22 results found
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
<jats:title>Abstract</jats:title><jats:p>Cigarette smoke impairs autophagy, an intracellular protein degradation system, but the consequences of this defect have not been fully elucidated, especially in macrophages. Dysfunctional alveolar macrophages play an important role in chronic obstructive pulmonary disease (COPD). Here we show that galectin-8, a danger receptor that identifies damaged intracellular host vesicles and initiates autophagosome engulfment, is elevated due to activation of autophagy by cigarette smoke extract (CSE) in macrophages. CSE impaired autophagic flux in PMA-differentiated U937 macrophage-like cells, resulting in intracellular accumulation of galectin-8 and the autophagic adaptor protein NDP52. COPD patients showed elevated levels of galectin-8 and NDP52 in the lung homogenates with significant increase in the serum galectin-8 levels in patients with frequent acute exacerbations. Soluble galectin-8 induced interleukin (IL)-6 release in bronchial epithelial cells via PI3Kα signalling. Thus, increased galectin-8 due to CSE-induced impaired autophagy may be involved in the pathogenesis of COPD and may be a biomarker of this disease.</jats:p>
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
Fukuda Y, Akimoto K, Homma T, et al., 2020, Virus-Induced Asthma Exacerbations: SIRT1 Targeted Approach, JOURNAL OF CLINICAL MEDICINE, Vol: 9
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
Baker JR, Donnelly LE, Barnes PJ, 2020, Senotherapy A New Horizon for COPD Therapy, CHEST, Vol: 158, Pages: 562-570, ISSN: 0012-3692
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
Wrench CL, Baker JR, Fenwick PS, et al., 2020, Alterations in Antioxidant Expression with Oxidative Stress in Small Airway Fibroblasts from COPD Patients, 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 Bioadv, Vol: 1, Pages: 688-705
Bicaudal D1 (BICD1), an adaptor for the dynein-dynactin motor complex, has been identified as a susceptibility gene in chronic obstructive pulmonary disease (COPD). Autophagy, an essential cellular homeostasis process, is defective in COPD, in which oxidative stress-induced misfolded proteins accumulate into toxic aggregates dependent on the accumulation of the autophagic cargo receptor p62. Defective autophagy can be caused by mutations in the dynein and dynactin motor complex suggesting a possible link between BICD1 and defective autophagy in COPD. BICD1 levels were measured in peripheral lung tissue from COPD patients together with markers of autophagy and found to be increased in COPD together with autophagosomes, p62 and p62 oligomers. In vitro exposure of bronchial epithelial cells to cigarette smoke extracts (CSEs) revealed that high concentrations of CSE induced defective autophagosome maturation with accumulation of BICD1, p62 and ubiquitin-associated p62 oligomers. This was confirmed in vivo using CS-exposed mice. Furthermore, we identified that formation of CS-induced p62 oligomers required an interaction with Keap1. Overexpression and ablation of BICD1 confirmed that increased BICD1 negatively regulates autophagosome maturation inducing accumulation of p62 and p62 oligomers and that it can be reversed by cardiac glycosides. We conclude that defective autophagosome maturation in COPD is caused by oxidative stress-mediated BICD1 accumulation.
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.
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’). 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.
