scholarly journals Lymphocyte senescence in COPD is associated with decreased sirtuin 1 expression in steroid resistant pro-inflammatory lymphocytes

2020 ◽  
Vol 14 ◽  
pp. 175346662090528 ◽  
Author(s):  
Greg Hodge ◽  
Hai B. Tran ◽  
Paul N. Reynolds ◽  
Hubertus Jersmann ◽  
Sandra Hodge
Keyword(s):  
T Cells ◽  
Inflammatory Cytokine ◽  
Sirtuin 1 ◽  
Steroid Resistance ◽  
Chronic Obstructive ◽  
Class Iii ◽  
Obstructive Pulmonary Disease ◽  
Steroid Resistant ◽  
Sirt1 Expression ◽  
Ifnγ And Tnfα

Background: The class III NAD-dependent histone deacetylase (HDAC) sirtuin 1 (SIRT1) is an important regulator of senescence, aging, and inflammation. SIRT1de-acetylates chromatin histones, thereby silencing inflammatory gene transcription. We have reported increased steroid-resistant senescent pro-inflammatory CD28nullCD8+ T cells in patients with chronic obstructive pulmonary disease (COPD). We hypothesized that SIRT1 is reduced in these cells in COPD, and that treatment with SIRT1 activators (resveratrol, curcumin) and agents preventing NAD depletion (theophylline) would upregulate SIRT1 and reduce pro-inflammatory cytokine expression in these steroid-resistant cells. Methods: Blood was collected from n = 10 COPD and n = 10 aged-matched controls. Expression of CD28, SIRT1, and pro-inflammatory cytokines was determined in CD8+ and CD8– T and natural killer T (NKT)-like cells cultured in the presence of ±1 µM prednisolone, ±5 mg/L theophylline, ±1 µM curcumin, ±25 µM resveratrol, using flow cytometry and immunofluorescence. Results: There was an increase in the percentage of CD28nullCD8+ T and NKT-like cells in COPD patients compared with controls. Decreased SIRT1 expression was identified in CD28nullCD8+T and NKT-like cells compared with CD28+ counterparts from both patients and controls (e.g. CD28null 11 ± 3% versus CD28+ 57 ± 9%). Loss of SIRT1 was associated with increased production of IFNγ and TNFα, steroid resistance, and disease severity. SIRT1 expression was upregulated in the presence of all drugs and was associated with a decrease in steroid resistance and IFNγ and TNFα production by CD28nullCD8+T and NKT-like cells. The presence of the SIRT1 inhibitor, EX-527 negated [by 92 ± 12% (median ± SEM)] the effect of the SIRT1 activator SRT720 on the percentage of CD8+ T cells producing IFNγ and TNFα. Conclusions: Steroid resistance in pro-inflammatory CD28nullCD8+ T and NKT-like cells is associated with decreased SIRT1 expression. Treatment with prednisolone, in combination with theophylline, curcumin or resveratrol increases SIRT1 expression, restores steroid sensitivity, and inhibits pro-inflammatory cytokine production from these cells and may reduce systemic inflammation in COPD. The reviews of this paper are available via the supplemental material section.

scholarly journals Use of the routine complete blood count to predict steroid resistance in patients with chronic obstructive pulmonary disease

2019 ◽  
Vol 28 (6) ◽  
pp. 681-692
Author(s):  
A. G. Kadushkin ◽  
A. D. Taganovich ◽  
L. V. Movchan ◽  
T. V. Shman ◽  
V. K. Panasyuk ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Blood Count ◽  
Complete Blood Count ◽  
Lymphocyte Subpopulations ◽  
Steroid Resistance ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Steroid Resistant ◽  
Copd Patients ◽  
Steroid Sensitive

