Stress In Chronic Obstructive Pulmonary Disease Research Articles

Targeting accelerated pulmonary ageing to treat chronic obstructive pulmonary disease-induced neuropathological comorbidities.

Chronic obstructive pulmonary disease (COPD) is a major incurable health burden, ranking as the third leading cause of death worldwide, mainly driven by cigarette smoking. COPD is characterised by persistent airway inflammation, lung function decline and premature ageing with the presence of pulmonary senescent cells. This review proposes that cellular senescence, a state of stable cell cycle arrest linked to ageing, induced by inflammation and oxidative stress in COPD, extends beyond the lungs and affects the systemic circulation. This pulmonary senescent profile will reach other organs via extracellular vesicles contributing to brain inflammation and damage, and increasing the risk of neurological comorbidities, such as stroke, cerebral small vessel disease and Alzheimer's disease. The review explores the role of cellular senescence in COPD-associated brain conditions and investigates the relationship between cellular senescence and circadian rhythm in COPD. Additionally, it discusses potential therapies, including senomorphic and senolytic treatments, as novel strategies to halt or improve the progression of COPD.

Soluble epoxide hydrolase deficiency attenuates airway inflammation in COPD via IRE1α/JNK/AP-1 signaling pathway.

Soluble Epoxide Hydrolase (sEH) metabolizes anti-inflammatory epoxyeicosatrienoic acids and critically affects airway inflammation in chronic obstructive pulmonary disease (COPD). Considering the excessive endoplasmic reticulum stress is associated with the earlier onset of COPD. The role of sEH and endoplasmic reticulum stress in the pathogenesis of COPD remains unknown. 16 weeks of cigarette-exposed mice were used to detect the relationship between sEH and endoplasmic reticulum stress in COPD. Human epithelial cells were used in vitro to determine the regulation mechanism of sEH in endoplasmic reticulum stress induced by cigarette smoke. sEH deficiency helps reduce emphysema formation after smoke exposure by alleviating endoplasmic reticulum stress response. sEH deficiency effectively reverses the upregulation of phosphorylation IRE1α and JNK and the nuclear expression of AP-1, alleviating the secretion of inflammatory factors induced by cigarette smoke extract. Furthermore, the treatment with endoplasmic reticulum stress and IRE1α inhibitor downregulated cigarette smoke extract-induced sEH expression and the secretion of inflammatory factors. sEH probably alleviates airway inflammatory response and endoplasmic reticulum stress via the IRE1α/JNK/AP-1 pathway, which might attenuate lung injury caused by long-term smoking and provide a new pharmacological target for preventing and treating COPD.

Sequential inspiratory muscle exercise-noninvasive positive pressure ventilation alleviates oxidative stress in COPD by mediating SOCS5/JAK2/STAT3 pathway

BackgroundPulmonary rehabilitation training is of great significance for the prognosis of chronic obstructive pulmonary disease (COPD) patients. The purpose of this study was to investigate the therapeutic effect and pathway of a new sequential noninvasive positive pressure ventilation (NIPPV) + inspiratory muscle training (IMT) therapy.MethodsA total of 100 COPD patients were enrolled and randomly divided into oxygen therapy (OT), NIPPV, IMT and sequential (NIPPV + IMT) group. Lung function, exercise endurance, quality of life, and dyspnea symptoms were examined and recorded. Then, reactive oxygen species (ROS), malonaldehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH) levels were detected by enzyme-linked immunoassay, and suppressor of cytokine signaling 5 (SOCS5)/janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway expression changes were detected by quantitative real time-polymerase chain reaction (qRT-PCR) and western blot. A mouse model of COPD was then established to further verify the effects of SOCS5/JAK2/STAT3 pathways on lung function and oxidative stress.ResultsAfter 8 weeks of treatment, NIPPV, IMT or sequential (NIPPV + IMT) significantly improved exercise endurance, quality of life and dyspnea, reduced oxidative stress, promoted SOCS5 expression and inhibited the activation of JAK2/STAT3 pathway, and no significant effect was observed on lung function of COPD patients. Notably, sequential (NIPPV + IMT) showed better therapeutic outcomes than either IMT or NIPPV alone. Moreover, results at the animal level showed that overexpression of SOCS5 significantly reduced pulmonary inflammatory infiltration, pathological changes and oxidative stress levels in COPD mice, enhanced lung function, and inhibited the activation of JAK2/STAT3 pathway.ConclusionOur results elucidated that sequential (NIPPV + IMT) significantly relieved COPD development by regulating SOCS5/JAK2/STAT3 signaling-mediated oxidative stress.

