Association Between Urinary Phthalate Metabolites and Chronic Obstructive Pulmonary Disease: A Cross-Sectional Study.

Objective: To determine the association of urinary phthalate metabolites with chronic obstructive pulmonary disease (COPD), airflow obstruction, lung function and respiratory symptoms. Methods: Our study included a total of 2023 individuals aged ≥ 40 years old in the National Health and Nutrition Examination Survey (NHANES). Multivariate logistic regression was conducted to explore the correlation of eleven urinary phthalate metabolites (MCNP, MCOP, MECPP, MnBP, MCPP, MEP, MEHHP, MEHP, MiBP, MEOHP, and MBzP) with COPD, airflow obstruction and respiratory symptoms. Linear regression analyses were used to evaluate the relationship between urinary phthalate metabolites and lung function. Results: When compared to the first tertile, the third tertile of MEHHP was associated with the risk of COPD [OR: 2.779; 95% confidence interval (CI): 1.129-6.840; P = 0.026]. Stratified analysis showed that MEHHP increased the risk of COPD by 7.080 times in male participants. Both MCPP and MBzP were positively correlated with the risk of airflow obstruction. The third tertile of MBzP increased the risk of cough by 1.545 (95% CI: 1.030-2.317; P = 0.035) times. Both FEV1 and FVC were negatively associated with MEHHP, MECPP, MnBP, MEP, MiBP and MEOHP. Conclusion: Higher levels of MEHHP are associated with increased risk of COPD, and lower measures of FEV1 and FVC. MBzP is positively related to airflow obstruction and cough.

MTMR14 Alleviates Chronic Obstructive Pulmonary Disease as a Regulator in Inflammation and Emphysema.

Extensive inflammation and apoptosis in structural cells of the lung are responsible for the progression and pathogenesis of chronic obstructive pulmonary disease (COPD). Myotubularin-related protein 14 (MTMR14) has been shown to participate in various biological processes, including apoptosis, inflammation, and autophagy. Nonetheless, the role of MTMR14 in COPD remains elusive. In the present study, we explored the expression of MTMR14 in human lung tissues and investigated the effects of overexpressed MTMR14 on in vitro and in vivo COPD models. Moreover, one of the possible mechanisms of MTMR14 alleviating COPD was explored based on mitochondrial function and mitophagy homeostasis. The results showed that MTMR14 expression was reduced in COPD patients' lungs in comparison to control subjects. MTMR14 overexpression inhibited cigarette smoke extract-induced inflammation and apoptosis and improved mitochondrial function and mitophagy in vitro. Further verification was carried out in COPD model mice. MTMR14 overexpression inhibited lung inflammation and reduced levels of IL-6 and KC in bronchoalveolar lavage fluid, as well as prevented emphysema and a decline in lung function. Furthermore, MTMR14 overexpression improved mitochondrial function and mitophagy to a certain extent. Collectively, our data support the hypothesis that MTMR14 participates in the pathogenesis of COPD. Improving mitochondrial function and mitophagy homeostasis may be one of the mechanisms by which MTMR14 alleviates COPD and may potentially be a novel therapeutic target for COPD.

Conditions Favoring Increased COVID-19 Morbidity and Mortality: Their Common Denominator and its Early Treatment.

The factors contributing to increased morbidity and mortality in SARS-CoV-2 infection are diverse, and include diabetes, obesity, Chronic Obstructive Pulmonary Disease (COPD), advanced age, and male sex. Although there is no obvious connection between these, they do have one common denominator-they all have a tendency towards lower urine pH, which may indicate a lower-than-normal tissue pH. Furthermore, it has been shown that lower pH has two important negative influences: 1) it enhances viral fusion via the endosomal route, thereby facilitating viral multiplication; and 2) it facilitates increased production of inflammatory cytokines, thereby exacerbating the cytokine storm. This paper discusses published literature on lower tissue/interstitial pH in those diseases/co-morbidities that are known risk factors of severe COVID-19, and hypothesize that small doses of baking soda could be a simple, cost-effective, and rapid method of reducing both morbidity and mortality in COVID-19 patients.