The aimof the present study was to investigate the significance of complete blood count, lymphocyte subpopulations, and cytokines in the peripheral blood in order to evaluate steroid resistance in patients with chronic obstructive pulmonary disease (COPD).Methods.Forty five patients with acute exacerbation of COPD (AECOPD) who underwent bronchoscopy the next day after hospital admission were included in the study. The patients were considered as steroid-sensitive or steroid-resistant according to the ability of dexamethasone to inhibit 50% of interleukin-8 production by alveolar macrophages. Complete blood count, lymphocyte subpopulations, cytokines, immunoglobulin E, and hormone level were measured in the peripheral blood of all patients with COPD.Results.Macrophage migration inhibitory factor (MIF) level, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were higher, and absolute and relative eosinophil numbers were lower in steroid-resistant patients with COPD compared to steroid-sensitive COPD patients. Absolute eosinophil number below the cut-off value of 0.126 × 109/L was predictive for steroid resistance with the sensitivity of 83.3%, the specificity of 55.6% and the area under ROC curve (AUC) of 0.677. Relative eosinophil number below 1.2% predicted steroid resistance with sensitivity, specificity and AUC of 83.3%, 63.0%, and 0.751, respectively. NLR, PLR, and MIF higher than 2.75, 116, and 2.24 ng/mL, respectively, predicted steroid resistance with the sensitivities of 66.7%, 61.1%, and 72.2%, respectively; the specificities of 74.1%, 77.8%, and 70.4%, respectively; and the AUCs of 0.731, 0.678, and 0.740, respectively. The combination of relative eosinophil number, NLR and PLR increased the sensitivity to 83.3%, specificity to 77.8%, and AUC to 0.805. The combination of relative eosinophil number, PLR and MIF increased the sensitivity to 83.3%, specificity to 88.9%, and AUC to 0.889.Conclusion.Steroid-resistant and steroid-sensitive COPD patients differ in absolute and relative eosinophil numbers, LNR, PLR, and MIF level. These parameters could be used to predict steroid resistance in COPD.

scholarly journals Impact of smoking status on the efficacy of inhaled corticosteroids in chronic obstructive pulmonary disease: a systematic review

BMJ Open ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. e037509
Author(s):  
Kimberley Sonnex ◽  
Hanna Alleemudder ◽  
Roger Knaggs
Keyword(s):  
Systematic Review ◽  
Chronic Obstructive Pulmonary Disease ◽  
Lung Function ◽  
Pulmonary Disease ◽  
Inhaled Corticosteroids ◽  
Smoking Status ◽  
Steroid Resistance ◽  
Cochrane Library ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease

ObjectivesInhaled corticosteroids (ICS) reduce exacerbation rates and the decline in lung function in people with chronic obstructive pulmonary disease (COPD). There is evidence that smoking causes ‘steroid resistance’ and thus reduces the effect of ICS. This systematic review aimed to investigate the effect of smoking on efficacy of ICS in COPD in terms of lung function and exacerbation rates.DesignSystematic review.Data sourcesAn electronic database search of PubMed, Ovid MEDLINE, Ovid Embase and Cochrane Library (January 2000 to January 2020).Eligibility criteriaFully published randomised controlled trials (RCTs), in the English language, evaluating the use of ICS in COPD adults that stratified the participants by smoking status. Trials that included participants with asthma, lung cancer and pneumonia were excluded. The primary outcome measures were changes in lung function and yearly exacerbation rates.Data extraction and synthesisTwo independent reviewers extracted data and assessed risk of bias using the Cochrane Collaboration’s tool.ResultsSeven studies were identified. Four trials (17 892 participants) recorded change in forced expiratory volume in one second (FEV1) from baseline to up to 30 months after starting treatment. Heavier smokers (>36 pack years) using ICS had a greater decline in FEV1that ranged from −22 mL to −75 mL in comparison to lighter smokers. Smokers using ICS had mixed results in FEV1change: −8 mL to +77 mL in comparison to ex-smokers. Four trials (21 270 participants) recorded difference in COPD exacerbation rates at 52 weeks. The rate ratios favoured more exacerbations in ICS users who were current or heavier smokers than those who were ex-smokers or lighter smokers (0.81 to 0.99 vs 0.92 to 1.29).ConclusionsIn COPD, heavier or current smokers do not gain the same benefit from ICS use on lung function and exacerbation rates as lighter or ex-smokers do, however effects may not be clinically important.PROSPERO registration numberCRD42019121833

scholarly journals Correlation between Level of Autophagy and Amount of CD8+T Cells in Chronic Obstructive Pulmonary Disease

2020 ◽  
Author(s):  
Songming Zhuo ◽  
Hong Zhuang ◽  
Na Li ◽  
Sida Chen ◽  
Wugen Zhan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lung Function ◽  
Normal Lung ◽  
Stable Phase ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Normal Lung Function ◽  
Healthy Control ◽  
Function Group