A Proteomics Investigation of Cigarette Smoke Exposed Wistar Rats Revealed Improved Anti-Inflammatory Effects of the Cysteamine Nanoemulsions Delivered via Inhalation.

Cigarette smoking is the major cause of chronic inflammatory diseases such as chronic obstructive pulmonary disease (COPD). It is paramount to develop pharmacological interventions and delivery strategies against the cigarette smoke (CS) associated oxidative stress in COPD. This study in Wistar rats examined cysteamine in nanoemulsions to counteract the CS distressed microenvironment. In vivo, 28 days of CS and 15 days of cysteamine nanoemulsions treatment starting on 29th day consisting of oral and inhalation routes were established in Wistar rats. In addition, we conducted inflammatory and epithelial-to-mesenchymal transition (EMT) studies in vitro in human bronchial epithelial cell lines (BEAS2B) using 5% CS extract. Inflammatory and anti-inflammatory markers, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-1β, IL-8, IL-10, and IL-13, have been quantified in bronchoalveolar lavage fluid (BALF) to evaluate the effects of the cysteamine nanoemulsions in normalizing the diseased condition. Histopathological analysis of the alveoli and the trachea showed the distorted, lung parenchyma and ciliated epithelial barrier, respectively. To obtain mechanistic insights into the CS COPD rat model, "shotgun" proteomics of the lung tissues have been carried out using high-resolution mass spectrometry wherein genes such as ABI1, PPP3CA, PSMA2, FBLN5, ACTG1, CSNK2A1, and ECM1 exhibited significant differences across all the groups. Pathway analysis showed autophagy, signaling by receptor tyrosine kinase, cytokine signaling in immune system, extracellular matrix organization, and hemostasis, as the major contributing pathways across all the studied groups. This work offers new preclinical findings on how cysteamine taken orally or inhaled can combat CS-induced oxidative stress.

Design and synthesis of a novel class of PDE4 inhibitors with antioxidant properties as bifunctional agents for the potential treatment of COPD

It is well known that chronic obstructive pulmonary disease (COPD) patients are always trapped in the vicious circle of inflammation and oxidative stress, therefore anti-inflammatory and antioxidant bifunctional agents may interrupt this vicious cycle in COPD. Phosphodiesterase 4 (PDE4) inhibitors, as anti-inflammatory drugs, have been used for COPD treatment in clinical, and the PDE4 inhibitors with antioxidant properties may be a good strategy to design bifunctional agents for COPD. Sappanone A was the first PDE4 inhibitor with antioxidant properties we identified from natural products in our previous study, which was used by us as a hit compound to design new bifunctional agents for COPD in this study. 27 derivatives of sappanone A including homoisoflavonoids, aurones and chalcones were designed and synthesized by innovatively fusing the antioxidant pharmacophore of catechol from polyphenols and the pharmacophore of catechol ether abstracted from the PDE4 inhibitors of the catechol ether class such as rolipram, roflumilast and apremilast respectively. All the compounds were assayed for the PDE4 inhibitory and radical scavenging against 2, 2-diphenyl-1-picrylhydrazyl (DPPH) activities in vitro. Herein we obtained a series of bifunctional compounds with better PDE4 inhibitory activity than sappanone A, and their free radical scavenging activities were superior to edaravone in vitro. In addition, they can reduce tumour necrosis factor-alpha (TNF-α) production induced by lipopolysaccharide (LPS) in RAW264.7 macrophages and malondialdehyde (MDA) production induced by Fe2+ in mouse lung homogenate. Meanwhile, it showed outstanding abilities in reducing Fe3+ and complexing Fe2+. 6o, as the candidate anti-inflammatory and antioxidant bifunctional compound, exhibited good drug-likeness, ADME (Absorption, Distribution, Metabolism, Excretion) properties and human liver microsomal stability. In vivo, 6o (50 mg/kg and 100 mg/kg, i. p.) distinctly prevented LPS-induced serum levels of TNF-α in mice. In conclusion, the preliminary investigation provided a novel class of PDE4 inhibitors with antioxidant properties as bifunctional agents for the potential treatment of COPD, which can interrupt the vicious cycle of chronic inflammation and oxidative stress in COPD.

