scholarly journals Sensitivity to glucocorticosteroids and heterogeneity of in vitro cell response in patients with chronic obstructive pulmonary disease

2018 ◽  
Vol 28 (5) ◽  
pp. 558-566 ◽  
Author(s):  
A. G. Kadushkin ◽  
A. D. Taganovich ◽  
A. A. Arabey ◽  
L. M. Shishlo ◽  
A. P. Lyubetskaya ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Fluorescence Intensity ◽  
Alveolar Macrophages ◽  
Cell Response ◽  
Blood Cells ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients ◽  
Tnf Α

Inhaled corticosteroids are widely used for the treatment of chronic obstructive pulmonary disease (COPD), but their efficacy significantly varies between patients. The aim of the study was to establish approaches to reveal steroid-sensitive and steroid-resistant patients with COPD using the blood and lung cells. Methods. Forty five patients with COPD undergoing bronchoscopy were recruited for the study of cytokine secretion by alveolar macrophages under the influence of glucocorticoids. Alveolar macrophages isolated from bronchoalveolar lavage fluid were cultured with lipopolysaccharide (LPS) and different concentrations of dexamethasone (0.01 – 1000 nM) for 24 h. Then, supernatants were removed and analyzed for concentrations of interleukin 6 (IL-6), IL-8 and tumor necrosis factor α (TNF-α). Binding of the glucocorticoid with its receptors was investigated in 24 patients with COPD, 20 healthy smokers and 20 healthy non-smokers. Blood cells were cultured with fluorescein isothiocyanate (FITC)-labelled dexamethasone and monoclonal antibodies against surface antigens of lymphocyte and monocyte populations. Fluorescence intensity of FITC-labelled dexamethasone was analyzed in blood cells using flow cytometry. Results. Dexamethasone significantly inhibited IL-6, IL-8, and TNF-α production in alveolar macrophages in a dose dependent manner. The maximal inhibition of cytokine production was observed at dexamethasone concentration of 100 nM, and the maximal cell response variability was found at 10 nM. IL-8 was less sensitive to the corticosteroid compared to IL-6 and TNF-α. Dexamethasone at any concentration failed to reach >50% inhibition of LPS-induced production of IL-8, IL-6 and TNF-α in alveolar macrophages of 40.0%; 11.1% and 8.9% of COPD patients, respectively. The fluorescence intensity of FITC-labelled dexamethasone in blood lymphocytes and monocytes was lower in smokers with COPD compared to healthy smokers and healthy non-smokers. The binding of dexamethasone with its receptors in the blood cells was higher in healthy non-smokers compared to healthy smokers. Conclusion. In vitro response of alveolar macrophages to glucocorticoids in COPD patients is characterized by significant inter-individual variability. The weak corticosteroid-related inhibition of IL-8 production can contribute to neutrophilic inflammation in COPD. The capacity of glucocorticoid receptors to bind with their ligands in blood lymphocytes and monocytes is decreased in COPD patients.

scholarly journals Methylation of SERPINA1 gene promoter may predict chronic obstructive pulmonary disease in patients affected by acute coronary syndrome

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
John Charles Rotondo ◽  
Giorgio Aquila ◽  
Lucia Oton-Gonzalez ◽  
Rita Selvatici ◽  
Paola Rizzo ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Acute Coronary Syndrome ◽  
Pulmonary Disease ◽  
Blood Cells ◽  
Gene Promoter ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Coronary Syndrome ◽  
Copd Patients ◽  
Potential Biomarker

Abstract Background Diagnostic biomarkers for detecting chronic obstructive pulmonary disease (COPD) in acute coronary syndrome (ACS) patients are not available. SERPINA1, coding for the most potent circulating anti-inflammatory protein in the lung, has been found to be differentially methylated in blood cells from COPD patients. This study aimed to investigate the methylation profile of SERPINA1 in blood cells from ACS patients, with (COPD+) or without COPD (COPD−). Methods Blood samples were from 115 ACS patients, including 30 COPD+ and 85 COPD− according to lung function phenotype, obtained with spirometry. DNA treated with sodium bisulfite was PCR-amplified at SERPINA1 promoter region. Methylation analysis was carried out by sequencing the PCR products. Lymphocytes count in ACS patients was recorded at hospital admission and discharge. Results SERPINA1 was hypermethylated in 24/30 (80%) COPD+ and 48/85 (56.5%) COPD− (p < 0.05). Interestingly, at hospital discharge, lymphocytes count was higher in COPD− patients carrying SERPINA1 hypermethylated (1.98 × 103 ± 0.6 cell/µl) than in COPD− carrying SERPINA1 hypomethylated (1.7 × 103 ± 0.48 cell/µl) (p < 0.05). Conclusions SERPINA1 is hypermethylated in blood cells from COPD+ patients. COPD− carrying SERPINA1 hypermethylated and high lymphocytes count may be at risk of COPD development. Therefore, SERPINA1 hypermethylation may represent a potential biomarker for predicting COPD development in ACS patients.