Association of urine mitochondrial DNA with clinical measures of COPD in the SPIROMICS cohort.

BACKGROUNDMitochondrial dysfunction, a proposed mechanism of chronic obstructive pulmonary disease (COPD) pathogenesis, is associated with the leakage of mitochondrial DNA (mtDNA), which may be detected extracellularly in various bodily fluids. Despite evidence for the increased prevalence of chronic kidney disease in COPD subjects and for mitochondrial dysfunction in the kidneys of murine COPD models, whether urine mtDNA (u-mtDNA) associates with measures of disease severity in COPD is unknown.METHODSCell-free u-mtDNA, defined as copy number of mitochondrially encoded NADH dehydrogenase-1 (MTND1) gene, was measured by quantitative PCR and normalized to urine creatinine in cell-free urine samples from participants in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Urine albumin/creatinine ratios (UACR) were measured in the same samples. Associations between u-mtDNA, UACR, and clinical disease parameters - including FEV1 % predicted, clinical measures of exercise tolerance, respiratory symptom burden, and chest CT measures of lung structure - were examined.RESULTSU-mtDNA and UACR levels were measured in never smokers (n = 64), smokers without airflow obstruction (n = 109), participants with mild/moderate COPD (n = 142), and participants with severe COPD (n = 168). U-mtDNA was associated with increased respiratory symptom burden, especially among smokers without COPD. Significant sex differences in u-mtDNA levels were observed, with females having higher u-mtDNA levels across all study subgroups. U-mtDNA associated with worse spirometry and CT emphysema in males only and with worse respiratory symptoms in females only. Similar associations were not found with UACR.CONCLUSIONU-mtDNA levels may help to identify distinct clinical phenotypes and underlying pathobiological differences in males versus females with COPD.TRIAL REGISTRATIONThis study has been registered at ClinicalTrials.gov ( NCT01969344).FUNDINGUS NIH, National Heart, Lung and Blood Institute, supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from AstraZeneca/MedImmune, Bayer, Bellerophon Therapeutics, Boehringer-Ingelheim Pharmaceuticals Inc., Chiesi Farmaceutici S.p.A., Forest Research Institute Inc., GlaxoSmithKline, Grifols Therapeutics Inc., Ikaria Inc., Novartis Pharmaceuticals Corporation, Nycomed GmbH, ProterixBio, Regeneron Pharmaceuticals Inc., Sanofi, Sunovion, Takeda Pharmaceutical Company, and Theravance Biopharma and Mylan.

Videogames in the Treatment of Obstructive Respiratory Diseases: A Systematic Review.

Introduction: Millions of people suffer from obstructive respiratory conditions globally. Including videogames in rehabilitation programs can be an interesting alternative to traditional programs or a complementary activity. Objective: To explore the use of videogames in the treatment of patients with obstructive respiratory diseases. Methods: A systematic literature search was performed to identify randomized clinical trials evaluating the effects of videogames on health outcomes in patients with respiratory obstructive diseases. The following databases were searched: PubMed, Web of Science, ScienceDirect, and Scopus. The methodological quality of the studies included was assessed with the Downs and Black quality assessment method. Results: Nine articles were included, of which three used videogames as physical training methods and managed to improve exercise capacity, strength, quality of life, and symptoms. The remaining six articles used videogames to educate patients about the disease and showed slight improvements in knowledge of the disease and use of medication. Conclusion: The results of this review show that videogames are a very useful complementary therapy. They can contribute to enhance rehabilitation programs, as they improve exercise capacity, muscle strength, quality of life, severity, control, and knowledge of the disease. Videogames should be supervised by a professional so that programs can be tailored to patients, proposing different activities in the game and controlling the correct performance, and generating an increase in adherence to treatment. Registry: prospective register of systematic reviews (PROSPERO) CRD42018094094.

Does the Coexistence of Chronic Obstructive Pulmonary Disease and Atrial Fibrillation Affect Nox2 Activity and Urinary Isoprostanes Excretion?