Serum Free Radical Scavenging Capacity Profiles of Patients with Chronic Obstructive Pulmonary Disease.

Oxidative stress is an important mechanism for the development and progression of chronic obstructive pulmonary disease (COPD). It may also contribute to systemic manifestation in patients with COPD. Reactive oxygen species (ROS) including free radicals play a crucial role in oxidative stress in COPD. The aims of this study were to determine serum scavenging capacity profile against multiple free radicals and to evaluate its correlation with pathophysiology, exacerbations, and prognosis in patients with COPD. Serum scavenging capacity profile against multiple free radicals comprising hydroxyl radical (•OH), superoxide radical (O2 -•), alkoxy radical (RO•), methyl radical (•CH3), alkylperoxyl radical (ROO•), and singlet oxygen (1O2) was assessed using the multiple free-radical scavenging method in 37 patients with COPD (mean age, 71 years; mean forced expiratory volume in 1 s, 55.2% predicted). The severity of emphysema was evaluated by Goddard classification on chest computed tomography. Exacerbations were recorded prospectively for 1 year and the overall mortality was assessed 5 years after the initial assessment. •OH scavenging capacity was significantly decreased (p < 0.05) and O2 -• and •CH3 scavenging capacity tended to decrease in patients with COPD compared to that in healthy controls. On the other hand, ROO• scavenging capacity tended to increase. In addition, RO• scavenging capacity was associated with severity of emphysema (p < 0.05) and exacerbation frequency (p < 0.02). There was a difference in the profile of the scavenging capacity between survived and deceased patients with COPD for 5 years after initial assessment. Characteristic profile of free radical scavenging capacity can provide insight into the pathophysiology and prognosis of patients with COPD.

Luteolin suppresses inflammation and oxidative stress in chronic obstructive pulmonary disease through inhibition of the NOX4‐mediated NF‐κB signaling pathway

Chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation that predominantly affects the lung and peripheral airways. Previous investigation has underlined the efficacy of luteolin in the treatment of inflammation-related symptoms. Accordingly, our study concentrates on unveiling the effect of luteolin on COPD. Mice or A549 cells were treated with cigarette smoke (CS) to establish COPD models in vivo and in vitro. Then, the serum and bronchoalveolar lavage fluidof mice were harvested. The lung tissues of mice were subjected to hematoxylin-eosin staining to observe the degree of damage. The inflammation and oxidative stress factors level were calculated via enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction. The expressions of nuclear factor-kappa B (NF-κB) pathway-related factors were detected by Western blot. In in vivo experiments, CS treatment reduced the weight of mice and promoted lung tissue damage, while luteolin attenuated the effect of CS on the mice. Moreover, luteolin inhibited the inflammation factors level, oxidative stress, and NADPH oxidase 4 (NOX4)-mediated NF-κB signaling pathway in CS-induced COPD mice. Similar results were obtained in in vitro experiments that luteolin alleviated CS-induced inflammation, oxidative stress, and NOX4-mediated NF-κB signaling pathway activation in CS-treated A549 cells. Besides, NOX4 overexpression offset the impacts of luteolin on the CS-induced A549 cells. Luteolin alleviates inflammation and oxidative stress in COPD via NOX4-mediated NF-κB signaling pathway, which provides a theoretical basis for the treatment of COPD with luteolin.

Metformin alleviates chronic obstructive pulmonary disease and cigarette smoke extract-induced glucocorticoid resistance by activating the nuclear factor E2-related factor 2/heme oxygenase-1 signaling pathway.