Oxidative stress and damage to erythrocytes in patients with chronic obstructive pulmonary disease — changes in ATPase and acetylcholinesterase activity

2015 ◽  
Vol 93 (6) ◽  
pp. 574-580 ◽  
Author(s):  
Bożena Bukowska ◽  
Paulina Sicińska ◽  
Aneta Pająk ◽  
Aneta Koceva-Chyla ◽  
Tadeusz Pietras ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chronic Obstructive Pulmonary Disease ◽  
Red Blood Cells ◽  
Pulmonary Disease ◽  
Blood Cells ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Membrane Enzymes ◽  
Copd Patients ◽  
The Impact

The study indicates, for the first time, the changes in both ATPase and AChE activities in the membrane of red blood cells of patients diagnosed with COPD. Chronic obstructive pulmonary disease (COPD) is one of the most common and severe lung disorders. We examined the impact of COPD on redox balance and properties of the membrane of red blood cells. The study involved 30 patients with COPD and 18 healthy subjects. An increase in lipid peroxidation products and a decrease in the content of -SH groups in the membrane of red blood cells in patients with COPD were observed. Moreover, an increase in the activity of glutathione peroxidase and a decrease in superoxide dismutase, but not in catalase activity, were found as well. Significant changes in activities of erythrocyte membrane enzymes in COPD patients were also evident demonstrated by a considerably lowered ATPase activity and elevated AChE activity. Changes in the structure and function of red blood cells observed in COPD patients, together with changes in the activity of the key membrane enzymes (ATPases and AChE), can result from the imbalance of redox status of these cells due to extensive oxidative stress induced by COPD disease.

scholarly journals AIM2 Nuclear Exit and Inflammasome Activation in Chronic Obstructive Pulmonary Disease and Response to Cigarette Smoke 

2020 ◽  
Author(s):  
Hai B Tran ◽  
Rhys Hamon ◽  
Hubertus Jersmann ◽  
Miranda P Ween ◽  
Patrick Asare ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Cigarette Smoke ◽  
Nuclear Localization ◽  
Alveolar Macrophages ◽  
Fold Increase ◽  
Cigarette Smoke Extract ◽  
Chronic Obstructive ◽  
Inflammasome Activation ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients

Abstract IntroductionThe role inflammasomes play in chronic obstructive pulmonary disease (COPD) is unclear. We hypothesised that the AIM2 inflammasome is activated in the airways of COPD patients, and in response to cigarette smoke.Methods Lung tissue, bronchoscopy-derived alveolar macrophages and bronchial epithelial cells from COPD patients and healthy donors; lungs from cigarette smoke-exposed mice; and cigarette smoke extract-stimulated alveolar macrophages from healthy controls and HBEC30KT cell line were investigated. AIM2 inflammasome activation was assessed by multi-fluorescence quantitative confocal microscopy of speck foci positive for AIM2, inflammasome component ASC and cleaved IL-1β. Subcellular AIM2 localization was assessed by confocal microscopy, and immunoblot of fractionated cell lysates. Nuclear localization was supported by in-silico analysis of nuclear localization predicted scores of peptide sequences. Nuclear and cytoplasmic AIM2 was demonstrated by immunoblot in both cellular fractions from HBEC30KT cells.Results Increased cytoplasmic AIM2 speck foci, colocalized with cleaved IL-1β, were demonstrated in COPD lungs (n=9) vs. control (n=5), showing significant positive correlations with GOLD stages. AIM2 nuclear-to-cytoplasmic redistribution was demonstrated in bronchiolar epithelium in cigarette-exposed mice and in HBEC30KT cells post 24 hrs stimulation with 5% cigarette smoke extract. Alveolar macrophages from 8 healthy non-smokers responded to cigarette smoke extract with an >8-fold increase (p<0.05) of cytoplasmic AIM2 and >6-fold increase (p<0.01) of colocalized cleaved IL-1β speck foci, which were also localized with ASC.Conclusion The AIM2 inflammasome is activated in the airway of COPD patients, and in response to cigarette smoke exposure, associated with a nuclear to cytoplasmic shift in the distribution of AIM2.