Chronic obstructive pulmonary disease (COPD) and atrial fibrillation (AF) are characterized by increased oxidative stress, but the impact of the coexistence of COPD and AF on systemic oxidative stress is unclear. We performed a cross-sectional study including 157 outpatients to investigate the Nox2-related oxidative stress in patients with AF and COPD. COPD was defined by an FEV1/FVC <0.70. Oxidative stress was measured by sNox2-dp, a marker of Nox2 activation, and urinary isoprostanes. We divided patients into four groups: Group 0: hypertension (n = 49, controls); Group 1: COPD (n = 42); Group 2: AF (n = 33); and Group 3: COPD and AF (n = 33). Mean age was 68.3 ± 11.0 years, and 46.5% were women. Patients with COPD or AF showed increased levels of sNox2-dp as compared with group 0; sNox2-dp further increased in patients with COPD + AF. In these patients, sNox2-dp was higher than in those with COPD (p < 0.001) or AF (p = 0.003). At multivariable logistic regression analysis, chronic kidney disease, COPD, and AF were associated with sNox2-dp above median. Similar results were observed for urinary isoprostanes. We hypothesize that the coexistence of COPD in AF patients may be associated with an increased systemic oxidative stress by the upregulation of Nox2. Antioxid. Redox Signal. 31, 786-790.

Fixed airflow obstruction relates to eosinophil activation in asthmatics.

BACKGROUND: Some asthmatics develop irreversible chronic airflow obstruction, for example, fixed airflow obstruction (fixed-AO). This is probably a consequence of airway remodelling, but neither its relation to inflammation nor which asthma biomarkers can be clinically useful are elucidated. We hypothesized that the presence of type 2 inflammation relates to fixed-AO. OBJECTIVES: To evaluate the presence of four markers for type 2 inflammation in fixed airflow obstruction among asthmatics. METHODS: This was a cross-sectional study of 403 participants with asthma, aged 17-75 years, from three Swedish centres. Fixed airflow obstruction was defined as forced expiratory volume during the first second (FEV1 ) over forced vital capacity (FVC) being below the lower limit of normal (LLN). The following type 2 inflammation markers were assessed: exhaled nitric oxide (FeNO), serum periostin, serum eosinophil cationic protein (S-ECP), and urinary eosinophil-derived neurotoxin (U-EDN). RESULTS: Elevated U-EDN (values in the highest tertile, ≥65.95 mg/mol creatinine) was more common in subjects with fixed-AO vs. subjects without fixed-AO: 55% vs. 29%, P < 0.001. Elevated U-EDN related to increased likelihood of having fixed-AO in both all subjects and never-smoking subjects, with adjusted (adjusted for sex, age group, use of inhaled corticosteroids last week, atopy, early-onset asthma, smoking history, and packyears) odds ratios (aOR) of 2.38 (1.28-4.41) and 2.51 (1.04-6.07), respectively. In a separate analysis, having both elevated S-ECP (>20 µg/L) and U-EDN was related to having the highest likelihood of fixed-AO (aOR (95% CI) 6.06 (2.32-15.75)). Elevated serum periostin or FeNO did not relate to fixed-AO. CONCLUSIONS AND CLINICAL RELEVANCE: These findings support that type 2 inflammation, and in particular eosinophil inflammation, is found in asthma with fixed-AO. This could indicate a benefit from eosinophil-directed therapies. Further longitudinal studies are warranted to investigate causality and relation to lung function decline.

Clinical relevance of guanine-derived urinary biomarkers of oxidative stress, determined by LC-MS/MS.