Chronic obstructive pulmonary disease (COPD) is an important healthcare problem worldwide. Often, glucocorticoid (GC) resistance develops during COPD treatment. As a classic hypoglycemic drug, metformin (MET) can be used as a treatment strategy for COPD due to its anti-inflammatory and antioxidant effects, but its specific mechanism of action is not known. We aimed to clarify the role of MET on COPD and cigarette smoke extract (CSE)-induced GC resistance. Through establishment of a COPD model in rats, we found that MET could improve lung function, reduce pathological injury, as well as reduce the level of inflammation and oxidative stress in COPD, and upregulate expression of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), multidrug resistance protein 1 (MRP1), and histone deacetylase 2 (HDAC2). By establishing a model of GC resistance in human bronchial epithelial cells stimulated by CSE, we found that MET reduced secretion of interleukin-8, and could upregulate expression of Nrf2, HO-1, MRP1, and HDAC2. MET could also increase the inhibition of MRP1 efflux by MK571 significantly, and increase expression of HDAC2 mRNA and protein. In conclusion, MET may upregulate MRP1 expression by activating the Nrf2/HO-1 signaling pathway, and then regulate expression of HDAC2 protein to reduce GC resistance.

Evidence Around the Impact of Pulmonary Rehabilitation and Exercise on Redox Status in COPD: A Systematic Review.

Introduction: Oxidative stress is increasingly recognized as a significant factor in the pathogenesis of chronic obstructive pulmonary disease (COPD). Pulmonary rehabilitation, a major component of which is prescribed exercise, is essential in COPD care. Regular exercise has been proposed to increase antioxidant defenses and overall enhance the ability of the body to counteract oxidative stress. However, the mechanisms through which it improves COPD outcomes remain unclear.Objectives: We aimed to appraise the current evidence around the impact of pulmonary rehabilitation on redox status, compared with other exercise interventions, to gain an understanding of optimal exercise interventions to modify this pathophysiological mechanism.Methods: We performed a systematic review through searching CENTRAL, MEDLINE, PubMed, Scopus, and Web of Science. Results were independently reviewed and relevant studies were selected by two independent assessors. Studies were assessed by two independent people using the modified RoB 2 tool and discrepancies were resolved through discussion.Results: We identified 1,710 records and 1,117 records after duplicate removal. Six studies were included in the final analysis. The evidence available was low quality and four studies had high risk of bias and two studies had unclear risk of bias. Studies were small (15–56 participants); only two included details of randomization and patient cohorts were of varying ages and poorly described. Differences in smoking status and previous exercise levels, which are known to impact redox status, were not well documented. Studies were not standardized and used different exercise doses and measured different outcomes. One study reported lower malondialdehyde levels, a marker of lipid peroxidation, after pulmonary rehabilitation, compared with control. However, one study saw no difference following whole-body vibration training and another study showed higher malondialdehyde levels following supervised modified arm swing exercise compared with control.Conclusion: Understanding the impact of exercise on oxidative stress in COPD could lead to tailored exercise programs and modification of pathological mechanisms. However, we identify a lack of high-quality evidence to determine this. Larger, standardized, and high quality randomized controlled trials (RCTs) are essential, which use carefully clinically characterized and controlled cohorts to determine the relative impact of different exercise interventions on redox status to guide COPD management. We propose an idealized RCT design, which could be used to try and meet this need.

Glutathione Peroxidase in Stable Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-analysis.

Chronic obstructive pulmonary disease (COPD) is a progressive disease that is characterized by a state of persistent inflammation and oxidative stress. The presence of oxidative stress in COPD is the result of an imbalance between pro-oxidant and antioxidant mechanisms. The aim of this review was to investigate a possible association between glutathione peroxidase (GPx), a key component of antioxidant defense mechanisms, and COPD. A systematic search for relevant studies was conducted in the electronic databases PubMed, Web of Science, Scopus, and Google Scholar, from inception to June 2021. Standardized mean differences (SMDs) were used to express the differences in GPx concentrations between COPD patients and non-COPD subjects. Twenty-four studies were identified. In 15 studies assessing whole blood/erythrocytes (GPx isoform 1), the pooled results showed that GPx concentrations were significantly lower in patients with COPD (SMD = −1.91, 95% CI −2.55 to −1.28, p < 0.001; moderate certainty of evidence). By contrast, in 10 studies assessing serum/plasma (GPx isoform 3), the pooled results showed that GPx concentrations were not significantly different between the two groups (very low certainty of evidence). The concentration of GPx-1, but not GPx-3, is significantly lower in COPD patients, suggesting an impairment of antioxidant defense mechanisms in this group.