scholarly journals Combination of Systemic Inflammatory Biomarkers in Assessment of Chronic Obstructive Pulmonary Disease: Diagnostic Performance and Identification of Networks and Clusters

Diagnostics ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1029
Author(s):  
Iva Hlapčić ◽  
Daniela Belamarić ◽  
Martina Bosnar ◽  
Domagoj Kifer ◽  
Andrea Vukić Dugac ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Chronic Obstructive ◽  
C Reactive Protein ◽  
Obstructive Pulmonary Disease ◽  
Extracellular Adenosine ◽  
Reactive Protein ◽  
Copd Patients ◽  
Tnf Α ◽  
Necrosis Factor

Interleukin (IL)-1α, IL-1β, IL-6, IL-8 and tumor necrosis factor (TNF)α contribute to inflammation in chronic obstructive pulmonary disease (COPD). We wanted to investigate their interrelations and association with disease severity, as well as to combine them with other inflammation-associated biomarkers and evaluate their predictive value and potential in identifying various patterns of systemic inflammation. One hundred and nine patients with stable COPD and 95 age- and sex-matched controls were enrolled in the study. Cytokines’ concentrations were determined in plasma samples by antibody-based multiplex immunosorbent assay kits. Investigated cytokines were increased in COPD patients but were not associated with disease or symptoms severity. IL-1β, IL-6 and TNFα showed the best discriminative values regarding ongoing inflammation in COPD. Inflammatory patterns were observed in COPD patients when cytokines, C-reactive protein (CRP), fibrinogen (Fbg), extracellular adenosine triphosphate (eATP), extracellular heat shock protein 70 (eHsp70) and clinical data were included in cluster analysis. IL-1β, eATP and eHsp70 combined correctly classified 91% of cases. Therefore, due to the heterogeneity of COPD, its assessment could be improved by combination of biomarkers. Models including IL-1β, eATP and eHsp70 might identify COPD patients, while IL-1β, IL-6 and TNFα combined with CRP, Fbg, eATP and eHsp70 might be informative regarding various COPD clinical subgroups.

scholarly journals Relationship between Vitamin D Level and Serum TNF-α Concentration on the Severity of Chronic Obstructive Pulmonary Disease

2019 ◽  
Vol 7 (14) ◽  
pp. 2298-2304
Author(s):  
Muhammad Ilyas ◽  
Agussalim Agussalim ◽  
Megawati Megawati ◽  
Nasrum Massi ◽  
Irawaty Djaharuddin ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Vitamin D ◽  
Airway Obstruction ◽  
Pulmonary Disease ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients ◽  
Vitamin D Levels ◽  
Tnf Α ◽  
The Relationship

Background: Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory disease and disturbed bacterial clearance. Vitamin D deficiency is sometimes observed in COPD patients and as significant roles in increasing inflammation of airway obstruction and systemic obstruction, increasing proinflammatory cytokine including TNF-α, reduction of bacterial clearance and increase exacerbation risk due to infection. Also, vitamin D plays significant roles in the metabolism of calcium and mineralization of bones and regulation system of immune. TNF-α also has essential roles in pathogenesis and inflammation of COPD.  Several studies that investigate the relationship between vitamin D level and serum TNF-α concentration in COPD patients are relatively uncommon, including in Indonesia. For that reason, this study aimed to assess the relationship between vitamin D level and TNF-α concentration in patients on the severity of the chronic obstructive pulmonary disease. Methods This study was a hospital-based descriptive cross-sectional study. Total samples were 50 COPD patients with the average age of older than 60 years during their enrollments at the Department of Pulmonology and Respiratory Medicine of the Dr.Wahidin Sudirohusodo General hospital  Makassar in September 2018-January 2019. All procedures of the present study were reviewed and approved by the Research Ethics Committee of Medicine Faculty of Hasanuddin University. The severity of COPD was assessed according to the combination of COPD assessment stages that referred to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guideline 2015 that consisted of the combination of scoring COPD Assessment Test (CAT), the modified Medical Research Council (mMRC) questionnaire and results of the spirometric measurement. Assessment of airway obstruction levels referred to the GOLD spirometric criteria. Determination of thoracic photographs was conducted to verify the COPD diagnosis of the severity of COPD. Determination of serum TNF-α concentration and vitamin D3 [1,25(OH)2D3] level used the ELISA method. Results  The majority of COPD patients were observed in the category of older than 60 years old accounted for 34 COPD patients (68%), and the majority of COPD patients were males accounted for 47 males with COPD (94%). The majority of COPD patients were observed in the group of D (38%). All the study subjects observed in this study were smokers, and 82% of them were in the category of heavy smokers. 21 study subjects had higher concentration of serum TNF-α  (tertile 3 = 0.21-1.83 pg/dl), 20 study subjects  and lower level of vitamin D (tertile 1 = 182.1-364.5 pg/dl). The majority of the study subjects (38%) were in the category of severe COPD (category D of the severity of COPD at the tertile 3) according to the GOLD Combine Assessment. In view of the relationship between vitamin D level and serum TNF-α concentration on the airway obstruction, there were significant positive correlations between the increase of vitamin D levels and the increase of serum TNF-α concentrations on airway obstruction. In view of the relationship between vitamin D level and serum TNF-α concentration on the severity of COPD, there were significant positive correlations between the increase of vitamin D levels (tertiles 1, 2 and 3) and the increase of serum TNF-α concentrations on the severity of COPD at p-value<0.05. Overall, there were non-linear relationships between vitamin D level and serum TNF-α concentration on the severity of COPD. Conclusions: Serum TNF-α concentration was positively associated with airway obstruction level and severity of COPD. Low level of vitamin D was negatively associated with airway obstruction level and severity of COPD. Vitamin D3 level (1,25(OH)2D) was negatively associated with serum TNF-α concentration and airway obstruction level and severity of COPD.

