakrishnan S, Nicolau D, Langford B, et al., 2021, Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial, LANCET RESPIRATORY MEDICINE, Vol: 9, Pages: 763-772, ISSN: 2213-2600
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- Citations: 187
Kono Y, Colley T, To M, et al., 2021, Cigarette smoke-induced impairment of autophagy in macrophages increases galectin-8 and inflammation, SCIENTIFIC REPORTS, Vol: 11, ISSN: 2045-2322
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- Citations: 9
Perez E, Baker JR, Di Giandomenico S, et al., 2020, Hepcidin Is Essential for Alveolar Macrophage Function and Is Disrupted by Smoke in a Murine Chronic Obstructive Pulmonary Disease Model, JOURNAL OF IMMUNOLOGY, Vol: 205, Pages: 2489-+, ISSN: 0022-1767
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- Citations: 8
Devulder J, Baker JR, Donnelly LE, et al., 2020, LSC-2020-Extracellular vesicles produced by bronchial epithelial cells in response to oxidative stress contain micro-RNAs associated with senescence, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Baker JR, Fenwick PS, Donnelly L, et al., 2020, Altered iron metabolism and elevated cellular senescence in COPD small airway epithelial cells, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 1
Wysoczanski R, Baker JR, Fenwick P, et al., 2020, Analysis of defective phagocytosis in COPD using super-resolution microscopy and automated bacterial quantification, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Fukuda Y, Akimoto K, Homma T, et al., 2020, Virus-Induced Asthma Exacerbations: SIRT1 Targeted Approach, JOURNAL OF CLINICAL MEDICINE, Vol: 9
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- Citations: 7
Baker JR, Donnelly LE, Barnes PJ, 2020, Senotherapy A New Horizon for COPD Therapy, CHEST, Vol: 158, Pages: 562-570, ISSN: 0012-3692
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- Citations: 24
Alter P, Baker JR, Dauletbaev N, et al., 2020, Update in Chronic Obstructive Pulmonary Disease 2019, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 202, Pages: 348-355, ISSN: 1073-449X
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- Citations: 11
Tsilogianni Z, Baker JR, Papaporfyriou A, et al., 2020, Sirtuin 1: Endocan and Sestrin 2 in Different Biological Samples in Patients with Asthma. Does Severity Make the Difference?, JOURNAL OF CLINICAL MEDICINE, Vol: 9
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- Citations: 9
Wrench CL, Baker JR, Fenwick PS, et al., 2020, Alterations in Antioxidant Expression with Oxidative Stress in Small Airway Fibroblasts from COPD Patients, Virtual International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Mercado N, Colley T, Baker JR, et al., 2019, Bicaudal D1 impairs autophagosome maturation in chronic obstructive pulmonary disease, FASEB BIOADVANCES, Vol: 1, Pages: 688-705
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- Citations: 7
Barnes PJ, Baker J, Donnelly LE, 2019, Cellular senescence as a mechanism and target in chronic lung diseases, American Journal of Respiratory and Critical Care Medicine, Vol: 200, ISSN: 1073-449X
Cellular senescence is now considered an important driving mechanism for chronic lung diseases, particularly COPD and idiopathic pulmonary fibrosis. Cellular senescence is due to replicative and stress-related senescence with activation of p53 and p16INK4a respectively, leading to activation of p21CIP1 and cell cycle arrest. Senescent cells secrete multiple inflammatory proteins known as the senescence-associated secretory phenotype (SASP), leading to low grade chronic inflammation, which further drives senescence. Loss of key anti-aging molecules sirtuin-1 and sirtuin-6 may be important in acceleration of aging and arises from oxidative stress reducing phosphatase PTEN, thereby activating PI3K (phosphoinositide-3-kinase) and mTOR (mammalian target of rapamycin). MicroRNA-34a, which is regulated by PI3K-mTOR signaling, plays a pivotal role in reducing sirtuin-1/6 and its inhibition with an antagomir results in their restoration, reducing markers of senescence, reducing SASP and reversing cell cycle arrest in epithelial cells from peripheral airways of COPD patients. MiR-570 is also involved in reduction of sirtuin-1 and cellular senescence and is activated by p38 MAP kinase. These miRNAs may be released from cells in extracellular vesicles that are taken up by other cells, thereby spreading senescence locally within the lung but outside the lung through the circulation; this may account for comorbidities of COPD and other lung diseases. Understanding the mechanisms of cellular senescence may result in new treatments for chronic lung disease, either by inhibiting PI3K-mTOR signaling, by inhibiting specific miRNAs or by deletion of senescent cells with senolytic therapies, already shown to be effective in experimental lung fibrosis.
Menzies-Gow A, McBrien CN, Baker JR, et al., 2019, Update in asthma/airway inflammation 2018, American Journal of Respiratory and Critical Care Medicine, Vol: 200, Pages: 14-19, ISSN: 1073-449X
Throughout 2018, the publications of the AJRCCM and associated ATS journals have continued to focus on the individual and societal impact of asthma and the challenges involved in managing this prevalent, but heterogeneous, condition. Asthma remains the most common chronic respiratory condition with ongoing significant unmet need at all levels of severity. The cardinal features of asthma, i.e. that it affects a significant proportion of all age‐groups, but generates highly individual effects on health and socioeconomic factors, have hampered previous attempts to gauge its true cost at a population level. Nurmagambetov et al. approached this task by utilising data from the 2008‐2013 household component of the Medical Expenditure Panel Survey, examining a total sample size of more than 200,000 persons (more than 10,000 of whom had ‘treated asthma’)[1]. Application of a two‐part regression model indicated the cost of asthma in the USA in 2013 to be $81.9 billion, underlining the huge potential for improvements in asthma care to benefit individuals and populations in multiple aspects, including financially.
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