A reliable and fast liquid chromatography-tandem mass spectrometry method has been developed for the simultaneous determination of three oxidized nucleic acid damage products in urine, 8-oxoguanine (8-oxoGua), 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo). We applied this method to assess the effect of various urine workup procedures on the urinary concentrations of the oxidized nucleic acid products. Our results showed that frozen urine samples must be warmed (i.e., to 37 °C) to re-dissolve any precipitates prior to analysis. We showed that common workup procedures, such as thawing at room temperature or dilution with deionized water, are not capable of releasing fully the oxidized nucleic acid products from the precipitates, and result in significant underestimation (up to ~ 100% for 8-oxoGua, ~ 86% for both 8-oxodGuo and 8-oxoGuo). With this method, we further assessed and compared the ability of the three oxidized nucleic acid products, as well as malondialdehyde (MDA, a product of lipid peroxidation), to biomonitor oxidative stress in vivo. We measured a total of 315 urine samples from subjects with burdens of oxidative stress from low to high, including healthy subjects, patients with chronic obstructive pulmonary disease (COPD), and patients on mechanical ventilation (MV). The results showed that both the MV and COPD patients had significantly higher urinary levels of 8-oxoGua, 8-oxodGuo, and 8-oxoGuo (P < 0.001), but lower MDA levels, compared to healthy controls. Receiver operating characteristic curve analysis revealed that urinary 8-oxoGuo is the most sensitive biomarker for oxidative stress with area under the curve (AUC) of 0.91, followed by 8-oxodGuo (AUC: 0.80) and 8-oxoGua (AUC: 0.76). Interestingly, MDA with AUC of 0.34 failed to discriminate the patients from healthy controls. Emerging evidence suggests a potential clinical utility for the measurement of urinary 8-oxoGuo, and to a lesser extent 8-oxodGuo, which is strongly supported by our findings.

Albuminuria in patients with chronic obstructive pulmonary disease: a cross-sectional study in an African patient cohort.

BACKGROUND: Cardiovascular disease (CVD) is remarkably frequent in patients with chronic obstructive pulmonary disease (COPD). Albuminuria is a marker of vascular endothelial dysfunction and predictor of CVD events. Albuminuria is prevalent in patients with COPD as it has been shown in Caucasian and Oriental populations with COPD. The objective of this study was to determine the prevalence of Albuminuria and COPD severity correlates among black patients with chronic obstructive pulmonary disease in order to see whether a similar trend of albuminuria is also prevalent in this population. METHODS: A total of 104 COPD patients were enrolled in the study. Lung functions were assessed by means of the Easy One™ spirometer. Albuminuria defined by urine albumin to creatinine ratio (ACR) was tested using CYBOW 12MAC microalbumin strips in a random spot urine collection. SPSS version 20 was used for data analysis. RESULTS: In the studied population, 25/104 (24%) patients had albuminuria and 16/104 (15.4%) patients had CVD. Abnormal urine albumin (Albuminuria and Proteinuria) was present in all patients with CVD. In the subset of 46 COPD patients assessed for severity, 60.9% (95%CIs 46.1-73.9) had moderate COPD and 30.4% (95% CIs, 17.9-49.0) severe COPD. Albuminuria was moderately significantly associated with COPD severity, p = 0.049; (0.049 < p < 0.05). Participants who ever smoked cigarettes had significantly likelihood of severe and very severe COPD (OR 11.5; 95% CIs, 1.3, 98.4) however, the significance was lost when adjusted for age and gender. CONCLUSION: Albuminuria was prevalent in patients with COPD and it had a significant association with COPD severity.

Increased urinary l-histidine in patients with asthma-COPD overlap: a pilot study.

Purpose: Asthma-COPD overlap (ACO) is heterogeneous in nature and requires a unified diagnostic approach. We investigated the urinary levels of l-histidine, a precursor of histamine related to inflammatory responses, as a new candidate biomarker for diagnosing this condition. Patients and methods: We performed a prospective multicenter cohort study with retrospective analysis of 107 patients, who were divided into three groups: asthma, COPD, and ACO, according to the Spanish guidelines algorithm. Urinary l-histidine levels were measured using liquid chromatography-mass spectrometry. High-resolution metabolomic analysis, coupled with liquid chromatography-mass spectrometry and followed by multivariate statistical analysis, was performed on urine samples to discriminate between the metabolic profiles of the groups. Results: Urinary l-histidine levels were significantly higher in patients with ACO than in those with asthma or COPD, but the subgroups of ACO, classified according to disease origin, did not differ significantly. High urinary l-histidine level was a significant factor for the diagnosis of ACO even after adjusting for age, sex, and smoking amount. Among patients with airflow obstruction, the urinary l-histidine levels were elevated in patients with a documented history of asthma before the age of 40 years or bronchodilator responsiveness ≥400 mL; bronchodilator responsiveness ≥200 mL of forced expiratory volume in 1 second and exceeding baseline values by 12% on two or more visits; blood eosinophil count ≥300 cells·mm-3; and frequent exacerbations (P < 0.05). Conclusion: Urinary l-histidine could be a potential biomarker for ACO, regardless of the diversity of diagnostic definitions used.