Reliability and Usefulness of Different Biomarkers of Oxidative Stress in Chronic Obstructive Pulmonary Disease.

Introduction Chronic obstructive pulmonary disease (COPD) is a progressive disease characterized by airflow limitation that is not fully reversible after inhaled bronchodilator use associated with an abnormal inflammatory condition. The biggest risk factor for COPD is cigarette smoking. The exposure to noxious chemicals contained within tobacco smoke is known to cause airway epithelial injury through oxidative stress, which in turn has the ability to elicit an inflammatory response. In fact, the disruption of the delicate balance between oxidant and antioxidant defenses leads to an oxidative burden that has long been held responsible to play a pivotal role in the pathogenesis of COPD. There are currently several biomarkers of oxidative stress in COPD that have been evaluated in a variety of biological samples. The aim of this review is to identify the best studied molecules by summarizing the key literature findings, thus shedding some light on the subject. Methods We searched for relevant case-control studies examining oxidative stress biomarkers in stable COPD, taking into account the analytical method of detection as an influence factor. Results Many oxidative stress biomarkers have been evaluated in several biological matrices, mostly in the blood. Some of them consistently differ between the cases and controls even when allowing different analytical methods of detection. Conclusions The present review provides an overview of the oxidative stress biomarkers that have been evaluated in patients with COPD, bringing focus on those molecules whose reliability has been confirmed by the use of different analytical methods.

Alantolactone suppresses inflammation, apoptosis and oxidative stress in cigarette smoke-induced human bronchial epithelial cells through activation of Nrf2/HO-1 and inhibition of the NF-\u03baB pathways

BackgroundIt is well established that airway remodeling and inflammation are characteristics for chronic obstructive pulmonary disease (COPD). Moreover, cigarette smoke extract (CSE) promots inflammation, apoptosis and oxidative stress in COPD. And, there is evidence suggested that alantolactone (ALT), a sesquiterpene lactone isolated from Inula helenium, plays an adverse role in inflammation, apoptosis and oxidative stress. However, few studies have investigated the function and mechanism of ALT treatment on the COPD pathological process.MethodsThe levels of IL-1 β, TNF-α, IL-6 and IFN-γ were examined by ELISA. Cells’ apoptosis and caspase-3 activity were detected by Cell Death Detection PLUS enzyme-linked immunosorbent assay and caspase-Glo 3/7 Assay, respectively. The content of malondialdehyde (MDA) and superoxide dismutase (SOD) were determined by using MDA and SOD assay kits. Reactive oxygen species (ROS) generation was measured by DCFH-DA assay. Protein expression was assayed by Western blot.ResultsIn the present study, we aimed to observe the protective effects of ALT against inflammation, apoptosis and oxidative stress in human bronchial epithelial Beas-2B and NHBE cells. Our results showed that different doses of CSE exposure induced Beas-2B and NHBE cell inflammatory cytokines IL-1 β, TNF-α, IL-6 and IFN-γ expression, cell apoptosis, caspase-3 activity and mediated oxidative stress markers MDA, ROS and SOD levels, while ALT treatment counteracted the effects of CSE. Further studies suggested that ALT attenuated NF-κB pathway activation. ALT also activated the Nrf2/HO-1 signal pathway through promoting Nrf2 nuclear aggregation and downstream HO-1 protein expression. HO-1 inhibitor tin protoporphyrin IX (SnPP IX) reversed the effects of ALT on Beas-2B and NHBE cell inflammation, apoptosis and oxidative stress.ConclusionsThe above results collectively suggested that ALT suppressed CSE-induced inflammation, apoptosis and oxidative stress by modulating the NF-ĸB and Nrf2/ HO-1 axis.

The relationship between acrolein and oxidative stress in COPD: in systemic plasma and in local lung tissue.