Abstract Background: This study aimed to shed light on the correlation between the amounts of CD8+ T cells and autophagy level in COPD. Results: The objects (n = 90) were divided into three groups: COPD group (patients in the stable phase; n = 30), SN group (healthy control of smoking with normal lung function group; n = 30), and NSN groups (healthy control of non-smoking with normal lung function group; n = 30). The amounts of CD8+ (32.33 ± 4.23%), CD8+ effector (25.63 ± 8.57%) and CD8+memory (11.94 ± 5.77%) T cell in the COPD group were significantly higher those in the other two groups, while the apoptotic rate was lower in the COPD group (P < 0.05). Significant linear correlations were found of P62/GAPDH (‰) with CD8+, CD8+effector, and CD8+ memory- T cell amounts (P<0.001). Conclusions: Autophagy level is positively and linearly associated with the amounts of CD8+ T cells, suggesting that cell autophagy might be involved in COPD pathogenesis.

scholarly journals IL-22 and its receptors are increased in human and experimental COPD and contribute to pathogenesis

2019 ◽  
Vol 54 (1) ◽  
pp. 1800174 ◽  
Author(s):  
Malcolm R. Starkey ◽  
Maximilian W. Plank ◽  
Paolo Casolari ◽  
Alberto Papi ◽  
Stelios Pavlidis ◽  
...  
Keyword(s):  
T Cells ◽  
Γδ T Cells ◽  
Lymphoid Cells ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Protein Levels ◽  
Copd Patients ◽  
Cellular Source ◽  
Group 3 ◽  
Underlying Mechanisms

Chronic obstructive pulmonary disease (COPD) is the third leading cause of morbidity and death globally. The lack of effective treatments results from an incomplete understanding of the underlying mechanisms driving COPD pathogenesis.Interleukin (IL)-22 has been implicated in airway inflammation and is increased in COPD patients. However, its roles in the pathogenesis of COPD is poorly understood. Here, we investigated the role of IL-22 in human COPD and in cigarette smoke (CS)-induced experimental COPD.IL-22 and IL-22 receptor mRNA expression and protein levels were increased in COPD patients compared to healthy smoking or non-smoking controls. IL-22 and IL-22 receptor levels were increased in the lungs of mice with experimental COPD compared to controls and the cellular source of IL-22 included CD4+ T-helper cells, γδ T-cells, natural killer T-cells and group 3 innate lymphoid cells. CS-induced pulmonary neutrophils were reduced in IL-22-deficient (Il22−/−) mice. CS-induced airway remodelling and emphysema-like alveolar enlargement did not occur in Il22−/− mice. Il22−/− mice had improved lung function in terms of airway resistance, total lung capacity, inspiratory capacity, forced vital capacity and compliance.These data highlight important roles for IL-22 and its receptors in human COPD and CS-induced experimental COPD.

scholarly journals Erythromycin Suppresses the Cigarette Smoke Extract-Exposed Dendritic Cell-Mediated Polarization of CD4+ T Cells into Th17 Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Jifeng Liu ◽  
Xiaoning Zhong ◽  
Zhiyi He ◽  
Jianquan Zhang ◽  
Jing Bai ◽  
...  
Keyword(s):  
T Cells ◽  
Cigarette Smoke ◽  
Th17 Cells ◽  
Mixed Lymphocyte Reaction ◽  
Mononuclear Cells ◽  
Cigarette Smoke Extract ◽  
Exposed Group ◽  
Control Group ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease

Cigarette smoke is a major effector of chronic obstructive pulmonary disease (COPD), and Th17 cells and dendritic cells (DCs) involve in the pathogenesis of COPD. Previous studies have demonstrated the anti-inflammatory effects of macrolides. However, the effects of macrolides on the cigarette smoke extract- (CSE-) induced immune response are unclear. Accordingly, in this study, we evaluated the effects of erythromycin (EM) on CSE-exposed DCs polarizing naïve CD4+ T cells into Th17 cells. DCs were generated from bone marrow-derived mononuclear cells isolated from male BALB/c mice and divided into five groups: control DC group, CSE-exposed DC group, CD40-antibody-blocked CSE-exposed DC group, and EM-treated CSE-exposed DC group. The function of polarizing CD4+ T cells into Th17 cells induced by all four groups of DCs was assayed based on the mixed lymphocyte reaction (MLR) of naïve CD4+ T cells. CD40 expression in DCs in the CSE-exposed group increased significantly compared with that in the control group (P<0.05). The Th17 cells in the CSE-exposed DC/MLR group increased significantly compared with those in the control DC/MLR group (P<0.05). Moreover, Th17 cells in the CD40-blocked CSE-exposed DC/MLR group and EM-treated CSE-exposed DC/MLR group were reduced compared with those in the CSE-exposed DC/MLR group (P<0.05). Thus, these findings suggested that EM suppressed the CSE-exposed DC-mediated polarization of CD4+ T cells into Th17 cells and that this effect may be mediated through inhibition of the CD40/CD40L pathway.

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