scholarly journals Apoptosis signal-regulating kinase 1 inhibition attenuates human airway smooth muscle growth and migration in chronic obstructive pulmonary disease

2018 ◽  
Vol 132 (14) ◽  
pp. 1615-1627 ◽  
Author(s):  
Mathew S. Eapen ◽  
Anudeep Kota ◽  
Howard Vindin ◽  
Kielan D. McAlinden ◽  
Dia Xenaki ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Smooth Muscle ◽  
Pulmonary Disease ◽  
Airway Smooth Muscle ◽  
Airway Remodeling ◽  
Mitogen Activated Protein Kinase ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients

Increased airway smooth muscle (ASM) mass is observed in chronic obstructive pulmonary disease (COPD), which is correlated with disease severity and negatively affects lung function in these patients. Thus, there is clear unmet clinical need for finding new therapies which can target airway remodeling and disease progression in COPD. Apoptosis signal-regulating kinase 1 (ASK1) is a ubiquitously expressed mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) activated by various stress stimuli, including reactive oxygen species (ROS), tumor necrosis factor (TNF)-α, and lipopolysaccharide (LPS) and is known to regulate cell proliferation. ASM cells from COPD patients are hyperproliferative to mitogens in vitro. However, the role of ASK1 in ASM growth is not established. Here, we aim to determine the effects of ASK1 inhibition on ASM growth and pro-mitogenic signaling using ASM cells from COPD patients. We found greater expression of ASK1 in ASM bundles of COPD lung when compared with non-COPD. Pre-treatment of ASM cells with highly selective ASK1 inhibitor, TC ASK 10 resulted in a dose-dependent reduction in mitogen (FBS, PDGF, and EGF; 72 h)-induced ASM growth as measured by CyQUANT assay. Further, molecular targetting of ASK1 using siRNA in ASM cells prevented mitogen-induced cell growth. In addition, to anti-mitogenic potential, ASK1 inhibitor also prevented TGFβ1-induced migration of ASM cells in vitro. Immunoblotting revealed that anti-mitogenic effects are mediated by C-Jun N-terminal kinase (JNK) and p38MAP kinase-signaling pathways as evident by reduced phosphorylation of downstream effectors JNK1/2 and p38MAP kinases, respectively, with no effect on extracellular signal-regulated kinase (ERK) 1/2 (ERK1/2). Collectively, these findings establish the anti-mitogenic effect of ASK1 inhibition and identify a novel pathway that can be targetted to reduce or prevent excessive ASM mass in COPD.

scholarly journals Influence of disease severity, smoking status and therapy regimes on leukocyte subsets and their ratios in stable chronic obstructive pulmonary disease

2020 ◽  
Author(s):  
Iva Hlapčić ◽  
Andrea Vukić Dugac ◽  
Sanja Popović-Grle ◽  
Ivona Markelić ◽  
Ivana Rako ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Disease Severity ◽  
Blood Cells ◽  
Smoking Status ◽  
White Blood Cells ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Lymphocyte Ratio ◽  
Copd Patients