Indoor black carbon of outdoor origin and oxidative stress biomarkers in patients with chronic obstructive pulmonary disease.

OBJECTIVES: We assessed relationships between indoor black carbon (BC) exposure and urinary oxidative stress biomarkers, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and malondialdehyde (MDA), in participants with chronic obstructive pulmonary disease (COPD). METHODS: Eighty-two participants completed in-home air sampling for one week prior to providing urine samples up to four times in a year. Weekly indoor and daily outdoor concentrations were used to estimate indoor daily lags and moving averages. There were no reported in-home BC sources, thus indoor levels closely represented outdoor BC infiltration. Mixed effects regression models with a random intercept for each participant were used to assess relationships between indoor BC and 8-OHdG and MDA, adjusting for age, race, BMI, diabetes, heart disease, season, time of urine collection, urine creatinine, and outdoor humidity and temperature. RESULTS: There were positive effects of BC on 8-OHdG and MDA, with the greatest effect the day before urine collection (6.9% increase; 95% CI 0.9-13.3%, per interquartile range: 0.22 µg/m3) for 8-OHdG and 1 to 4 days before collection (8.3% increase; 95% CI 0.03-17.3% per IQR) for MDA. Results were similar in models adjusting for PM2.5 not associated with BC and NO2 (10.4% increase, 95% CI: 3.5-17.9 for 8-OHdG; 8.1% increase, 95% CI: -1.1-18.1 for MDA). Effects on 8-OHdG were greater in obese participants. CONCLUSIONS: We found positive associations between BC exposure and 8-OHdG and MDA, in which associations with 8-OHdG were stronger in obese participants. These results suggest that exposure to low levels of traffic-related pollution results in lipid peroxidation and oxidative DNA damage in individuals with COPD.

Urinary desmosine is associated with emphysema severity and frequent exacerbation in patients with COPD.

BACKGROUND AND OBJECTIVE: Matrix degradation is a key feature of chronic obstructive pulmonary disease (COPD). Desmosine and isodesmosine (desmosines) are excreted in urine following matrix degradation. The main purpose of this study was to investigate the association between computed tomography (CT) emphysema indices and urinary desmosines in patients with COPD. METHODS: A total of 152 subjects were selected from the Korean Obstructive Lung Disease cohort. Their urine samples were assayed for desmosines using liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. The cohort was divided into emphysema-dominant (n = 80) and non-emphysema dominant- (n = 72) groups according to the CT emphysema index. RESULTS: The level of urinary desmosines was significantly higher in the emphysema-dominant group. Significant differences were also observed between the two groups for body mass index and lung function. Multivariate analysis indicated that a high level of urinary desmosines was a significant independent predictor of emphysema (relative risk: 2.6; 95% CI: 1.11-6.09; P = 0.028). The percentage of frequent exacerbators was significantly higher in the high urinary desmosine group in the first year of follow-up (P = 0.041). The mean number of exacerbations was higher in the high urinary desmosine group, although this difference was not statistically significant (P = 0.067). The changes in emphysema index did not differ between the two urinary desmosine groups over 3 years of follow-up. CONCLUSION: This study indicates that the level of urinary desmosines measured by LC-MS/MS methods is associated with the CT emphysema index. Urinary desmosine can be a useful predictor in identifying frequent exacerbators.

Examining of Thallium in Cigarette Smokers.