PurposeCigarette smoke produces a high level of acrolein, which is thought to be pathogenically involved in the development of chronic obstructive pulmonary disease (COPD). The present study investigated the pathological role of acrolein in the development of COPD.Patients and methodsAcrolein concentration was measured in plasmas obtained from 47 patients with COPD and 18 current smokers without COPD, and in supernatants of homogenized lung tissues obtained from 10 never-smokers, 8 current smokers, and 8 patients with COPD by high-performance liquid chromatography. Oxidant status and antioxidant activity were measured using derivatives of reactive oxygen metabolite (d-ROM) and bio-antioxidant power (BAP), respectively, in the Free Radical Elective Evaluation FRAS4 system. In addition, immunohistochemistry was used to evaluate the over-presentation of acrolein in lung tissues of patients with COPD.ResultsPlasma concentrations of acrolein were significantly higher in the patients with COPD than the non-COPD smokers (P<0.001), which significantly correlated with the oxidant status in patients with COPD (R=0.69, P<0.05). Similar pathological alterations in acrolein concentrations were found in the lung tissue supernatants of patients with COPD, which significantly correlated with the oxidant status in patients with COPD. Furthermore, acrolein was strongly expressed in the lung tissues of patients with COPD.ConclusionThe increased acrolein concentrations were highly involved in the pathogenesis of COPD through interference in the balance of oxidative stress versus antioxidant potentiality.

Increased Serum Romo1 Was Correlated with Lung Function, Inflammation, and Oxidative Stress in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is associated with abnormal inflammation and high oxidative stress. Studies suggest that reactive oxygen species modulator 1 (Romo1) involve in diseases associated with oxidative stress and inflammation. However, the relationship between COPD and Romo1 is still not clear. In this study, we compared serum Romo1 in 49 COPD patients and 34 health controls, and their correlation with lung function, systematic inflammation, and oxidative stress. In addition, serum levels of Romo1, C-reactive protein (CRP), and oxidative stress (measured by reactive oxygen species, ROS) were analyzed using commercial kits. Serum Romo1 was significantly higher in COPD patients than that of control (132.24 ± 10.34 vs. 93.26 ± 7.75pg/ml, P < 0.05). Serum CRP and ROS were also significantly higher in COPD patients. Serum Romo1 was correlated inversely with FEV1% predicted in COPD patients (푟 = - 0.347, 푃 = 0.016), while it was correlated positively with CRP and ROS levels, respectively. These results suggest that serum Romo1 increase in COPD patients and that these levels are associated with lung function, inflammation, and oxidative stress in COPD.

New frontiers in the treatment of comorbid cardiovascular disease in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a disease characterised by persistent airflow limitation that is not fully reversible and is currently the fourth leading cause of death globally. It is now well established that cardiovascular-related comorbidities contribute to morbidity and mortality in COPD, with approximately 50% of deaths in COPD patients attributed to a cardiovascular event (e.g. myocardial infarction). Cardiovascular disease (CVD) and COPD share various risk factors including hypertension, sedentarism, smoking and poor diet but the underlying mechanisms have not been fully established. However, there is emerging and compelling experimental and clinical evidence to show that increased oxidative stress causes pulmonary inflammation and that the spill over of pro-inflammatory mediators from the lungs into the systemic circulation drives a persistent systemic inflammatory response that alters blood vessel structure, through vascular remodelling and arterial stiffness resulting in atherosclerosis. In addition, regulation of endothelial-derived vasoactive substances (e.g. nitric oxide (NO)), which control blood vessel tone are altered by oxidative damage of vascular endothelial cells, thus promoting vascular dysfunction, a key driver of CVD. In this review, the detrimental role of oxidative stress in COPD and comorbid CVD are discussed and we propose that targeting oxidant-dependent mechanisms represents a novel strategy in the treatment of COPD-associated CVD.

The relationship between hematological parameters and the severity level of chronic obstructive lung disease.