IntroductionBlood cells are involved in systemic inflammation in chronic obstructive pulmonary disease (COPD). We aimed to assess differences in leukocyte subsets and their ratios between COPD patients and healthy individuals as well as their association with disease severity, smoking status and therapy in COPD.Material and methodsOne hundred and nine patients in the stable phase of COPD and 95 controls participated in the study. After blood sampling, white blood cells (WBC), neutrophils (NEUTRO), monocytes (MO), lymphocytes (LY) and basophils (BA) were determined on a Sysmex XN-1000 analyser, and ratios were calculated afterwards.ResultsWhite blood cells, NEUTRO, MO and BA were higher in COPD patients than in controls. Also, COPD patients had increased neutrophil to lymphocyte ratio (NLR), derived NLR (dNLR), monocyte to lymphocyte ratio (MLR), basophil to lymphocyte ratio (BLR), basophil to monocyte ratio (BMR) and monocyte/granulocyte to lymphocyte ratio (M/GLR). Smoking has an impact on leukocyte counts, with BA, BLR and BMR being higher in COPD smokers vs. ex-smokers. Patients with very severe COPD were distinguished from moderate COPD by NLR, dNLR and M/GLR. In addition, those parameters were associated with lung function and dyspnoea, and NLR and dNLR also with multicomponent COPD indices BODCAT and DOSE. Great potential of dNLR, NLR and M/GLR in identifying COPD patients was observed regarding their odds ratios (OR) of 5.07, 2.86, 2.60, respectively (p < 0.001). Common COPD therapy did not affect any of the parameters investigated.ConclusionsLeukocyte subsets and their ratios could be implemented in COPD assessment, especially in evaluating disease severity and prediction.

scholarly journals Quadriceps miR-542-3p and -5p are elevated in COPD and reduce function by inhibiting ribosomal and protein synthesis

2019 ◽  
Vol 126 (6) ◽  
pp. 1514-1524 ◽  
Author(s):  
Roser Farre-Garros ◽  
Jen Y. Lee ◽  
S. Amanda Natanek ◽  
Martin Connolly ◽  
Avan A. Sayer ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Protein Synthesis ◽  
Mitochondrial Dysfunction ◽  
Pulmonary Disease ◽  
Physical Performance ◽  
Quadriceps Muscle ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients

Reduced physical performance reduces quality of life in patients with chronic obstructive pulmonary disease (COPD). Impaired physical performance is, in part, a consequence of reduced muscle mass and function, which is accompanied by mitochondrial dysfunction. We recently showed that miR-542-3p and miR-542-5p were elevated in a small cohort of COPD patients and more markedly in critical care patients. In mice, these microRNAs (miRNAs) promoted mitochondrial dysfunction suggesting that they would affect physical performance in patients with COPD, but we did not explore the association of these miRNAs with disease severity or physical performance further. We therefore quantified miR-542-3p/5p and mitochondrial rRNA expression in RNA extracted from quadriceps muscle of patients with COPD and determined their association with physical performance. As miR-542-3p inhibits ribosomal protein synthesis its ability to inhibit protein synthesis was also determined in vitro. Both miR-542-3p expression and -5p expression were elevated in patients with COPD (5-fold P < 0.001) and the degree of elevation associated with impaired lung function (transfer capacity of the lung for CO in % and forced expiratory volume in 1 s in %) and physical performance (6-min walk distance in %). In COPD patients, the ratio of 12S rRNA to 16S rRNA was suppressed suggesting mitochondrial ribosomal stress and mitochondrial dysfunction and miR-542-3p/5p expression was inversely associated with mitochondrial gene expression and positively associated with p53 activity. miR-542-3p suppressed RPS23 expression and maximal protein synthesis in vitro. Our data show that miR-542-3p and -5p expression is elevated in COPD patients and may suppress physical performance at least in part by inhibiting mitochondrial and cytoplasmic ribosome synthesis and suppressing protein synthesis. NEW & NOTEWORTHY miR-542-3p and -5p are elevated in the quadriceps muscle of patients with chronic obstructive pulmonary disease (COPD) in proportion to the severity of their lung disease. These microRNAs inhibit mitochondrial and cytoplasmic protein synthesis suggesting that they contribute to impaired exercise performance in COPD.

Sign in / Sign up

Export Citation Format

Share Document