Smoking is one of the sources of thallium which is considered as a toxic heavy metal. The aim of this study was to determine urinary thallium levels and related variables in smokers, compared to a control group. The study was conducted on 56 participants who had smoked continuously during the year before they were referred to Kashan Smoking Cessation Clinic. Fifty-three nonsmokers who were family members or friends of the smokers were selected as the control group. Urinary thallium was measured in both groups (n = 109) using atomic absorption spectrophotometry. The mean value (with SD) for urinary thallium in the smokers (10.16 ± 1.82 µg/L) was significantly higher than in the control group (2.39 ± 0.63 µg/L). There was a significant relationship between smoking duration and urinary thallium levels (P = 0.003). In a subgroup of smokers who was addicted to opium and opium residues (n = 9), the mean level of thallium (37.5 ± 13.09 µg/L) was significantly higher than in the other smokers (4.93 ± 4.45; P = 0.001). Multiple regression analysis showed opioid abuse, insomnia, and chronic obstructive pulmonary disease (COPD), together were strong predictors of urinary thallium levels in smokers. There was no significant difference in thallium level in hookah smokers (P = 0.299) or in those with COPD compared to other smokers (P = 0.375). Urinary thallium levels of smokers with clinical signs of depression, sleep disorders, memory loss, and sweating were higher than those of smokers without these signs. Since thallium, as other toxic metals is accumulated in the body, and cigarette smoking also involves carcinogenic exposures and health hazards for passively exposed people, the need for cigarette control policies is emphasized.

Comparative analysis of creatinine and osmolality as urine normalization strategies in targeted metabolomics for the differential diagnosis of asthma and COPD.

INTRODUCTION: Urine is an ideal matrix for metabolomics investigation due to its non-invasive nature of collection and its rich metabolite content. Despite the advancements in mass spectrometry and 1H-NMR platforms in urine metabolomics, the statistical analysis of the generated data is challenged with the need to adjust for the hydration status of the person. Normalization to creatinine or osmolality values are the most adopted strategies, however, each technique has its challenges that can hinder its wider application. We have been developing targeted urine metabolomic methods to differentiate two important respiratory diseases, namely asthma and chronic obstructive pulmonary disease (COPD). OBJECTIVE: To assess whether the statistical model of separation of diseases using targeted metabolomic data would be improved by normalization to osmolality instead of creatinine. METHODS: The concentration of 32 metabolites was previously measured by two liquid chromatography-tandem mass spectrometry methods in 51 human urine samples with either asthma (n = 25) or COPD (n = 26). The data was normalized to creatinine or osmolality. Statistical analysis of the normalized values in each disease was performed using partial least square discriminant analysis (PLS-DA). Models of separation of diseases were compared. RESULTS: We found that normalization to creatinine or osmolality did not significantly change the PLS-DA models of separation (R2Q2 = 0.919, 0.705 vs R2Q2 = 0.929, 0.671, respectively). The metabolites of importance in the models remained similar for both normalization methods. CONCLUSION: Our findings suggest that targeted urine metabolomic data can be normalized for hydration using creatinine or osmolality with no significant impact on the diagnostic accuracy of the model.

Development of a validated LC- MS/MS method for the quantification of 19 endogenous asthma/COPD potential urinary biomarkers.

Obstructive airways inflammatory diseases sometimes show overlapping symptoms that hinder their early and correct diagnosis. Current clinical tests are tedious and are of inadequate specificity in special population such as the elderly and children. Therefore, we are developing tandem mass spectrometric (MS/MS) methods for targeted analysis of urine biomarkers. Recently, proton-nuclear magnetic resonance (1H-NMR) analysis proposed 50 urinary metabolites as potential diagnostic biomarkers among asthma and chronic obstructive pulmonary disease (COPD) patients. Metabolites are divided into 3 groups based on chemical nature. For group 1 (amines and phenols, 19 urinary metabolites), we developed and validated a high performance liquid chromatographic (HPLC)-MS/MS method using differential isotope labeling (DIL) with dansyl chloride. Method development included the optimization of the derivatization reaction, the MS/MS conditions, and the chromatographic separation. Linearity varied from 2 to 4800 ng/mL and the use of 13C2-labeled derivatives allowed for the correction of matrix effects as well as the unambiguous confirmation of the identity of each metabolite in the presence of interfering isomers in urine. Despite the challenges associated with method validation, the method was fully validated as per the food and drug administration (FDA) and the European medicines agency (EMA) recommendations. Validation criteria included linearity, precision, accuracy, dilution integrity, selectivity, carryover, and stability. Challenges in selectivity experiments included the isotopic contributions of the analyte towards its internal standard (IS), that was addressed via the optimization of the IS concentration. In addition, incurred sample analysis was performed to ensure that results from patient samples are accurate and reliable. The method was robust and reproducible and is currently being applied in a cohort of asthma and COPD patient urine samples for biomarker discovery purposes.