Baker J, Fenwick PS, Tilman J, et al., 2019, IL-36 gamma is Released from Small Airway Epithelial Cells and Drives Macrophage Inflammation in COPD, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Wrench CL, Baker JR, Fenwick PS, et al., 2019, Senescence and Fibrotic Markers Are Induced by Oxidative Stress in Small Airway Fibroblasts from COPD Patients, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Gorlitz F, Lightley J, Kumar S, et al., 2019, Automated multiwell plate STORM: towards open source super-resolved high content analysis, Conference on Advances in Microscopic Imaging II, Publisher: SPIE-INT SOC OPTICAL ENGINEERING, ISSN: 0277-786X
Baker JR, 2018, Sirtuin-1: a new potential therapeutic target for rhinosinusitis? Who 'nose'?, American Journal of Respiratory Cell and Molecular Biology, Vol: 59, Pages: 412-414, ISSN: 1044-1549
Chronic rhinosinusitis is one of the most common upper respiratory tract diseases. In the USA chronic rhinosinusitis has a high prevalence, with around 12% of the population having the disease, and therefore as a consequence the disease has a high health cost burden (1). Chronic rhinosinusitis is classified as an inflammatory nasal disease in which the nasal cavities become inflamed and swollen. The disease can be divided into two distinct disease phenotypes: Chronic rhinosinusitis without nasal polyps (CRSsNP) and Chronic rhinosinusitis with nasal polyps(CRSwNP) (2). One of the major clinical differences between the two subsets of disease is that CRSwNP patients form nasal polyps within their nasal cavities, with these being described as inflammatory lesions of sinonasal tissue which further narrow this space (3). This leads to symptoms of nasal congestion, rhinorrhoea and facial pressure or pain that is of duration of 12 weeks or longer (3). CRSwNP is believed to be a disease of eosinophilia, with an impaired sinonasal epithelial barrier that causes hypersensitivity to inhaled pathogens and particulates, as well as increased permeability, exacerbating the recruitment of inflammatory cells in response to the stimulus.
Baker J, Vuppusetty C, Colley T, et al., 2018, MicroRNA-570 is a novel regulator of cellular senescence and inflammaging, FASEB Journal, ISSN: 0892-6638
Diseases of accelerated aging often occur together (multimorbidity), and their prevalence is increasing, with high societal and health care costs. Chronic obstructive pulmonary disease (COPD) is one such condition, in which one half of patients exhibit ≥4 age-related diseases. Diseases of accelerated aging share common molecular pathways, which lead to the detrimental accumulation of senescent cells. These senescent cells no longer divide but release multiple inflammatory proteins, known as the senescence-associated secretory phenotype, which may perpetuate and speed disease. Here, we show that inhibiting miR-570-3p, which is increased in COPD cells, reverses cellular senescence by restoring the antiaging molecule sirtuin-1. MiR-570-3p is induced by oxidative stress in airway epithelial cells through p38 MAP kinase-c-Jun signaling and drives senescence by inhibiting sirtuin-1. Inhibition of elevated miR-570-3p in COPD small airway epithelial cells, using an antagomir, restores sirtuin-1 and suppresses markers of cellular senescence (p16INK4a, p21Waf1, and p27Kip1), thereby restoring cellular growth by allowing progression through the cell cycle. MiR-570-3p inhibition also suppresses the senescence-associated secretory phenotype (matrix metalloproteinases-2/9, C-X-C motif chemokine ligand 8, IL-1β, and IL-6). Collectively, these data suggest that inhibiting miR-570-3p rejuvenates cells via restoration of sirtuin-1, reducing many of the abnormalities associated with cellular senescence.—Baker, J. R., Vuppusetty, C., Colley, T., Hassibi, S., Fenwick, P. S., Donnelly, L. E., Ito, K., Barnes, P. J. MicroRNA-570 is a novel regulator of cellular senescence and inflammaging.
Baker JR, Falconer AMD, Wilkinson DJ, et al., 2018, Protein kinase D3 modulates MMP1 and MMP13 expression in human chondrocytes, PLoS ONE, Vol: 13, ISSN: 1932-6203
Many catabolic stimuli, including interleukin-1 (IL-1) in combination with oncostatin M (OSM), promote cartilage breakdown via the induction of collagen-degrading collagenases such as matrix metalloproteinase 1 (MMP1) and MMP13 in human articular chondrocytes. Indeed, joint diseases with an inflammatory component are characterised by excessive extracellular matrix (ECM) catabolism. Importantly, protein kinase C (PKC) signalling has a primary role in cytokine-induced MMP1/13 expression, and is known to regulate cellular functions associated with pathologies involving ECM remodelling. At present, substrates downstream of PKC remain undefined. Herein, we show that both IL-1- and OSM-induced phosphorylation of protein kinase D (PKD) in human chondrocytes is strongly associated with signalling via the atypical PKCι isoform. Consequently, inhibiting PKD activation with a pan-PKD inhibitor significantly reduced the expression of MMP1/13. Specific gene silencing of the PKD isoforms revealed that only PKD3 (PRKD3) depletion mirrored the observed MMP repression, indicative of the pharmacological inhibitor specifically affecting only this isoform. PRKD3 silencing was also shown to reduce serine phosphorylation of signal transducer and activator of transcription 3 (STAT3) as well as phosphorylation of all three mitogen-activated protein kinase groups. This altered signalling following PRKD3 silencing led to a significant reduction in the expression of the activator protein-1 (AP-1) genes FOS and JUN, critical for the induction of many MMPs including MMP1/13. Furthermore, the AP-1 factor activating transcription factor 3 (ATF3) was also reduced concomitant with the observed reduction in MMP13 expression. Taken together, we highlight an important role for PKD3 in the pro-inflammatory signalling that promotes cartilage destruction.