INTRODUCTION Chronic obstructive pulmonary disease (COPD) is the most important lung disease leading to disability and even death. Recent studies have shown that the platelet indices are associated with several cardiovascular diseases; however, there is little data on COPD. OBJECTIVES We aimed to explore the relationship between platelet indices, together with the platelet-to-lymphocyte ratio (PLR), white blood cell count to mean platelet volume ratio (WMR), and red cell distribution width (RDW) and the severity of COPD. PATIENTS AND METHODS This retrospective study was based on data collected from a total of 153 COPD patients admitted to our outpatient clinic between March 2014 and March 2015. All of the participants underwent pulmonary function tests; FEV1, FVC, and FEV1/FVC were measured. The study population was divided into four according to the severity of COPD as group A (mild), group B (mild to moderate), group C (moderate to severe), and group D (severe). RESULTS A significant increase was found in platelet distribution width (PDW), MPV, plateletcrit, PLR, and RDW while WMR decreased as the COPD severity increases. In the multiple logistic regression analysis, we found that PDW and RDW were independently associated with the presence of severe COPD. ROC curve analysis showed that a PDW>14.85 was associated with severe COPD with 85% sensitivity and 86% specificity while RDW>14.45 was associated with severe COPD with 90% sensitivity and 87% specificity. CONCLUSIONS The PDW and the RDW are independently associated with disease severity, which may indicate hypoxemia, underlying inflammation, and oxidative stress in COPD.

Metabolomics analysis identifies sex-associated metabotypes of oxidative stress and the autotaxin-lysoPA axis inCOPD.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease and a leading cause of mortality and morbidity worldwide. The aim of this study was to investigate the sex dependency of circulating metabolic profiles in COPD.Serum from healthy never-smokers (healthy), smokers with normal lung function (smokers), and smokers with COPD (COPD; Global Initiative for Chronic Obstructive Lung Disease stages I–II/A–B) from the Karolinska COSMIC cohort (n=116) was analysed using our nontargeted liquid chromatography–high resolution mass spectrometry metabolomics platform.Pathway analyses revealed that several altered metabolites are involved in oxidative stress. Supervised multivariate modelling showed significant classification of smokers from COPD (p=2.8×10−7). Sex stratification indicated that the separation was driven by females (p=2.4×10−7) relative to males (p=4.0×10−4). Significantly altered metabolites were confirmed quantitatively using targeted metabolomics. Multivariate modelling of targeted metabolomics data confirmed enhanced metabolic dysregulation in females with COPD (p=3.0×10−3) relative to males (p=0.10). The autotaxin products lysoPA (16:0) and lysoPA (18:2) correlated with lung function (forced expiratory volume in 1 s) in males with COPD (r=0.86; p<0.0001), but not females (r=0.44; p=0.15), potentially related to observed dysregulation of the miR-29 family in the lung.These findings highlight the role of oxidative stress in COPD, and suggest that sex-enhanced dysregulation in oxidative stress, and potentially the autotaxin–lysoPA axis, are associated with disease mechanisms and/or prevalence.

Oxidative Stress in COPD: Sources, Markers, and Potential Mechanisms.

Markers of oxidative stress are increased in chronic obstructive pulmonary disease (COPD) and reactive oxygen species (ROS) are able to alter biological molecules, signaling pathways and antioxidant molecule function, many of which have been implicated in the pathogenesis of COPD. However, the involvement of ROS in the development and progression of COPD is not proven. Here, we discuss the sources of ROS, and the defences that have evolved to protect against their harmful effects. We address the role that ROS may have in the development and progression of COPD, as well as current therapeutic attempts at limiting the damage they cause. Evidence has indicated that the function of several key cells appears altered in COPD patients, and expression levels of important oxidant and antioxidant molecules may be abnormal. Therapeutic trials attempting to restore equilibrium to these molecules have not impacted upon all facets of disease and whilst the theory behind ROS influence in COPD appears sound, current models testing relevant pathways to tissue damage are limited. The heterogeneity seen in COPD patients presents a challenge to our understanding, and further research is essential to identify potential targets and stratified COPD patient populations where ROS therapies may be maximally efficacious.