Does urinary peptide content differ between COPD patients with and without inherited alpha-1 antitrypsin deficiency?

Differentiating between chronic obstructive pulmonary disease (COPD) patients with normal (PiMM) or deficient (PiZZ) genetic variants of alpha-1 antitrypsin (A1AT) is important not only for understanding the pathobiology of disease progression but also for improving personalized therapies. This pilot study aimed to investigate whether urinary peptides reflect the A1AT-related phenotypes of COPD. Urine samples from 19 clinically stable COPD cases (7 PiMM and 12 PiZZ A1AT) were analyzed by capillary electrophoresis coupled to mass spectrometry. We identified 66 peptides (corresponding to 36 unique proteins) that differed between PiZZ and PiMM COPD. Among these, peptides from the collagen family were the most abundant and divergent. A logistic regression model based on COL1A1 or COL5A3 peptides enabled differentiation between PiMM and PiZZ groups, with a sensitivity of 100% and specificity of 85.71% for COL1A1 and a sensitivity of 91.67% and specificity of 85.71% for COL5A3. Furthermore, patients with PiZZ presented low levels of urinary peptides involved in lipoproteins/lipids and retinoic acid metabolism, such as apolipoprotein A-I and C4, retinol-binding protein 4 and prostaglandin-H2 D-isomerase. However, peptides of MDS1 and EVII complex locus, gelsolin and hemoglobin alpha were found in the urine of COPD cases with PiZZ, but not with PiMM. These capillary electrophoresis coupled to mass spectrometry-based results provide the first evidence that urinary peptide content differs between PiMM and PiZZ patients with COPD.

Microalbuminuria in Subjects With COPD: Relationship to the New Version of Global Initiative for Chronic Obstructive Lung Disease Staging.

BACKGROUND: Microalbuminuria, used as a marker of endothelial dysfunction, is a predictor of mortality for any reason and of cardiovascular events. Recent research on the management of COPD has focused more on comorbidities, including cardiovascular events. The objective of this study was to investigate the incidence of microalbuminuria and whether it is associated with physiological and clinical features in a subject group that was classified in line with the new version of the Global Initiative for Chronic Obstructive Lung Disease stages. METHODS: The study included 105 stable subjects with mild to very severe COPD. The urinary albumin/creatinine ratio was calculated using a previously defined formula. The presence of microalbuminuria was accepted as a urinary albumin/creatinine ratio ≥20 in males and ≥30 in females. RESULTS: Urinary albumin/creatinine ratios were significantly higher in subjects grouped as having more symptoms and high future risk than in those with fewer symptoms and low future risk. In addition, significant differences were observed when the subjects were grouped based on PaO2 (≤65 mm Hg vs >65 mm Hg), PaCO2 (≤41 mm Hg vs >41 mm Hg), arterial oxygen saturation (≤92% vs >92%), and median split C-reactive protein (≤4.6 mg/L vs >4.6 mg/L). Pearson correlation analysis revealed that the urinary albumin/creatinine ratio was significantly inversely correlated with percent-of-predicted FEV1 (r = -0.56, P = .001), percent-of-predicted SaO2 (r = -0.48, P = .001), and PaO2 (r = 0.60, P = .001). A positive correlation was also found between urinary albumin/creatinine ratio and COPD assessment test scores (r = 0.53, P = .001). CONCLUSIONS: The results of this study indicate a strong relationship between microalbuminuria and cardiovascular events in subjects with COPD, particularly in subjects with more symptoms and high future risk. Therefore, microalbuminuria should be regularly monitored in this subgroup of subjects with COPD for risk of cardiovascular morbidity or mortality.

