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      Disruption of histidine and energy homeostasis in chronic obstructive pulmonary disease

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          Chronic obstructive pulmonary disease (COPD) is a systemic condition that is too complex to be assessed by lung function alone. Metabolomics has the potential to help understand the mechanistic underpinnings that contribute to COPD pathogenesis. Since blood metabolomics may be affected by sex and body mass index (BMI), the aim of this study was to determine the metabolomic variability in male smokers with and without COPD who have a narrow BMI range.


          We compared the quantitative proton nuclear magnetic resonance acquired serum metabolomics of a male Chinese Han population of non-smokers without COPD, and smokers with and without COPD. We also assessed the impact of smoking status on metabolite concentrations and the associations between metabolite concentrations and inflammatory markers such as serum interleukin-6 and histamine, and blood cell differential (%). Metabolomics data were log-transformed and auto-scaled for parametric statistical analysis. Mean normalized metabolite concentration values and continuous demographic variables were compared by Student’s t-test with Welch correction or ANOVA with post-hoc Tukey’s test, as applicable; t-test p-values for metabolomics data were corrected for false discovery rate (FDR). A Pearson association matrix was built to evaluate the relationship between metabolite concentrations, clinical parameters and markers of inflammation.


          Twenty-eight metabolites were identified and quantified. Creatine, glycine, histidine, and threonine concentrations were reduced in COPD patients compared to non-COPD smokers (FDR ≤15%). Concentrations of these metabolites were inversely correlated with interleukin-6 levels. COPD patients had overall dampening of metabolite concentrations including energy-related metabolic pathways such as creatine metabolism. They also had higher histamine levels and percent basophils compared to smokers without COPD.


          COPD is associated with alterations in the serum metabolome, including a disruption in the histidine-histamine and creatine metabolic pathways. These findings support the use of metabolomics to understand the pathogenic mechanisms involved in COPD.

          Trial registration, NCT03310177.

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          Most cited references 32

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          Human metabolic phenotype diversity and its association with diet and blood pressure.

          Metabolic phenotypes are the products of interactions among a variety of factors-dietary, other lifestyle/environmental, gut microbial and genetic. We use a large-scale exploratory analytical approach to investigate metabolic phenotype variation across and within four human populations, based on 1H NMR spectroscopy. Metabolites discriminating across populations are then linked to data for individuals on blood pressure, a major risk factor for coronary heart disease and stroke (leading causes of mortality worldwide). We analyse spectra from two 24-hour urine specimens for each of 4,630 participants from the INTERMAP epidemiological study, involving 17 population samples aged 40-59 in China, Japan, UK and USA. We show that urinary metabolite excretion patterns for East Asian and western population samples, with contrasting diets, diet-related major risk factors, and coronary heart disease/stroke rates, are significantly differentiated (P < 10(-16)), as are Chinese/Japanese metabolic phenotypes, and subgroups with differences in dietary vegetable/animal protein and blood pressure. Among discriminatory metabolites, we quantify four and show association (P < 0.05 to P < 0.0001) of mean 24-hour urinary formate excretion with blood pressure in multiple regression analyses for individuals. Mean 24-hour urinary excretion of alanine (direct) and hippurate (inverse), reflecting diet and gut microbial activities, are also associated with blood pressure of individuals. Metabolic phenotyping applied to high-quality epidemiological data offers the potential to develop an area of aetiopathogenetic knowledge involving discovery of novel biomarkers related to cardiovascular disease risk.
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            Comparison of computed density and macroscopic morphometry in pulmonary emphysema.

            High-resolution computed tomography (HRCT) scans were obtained at 1 cm intervals in 63 subjects referred for surgical resection of a cancer or for transplantation to find out whether the relative area of lung occupied by attenuation values lower than a threshold would be a measurement of macroscopic emphysema. Using a semiautomatic procedure, the relative areas occupied by attenuation values lower than eight thresholds ranging from -900 to -970 HU were calculated on the set of scans obtained through the lobe or the lung to be resected. The extent of emphysema was quantified by a computer-assisted method on horizontal paper-mounted lung sections obtained every 1 to 2 cm. The only level for which no statistically significant difference was found between the HRCT and the morphometric data was -950 HU. To determine the number of scans sufficient for an accurate quantification, we recalculated the relative area occupied by attenuation values lower than -950 HU on progressively fewer numbers of scans and investigated the departure from the results obtained with 1 cm intervals. Because of wide variations in this departure from patient to patient, a standard cannot be recommended as the optimal distance between scans.
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              Metabolic profiling detects biomarkers of protein degradation in COPD patients.

              There is a paucity of biomarkers for chronic obstructive pulmonary disease (COPD). Metabolomics were applied to a defined COPD patient cohort from the ECLIPSE study (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points). Results were correlated with accepted biomarkers for the disease. Baseline control serum (n=66) and Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II (n=70), III (n=64) and IV (n=44) COPD patients were analysed by proton nuclear magnetic resonance ((1)H NMR). Liquid chromatography with tandem mass spectrometry (LC-MS/MS) was used to confirm amino acid changes detected by (1)H NMR. Data were correlated with body composition, emphysema and systemic inflammation. (1)H NMR identified decreased lipoproteins, N,N-dimethylglycine, and increased glutamine, phenylalanine, 3-methylhistidine and ketone bodies in COPD patients with decreased branched-chain amino acids (BCAAs) observed in GOLD stage IV patients. BCAAs, their degradation products, 3-methylhistidine, ketone bodies, and triglycerides were correlated negatively with cachexia and positively with systemic inflammation. Emphysema patients also displayed decreased serum creatine, glycine and N,N-dimethylglycine. LC-MS/MS confirmed (1)H NMR findings relating to BCAAs, glutamine and 3-methylhistidine in GOLD stage IV patients. NMR-based metabolomics characterised COPD patients based on systemic effects and lung function parameters. Increased protein turnover occurred in all COPD patients with increased protein degradation in individuals with emphysema and cachexia.

                Author and article information

                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of Chronic Obstructive Pulmonary Disease
                03 September 2019
                : 14
                : 2015-2025
                [1 ]Department of Respiratory Medicine, Peking University Third Hospital , Beijing, People’s Republic of China
                [2 ]Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, School of Medicine, University of Michigan , Ann Arbor, MI, USA
                [3 ]Biochemical Nuclear Magnetic Resonance Core, College of Pharmacy, University of Michigan , Ann Arbor, MI, USA
                [4 ]NMR Metabolomics Laboratory, Department of Clinical Pharmacy, College of Pharmacy, University of Michigan , Ann Arbor, MI, USA
                [5 ]Department of Respiratory and Critical Care Medicine, Shou-Gang Hospital Affiliated to Peking University , Beijing, People’s Republic of China
                [6 ]Department of Respiratory Medicine, Peking University Third Hospital , Beijing 100191, People’s Republic of China
                [7 ]Department of Respiratory Medicine, Peking University Health Sciences Center, Third Hospital , Beijing, People’s Republic of China
                Author notes
                Correspondence: Kathleen A StringerCollege of Pharmacy, University of Michigan , Ann Arbor, MI48104, USATel +1 734 647 4775Email

                These authors contributed equally to this work

                © 2019 Diao et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (

                Page count
                Figures: 3, Tables: 1, References: 44, Pages: 11
                Original Research


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