Effect of PM2.5 on the level of nuclear factor erythroid-2 related factor 2 in chronic obstructive pulmonary disease mice and its relationship with oxidative stress

To explore the effects of fine particulate matter on the level of nuclear factor erythroid-2 related factor 2 (Nrf2) in pulmonary tissues of chronic obstructive pulmonary disease (COPD) mouse models and its relationship with oxidative stress. Totally 40 BALB/c mice were randomly divided into normal control group, normal PM2.5 group, COPD control group and COPD PM2.5 group.COPD mice were established using exposure of cigarette smoking.PM2.5 (20 mg/kg) was intratracheally instilled in PM2.5 group mice.Mice pulmonary function was measured by mice noninvasive body plethysmograph and lung histopathology was observed in normal control group and normal PM2.5 group mice.The mRNA and protein expression of Nrf2 was measured with real-time polymerase chain reaction (PCR) and Western blot methods.Total antioxidative capacity (TAC) was measured by O-phenanthroline colorimetry.Glutathione peroxidase (GSH-PX) was measured by improved Hafeman colorimetry and malondialdehyde (MDA) by thiobarbiturieacid colorimetry. Nrf2 mRNA and protein in normal control group, normal PM2.5 group, COPD control group and COPD PM2.5 group were 1.00, 4.46±0.42, 4.93±0.63, 6.41±0.35 and 0.92±0.08, 1.23±0.07, 1.20±0.09, 1.43±0.10.Nrf2 mRNA and protein in COPD control group were increased than those in normal control group while those in normal PM2.5 group and COPD PM2.5 group were respectively higher than each control group.Comparing to normal PM2.5 group, the Nrf2 mRNA and protein in COPD PM2.5 group were increased (all P<0.01). TAC and GSH-PX in each group were (5.1±0.4), (2.9±0.4), (3.3±0.3), (1.8±0.3) and (13.4±0.5), (9.9±0.7), (9.8±0.7), (7.0±0.6) U/mgpro.TAC and GSH-PX in COPD control group were decreased than those in normal control group while those in normal PM2.5 group and COPD PM2.5 group were respectively lower than each control group.Comparing to normal PM2.5 group, the Nrf2 mRNA and protein in COPD PM2.5 group were decreased (all P<0.01). MDA in each group were (2.9±0.4), (4.8±0.5), (4.5±0.3), and (6.2±0.4) nmol/mgpro.MDA in COPD control group were increased than those in normal control group while those in normal PM2.5 group and COPD PM2.5 group were respectively higher than each control group.Comparing to normal PM2.5 group, the MDA in COPD PM2.5 group were increased (all P<0.01). Positive correlations were observed between Nrf2 mRNA, protein and MDA, while negative correlations were observed between Nrf2 mRNA, protein and TAC, GSH-PX in all groups (all P<0.05). PM2.5 can induce Nrf2 expression and aggravate oxidative stress in COPD mice.The increased expression of Nrf2 is closely associated with oxidative stress.

Club Cell-16 and RelB as Novel Determinants of Arterial Stiffness in Exacerbating COPD Patients.

BackgroundExacerbations of chronic obstructive pulmonary disease (COPD) are acute events of worsened respiratory symptoms that may increase the risk of cardiovascular disease (CVD), a leading cause of mortality amongst COPD patients. The utility of lung-specific inflammatory mediators such as club cell protein-16 (CC-16) and surfactant protein D (SPD) and that of a novel marker of CV outcomes in COPD- RelB- in predicting adverse cardiovascular events during exacerbation is not known.MethodsThirty-eight subjects with COPD admitted to the hospital for severe exacerbation were included in this analysis. Clinical, physiological and arterial stiffness measurements were performed within 72 hours of admission; this was followed by measurements taken every 3 days until hospital discharge, then once a week until 30 days after discharge, and then again at 90 and 180 days. Plasma concentrations of inflammatory mediators were measured from peripheral venous blood taken at admission, and at days 15, 30, 90 and 180.ResultsCC-16 and RelB concentrations were increased at day 15 of exacerbations whereas SPD concentrations were decreased. The course of change in CC-16 and RelB levels over time was inversely associated with that of carotid-femoral pulse wave velocity, the gold-standard measure of arterial stiffness. Increases in CC-16 could predict a decreased number of subsequent exacerbations during follow-up.ConclusionsLung-specific (CC-16) and novel (RelB) biomarkers are associated with systemic cardiovascular changes over time. CC-16 can predict subsequent exacerbations in subjects with severe COPD and may be an important biomarker of pulmonary and systemic stress in COPD.