Oxidative Stress and Genetic Variants of Xenobiotic-Metabolising Enzymes Associated with COPD Development and Severity in Serbian Adults.

The genetic and non-genetic factors that contribute to the development of chronic obstructive pulmonary disease (COPD) are still poorly understood. We investigated the potential role of genetic variants of xenobiotic-metabolising enzymes (glutathione-S-transferase M1, GSTM1; glutathione-S-transferase T1, GSTT1; microsomal epoxide hydrolase, mEH), oxidative stress (assessed by urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine, 8-oxodG/creatinine), sex, ageing and smoking habits on susceptibility to development of COPD and its severity in Serbian population. The investigated population consisted of 153 healthy subjects (85 males and 68 females) and 71 patients with COPD (33 males and 38 females). Detection of GSTM1*null, GSTT1*null, mEH Tyr113His and mEH His139Arg gene variants was performed by PCR/RFLP method. Urinary 8-oxodG was determined using HPLC-MS/MS, and expressed as 8-oxodG/creatinine. We revealed that increased urinary 8-oxodG/creatinine and leucocytosis are the strongest independent predictors for COPD development. Increased level of oxidative stress increased the risk for COPD in males [odds ratio (OR), 95% confidence interval (CI): 8.42, 2.26-31.28], more than in females (OR, 95% CI: 3.60, 1.37-9.45). Additionally, independent predictors for COPD were ageing in males (OR, 95% CI: 1.29, 1.12-1.48), while in females they were at least one GSTM1 or GSTT1 gene deletion in combination (OR, 95% CI: 23.67, 2.62-213.46), and increased cumulative cigarette consumption (OR, 95% CI: 1.09, 1.01-1.16). Severity of COPD was associated with the combined effect of low mEH activity phenotype, high level of oxidative stress and heavy smoking. In conclusion, early identification of GSTM1*null or GSTT1*null genotypes in females, low mEH activity phenotype in heavy smokers and monitoring of oxidative stress level can be useful diagnostic and prognostic biomarkers.

Antioxidant nutrients in plasma of Japanese patients with chronic obstructive pulmonary disease, asthma-COPD overlap syndrome and bronchial asthma.

BACKGROUND: Few studies to date have investigated the antioxidant nutrients such as vitamin C (ascorbic acid), vitamin E (α-tocopherol), retinol and carotenoids in plasma from patients with pulmonary disease in Japan. To clarify the role of antioxidant nutrients such as vitamin C, vitamin E, retinol and various carotenoids in plasma of Japanese patients with chronic obstructive lung diseases (COPD), asthma-COPD overlap syndrome (ACOS) and/or bronchial asthma (BA), we compared to healthy elderly controls. METHODS: Ascorbic acid (AA), carotenoids (lutein, zeaxanthin, ß-cryptoxanthin, α-carotene, ß-carotene and lycopene), retinol and α-tocopherol levels in plasma were determined by using a high performance liquid chromatography. Reduced glutathione (GSH), oxidised glutathione (GSSG) in whole blood and urinary 8-OHdG were also determined. RESULTS: Plasma AA level of COPD subjects was significantly lower than that of healthy elderly people. Conversely, ACOS and BA subjects showed no significant difference from healthy elderly people. Moreover, plasma lycopene and total carotenoid levels and GSH content in blood were significantly lower in COPD subjects than these in healthy elderly people. However, other redox markers such as GSSG, GSH/GSSG ratio and urinary 8-OHdG found no significant differences between COPD, ACOS and BA compared to healthy elderly people. CONCLUSIONS: These results suggested that COPD of Japanese patients may develop partly because of oxidative stress derived from a shortage of antioxidant nutrients, especially of AA and lycopene, as well as GSH while this may not be the case in both ACOS and BA.