Yanagisawa S, Baker JR, Vuppusetty C, et al., 2018, The dynamic shuttling of SIRT1 between cytoplasm and nuclei in bronchial epithelial cells by single and repeated cigarette smoke exposure, PLoS ONE, Vol: 13, ISSN: 1932-6203
SIRT1 (silent information regulator 2 homolog 1) is a crucial cellular survival protein especially in oxidative stress environments, and has been thought to locate within the nuclei, but also known to shuttle between cytoplasm and nuclei in some cell types. Here, we show for the first time the dynamics of SIRT1 in the presence of single or concurrent cigarette smoke extract (CSE) exposure in human bronchial epithelial cells (HBEC). In BEAS-2B HBEC or primary HBEC, SIRT1 was localized predominantly in cytoplasm, and the CSE (3%) induced nuclear translocation of SIRT1 from cytoplasm in the presence of L-buthionine sulfoximine (an irreversible inhibitor of γ-glutamylcystein synthetase), mainly through the activation of phosphatidylinositol 3-kinase (PI3K) α subunit. This SIRT1 nuclear shuttling was associated with FOXO3a nuclear translocation and the strong induction of several anti-oxidant genes including superoxide dismutase (SOD) 2 and 3; therefore seemed to be an adaptive response. When BEAS-2B cells were pretreated with repeated exposure to a lower concentration of CSE (0.3%), the CSE-induced SIRT1 shuttling and resultant SOD2/3 mRNA induction were significantly impaired. Thus, this result offers a useful cell model to mimic the impaired anti-oxidant capacity in cigarette smoking-associated lung disease such as chronic obstructive pulmonary disease.
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
Yanagisawa S, Baker JR, Vuppusetty C, et al., 2017, Decreased phosphatase PTEN amplifies PI3K signaling and enhances pro-inflammatory cytokine release in COPD, American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol: 313, Pages: L230-L239, ISSN: 1522-1504
The phosphatidylinositol 3-kinase (PI3K) pathway is activated in chronic obstructive pulmonary disease (COPD), but the regulatory mechanisms for this pathway are yet to be elucidated. Our aim was to determine the expression and role of phosphatase and tensin homolog deleted from chromosome 10 (PTEN), a negative regulator of the PI3K pathway, in COPD. PTEN expression and activity were measured in the peripheral lung of COPD patients compared to smoking and non-smoking controls. The direct influence of cigarette smoke extract (CSE) on PTEN expression was assessed using primary lung epithelial cells and a cell line (BEAS-2B) in the presence or absence of L-buthionine-sulfoximine (BSO) to deplete intracellular glutathione. The impact of PTEN knock-down by RNA interference on cytokine production was also examined. In peripheral lung, PTEN protein was significantly decreased in patients with COPD compared to the subjects without COPD (p < 0.001), and positively correlated with the severity of air-flow obstruction (FEV1 % predicted; r = 0.50; p = 0.0012), although no difference was observed in PTEN activity. Conversely, phosphorylated Akt, as a marker of PI3K activation, showed a negative correlation with PTEN protein levels (r = -0.41; p = 0.0042). Both in primary bronchial epithelial cells and BEAS-2B cell line, CSE decreased PTEN protein, which was reversed by N-acetylcysteine treatment. PTEN knock-down potentiated Akt phosphorylation and enhanced production of pro-inflammatory cytokines, such as IL-6, CXCL8, CCL2 and CCL5. In conclusion, oxidative stress reduces PTEN protein levels, which may result in increased PI3K signaling and amplification of inflammation in COPD.
