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      Clinical validity of plasma and urinary desmosine as biomarkers for chronic obstructive pulmonary disease

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          Abstract

          Background

          Although an increased concentration of degraded elastin products in patients with chronic obstructive pulmonary disease (COPD) has been reported for many years, its clinical validity and utility remain uncertain due to technical difficulties, small study groups and the unknown relationship between exacerbation and elastin degradation. The objectives of this study were to determine the validity of urinary and blood total desmosine/isodesmosine in patients with COPD and asthma and to evaluate their relationship to exacerbation status and lung function.

          Methods

          Urinary and blood desmosine levels were measured using validated isotopic dilution liquid chromatography–tandem mass spectrometry methods.

          Results

          390 study participants were recruited from the following groups: healthy volunteers, stable asthma, stable and ‘during an exacerbation’ COPD. Compared with healthy non-smokers, we found increased urinary or blood desmosine levels in patients with COPD, but no differences in patients with asthma or healthy smokers. The elevation of urinary desmosine levels was associated with the exacerbation status in patients with COPD. Approximately 40% of patients with stable and ‘during an exacerbation’ COPD showed elevated blood desmosine levels. Blood desmosine levels were strongly associated with age and were negatively correlated with lung diffusing capacity for carbon monoxide.

          Conclusion

          The results suggest that urinary desmosine levels are raised by exacerbations of COPD whereas blood desmosine levels are elevated in a subgroup of patients with stable COPD and reduced lung diffusing capacity. The authors speculate that a raised blood desmosine level may identify patients with increased elastin degradation suitable for targeted therapy. Future prospective studies are required to investigate this hypothesis.

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          Most cited references26

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          Pathogenesis of emphysema: from the bench to the bedside.

          Chronic obstructive pulmonary disease (COPD) is characterized physiologically by expiratory flow limitation and pathologically by alveolar destruction and enlargement and small and large airway inflammation and remodeling. An imbalance between protease and antiprotease activity in the lung is proposed as the major mechanism resulting in emphysema. The imbalance is mostly due to an increase in the numbers of alveolar macrophages and neutrophils. Emphysema can also develop from increased alveolar wall cell death and/or failure in alveolar wall maintenance. Chronic inflammation and increased oxidative stress contribute to increased destruction and/or impaired lung maintenance and repair. Genetic factors may play an important role in disease susceptibility because only a minority of smokers develops emphysema. Recent literature implicates surfactant instability, malnutrition, and alveolar cell apoptosis as possible etiologies. Identification of cellular and molecular mechanisms of COPD pathogenesis is an area of active, ongoing research that may help to determine therapeutic targets for emphysema.
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            Desmosine as a biomarker of elastin degradation in COPD: current status and future directions.

            Desmosine (DES) and isodesmosine (IDES) are two unusual, tetrafunctional, pyridinium ring-containing amino acids involved in elastin cross-linking. Being amino acids unique to mature, cross-linked elastin, they are useful for discriminating peptides derived from elastin breakdown from precursor elastin peptides. According to these features, DES and IDES have been extensively discussed as potentially attractive indicators of elevated lung elastic fibre turnover and markers of the effectiveness of agents with the potential to reduce elastin breakdown. In the present manuscript, immunology-based and separation methods for the evaluation of DES and IDES are discussed, along with studies reporting increased levels of urine excretion in chronic obstructive pulmonary disease (COPD) patients with and without alpha(1)-antitrypsin deficiency. The results of the application of DES and IDES as surrogate end-points in early clinical trials in COPD are also reported. Finally, recent advances in detection techniques, including liquid chromatography tandem mass spectrometry and high-performance capillary electrophoresis with laser-induced fluorescence, are discussed. These techniques allow detection of DES and IDES at very low concentration in body fluids other than urine, such as plasma or sputum, and will help the understanding of whether DES and IDES are potentially useful in monitoring therapeutic intervention in COPD.
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              Differential expression of two tropoelastin genes in zebrafish.

              Elastin is the extracellular matrix protein responsible for properties of extensibility and elastic recoil in large blood vessels, lung and skin of most vertebrates. Elastin is synthesized as a monomer, tropoelastin, but is rapidly transformed into its final polymeric form in the extracellular matrix. Until recently information on sequence and developmental expression of tropoelastins was limited to mammalian and avian species. We have recently identified and characterized two expressed tropoelastin genes in zebrafish. This was the first example of a species with multiple tropoelastin genes, raising the possibility of differential expression and function of these tropoelastins in elastic tissues of the zebrafish. Here we have investigated the temporal expression and tissue distribution of the two tropoelastin genes in developing and adult zebrafish. Expression was detected early in skeletal cartilage structures of the head, in the developing outflow tract of the heart, including the bulbus arteriosus and the ventral aorta, and in the wall of the swim bladder. While the temporal pattern of expression was similar for both genes, the upregulation of eln2 was much stronger than that of eln1. In general, both genes were expressed and their gene products deposited in most of the elastic tissues examined, with the notable exception of the bulbus arteriosus in which eln2 expression and its gene product was predominant. This finding may represent a sub-specialization of eln2 to provide the unique architecture of elastin and the specific mechanical properties required by this organ.
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                Author and article information

                Journal
                Thorax
                Thorax
                thorax
                thoraxjnl
                Thorax
                BMJ Group (BMA House, Tavistock Square, London, WC1H 9JR )
                0040-6376
                1468-3296
                16 January 2012
                June 2012
                16 January 2012
                : 67
                : 6
                : 502-508
                Affiliations
                [1 ]Translational Medicine Research Collaboration, Dundee, UK
                [2 ]Clinical Research, Pfizer Worldwide Research & Development, Collegeville, Pennsylvania, USA
                [3 ]Medical Research Institute, School of Medicine, University of Dundee, Dundee, UK
                [4 ]Institute of Infection, Immunity & Inflammation, University of Glasgow, Glasgow, UK
                [5 ]MRC Hub for Trials Methodology Research, University of Edinburgh, Edinburgh, UK
                [6 ]Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK
                [7 ]Academic Department of Paediatrics, Brighton and Sussex Medical School, Brighton, UK
                Author notes
                Correspondence to Dr Jeffrey T-J Huang, Medical Research Institute, School of Medicine, University of Dundee, Dundee, DD1 9SY, UK; j.t.j.huang@ 123456dundee.ac.uk
                Article
                thoraxjnl-2011-200279
                10.1136/thoraxjnl-2011-200279
                3358730
                22250098
                7e705d1a-42b7-4643-a8da-f8c30c0866fe
                © 2012, Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

                History
                : 1 April 2011
                : 9 December 2011
                Categories
                Chronic Obstructive Pulmonary Disease
                1506
                Original article

                Surgery
                lung physiology,allergic lung disease,copd pharmacology,copd mechanisms,desmosine,allergic alveolitis,asthma,lung proteases,emphysema,asthma pharmacology,copd pathology,asthma guidelines,copd exacerbations,occupational lung disease,asthma mechanisms,asthma epidemiology,respiratory infection,tobacco and the lung,biomarker,copd

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