Yanagisawa S, Papaioannou A, Papaporfyriou A, et al., 2017, Decreased serum sirtuin-1 in chronic obstructive pulmonary disease, Chest, Vol: 152, Pages: 343-352, ISSN: 1931-3543
Background: The protein deacetylase sirtuin-1 (SIRT1) is an anti-aging molecule that is decreased in the lung from patients with chronic obstructive pulmonary disease (COPD). Recently, SIRT1 was reported to be detectable in serum, but serum SIRT1 levels have not yet been reported in patients with COPD.Methods: Serum SIRT1 was measured by Western blotting, and relative ratio of band density in samples against that of a positive control were calculated.Results: Several molecular sizes of SIRT1, including 120kDa (actual size) and fragments (102, 75kDa) were quantified by Western blotting. Among them, only the 120kDa serum SIRT1 (s120S) was significantly decreased in the patients with COPD compared to the control subjects without COPD (s120S ratio in healthy: 0.90±0.34, vs COPD: 0.68±0.24; p=0.014), and was positively correlated with airway obstruction (FEV1/ FVC; r=0.31; p=0.020) and its severity measured by FEV1 % predicted (r=0.29; p=0.029). Serum s120S also showed a positive correlation with body mass index (BMI; r=0.36; p=0.0077) and diffusing capacity of the lung per unit volume (KCO%; r=0.32; p=0.025). It was also significantly decreased with increasing severity of lung emphysema (r=-0.40, p=0.027) and with a clinical history of frequent COPD exacerbations (infrequent: 0.76±0.20 vs frequent: 0.56±0.26; p=0.027). SIRT1 was not detected in supernatant of A549 and primary epithelial cells in normal culture condition.Conclusions: Serum SIRT1 (s120S) was decreased in the patients with COPD, potentially as reflected by the reduced SIRT1 within cells as a result of oxidative stress, and might be a potential biomarkers for certain disease characteristics of COPD.
Baker J, Vuppusetty C, Ito K, et al., 2017, Antagomir Of Microrna-34a Rescues Cellular Senescence In Bronchial Epithelial Cells Of COPD Patients, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Baker JR, Vuppusetty C, Colley T, et al., 2016, Oxidative stress dependent microRNA-34a activation via PI3Kα reduces the expression of sirtuin-1 and sirtuin-6 in epithelial cells, Scientific Reports, Vol: 6, ISSN: 2045-2322
Sirtuin-1 (SIRT1) and SIRT6, NAD(+)-dependent Class III protein deacetylases, are putative anti-aging enzymes, down-regulated in patients with chronic obstructive pulmonary disease (COPD), which is characterized by the accelerated ageing of the lung and associated with increased oxidative stress. Here, we show that oxidative stress (hydrogen peroxide) selectively elevates microRNA-34a (miR-34a) but not the related miR-34b/c, with concomitant reduction of SIRT1/-6 in bronchial epithelial cells (BEAS2B), which was also observed in peripheral lung samples from patients with COPD. Over-expression of a miR-34a mimic caused a significant reduction in both mRNA and protein of SIRT1/-6, whereas inhibition of miR-34a (antagomir) increased these sirtuins. Induction of miR-34a expression with H2O2 was phosphoinositide-3-kinase (PI3K) dependent as it was associated with PI3Kα activation as well as phosphatase and tensin homolog (PTEN) reduction. Importantly, miR-34a antagomirs increased SIRT1/-6 mRNA levels, whilst decreasing markers of cellular senescence in airway epithelial cells from COPD patients, suggesting that this process is reversible. Other sirtuin isoforms were not affected by miR-34a. Our data indicate that miR-34a is induced by oxidative stress via PI3K signaling, and orchestrates ageing responses under oxidative stress, therefore highlighting miR-34a as a new therapeutic target and biomarker in COPD and other oxidative stress-driven aging diseases.
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