Chronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitis, small airway remodelling and emphysema. Emphysema is the destruction of alveolar structures, leading to enlarged airspaces and reduced surface area impairing the ability for gaseous exchange. To further understand the pathological mechanisms underlying progressive emphysema, we used MS-based approaches to quantify the lung, bronchoalveolar lavage fluid (BALF) and serum metabolome during emphysema progression in the established murine porcine pancreatic elastase (PPE) model on days 28, 56 and 161, compared with PBS controls. Partial least squares (PLS) analysis revealed greater changes in the metabolome of lung followed by BALF rather than serum during emphysema progression. Furthermore, we demonstrate for the first time that emphysema progression is associated with a reduction in lung-specific L-carnitine, a metabolite critical for transporting long-chain fatty acids into the mitochondria for their subsequent β-oxidation. In vitro, stimulation of the alveolar epithelial type II (ATII)-like LA4 cell line with L-carnitine diminished apoptosis induced by both PPE and H2O2. Moreover, PPE-treated mice demonstrated impaired lung function compared with PBS-treated controls (lung compliance; 0.067±0.008 ml/cmH20 compared with 0.035±0.005 ml/cmH20, P<0.0001), which improved following supplementation with L-carnitine (0.051±0.006, P<0.01) and was associated with a reduction in apoptosis. In summary, our results provide a new insight into the role of L-carnitine and, importantly, suggest therapeutic avenues for COPD.
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February 2016
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Image modified from a figure representing the 5 mechanisms of annexin A1 externalization through non-classic secretory pathways, discussed by Boudhraa et al in issue 130(4) of Clinical Science. For further details please see pp. 205–220. Image kindly provided by Z. Boudhraa, B. Bouchon, C. Viallard, M. D'Incan and F. Degoul.
Research Article|
January 14 2016
Metabolomics screening identifies reduced L-carnitine to be associated with progressive emphysema
Thomas M. Conlon;
Thomas M. Conlon
*Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
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Jörg Bartel;
Jörg Bartel
†Institute of Computational Biology, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
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Korbinian Ballweg;
Korbinian Ballweg
*Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
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Stefanie Günter;
Stefanie Günter
*Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
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Cornelia Prehn;
Cornelia Prehn
‡Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
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Jan Krumsiek;
Jan Krumsiek
†Institute of Computational Biology, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
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Silke Meiners;
Silke Meiners
*Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
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Fabian J. Theis;
Fabian J. Theis
†Institute of Computational Biology, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
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Jerzy Adamski;
Jerzy Adamski
‡Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
§German Center for Diabetes Research, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
║Chair for Experimental Genetics, Technical University of Munich, 85354 Freising-Weihenstephan, Germany
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Oliver Eickelberg;
Oliver Eickelberg
*Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
¶Klinikum der Universität München, Max-Lebsche-Platz 31, 81377 München, Germany
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Ali Önder Yildirim
*Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
Correspondence: Dr Ali Önder Yildirim (email [email protected]).
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Publisher: Portland Press Ltd
Received:
June 19 2015
Revision Received:
November 06 2015
Accepted:
November 12 2015
Accepted Manuscript online:
November 12 2015
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2016 Authors; published by Portland Press Limited
2016
Clin Sci (Lond) (2016) 130 (4): 273–287.
Article history
Received:
June 19 2015
Revision Received:
November 06 2015
Accepted:
November 12 2015
Accepted Manuscript online:
November 12 2015
Citation
Thomas M. Conlon, Jörg Bartel, Korbinian Ballweg, Stefanie Günter, Cornelia Prehn, Jan Krumsiek, Silke Meiners, Fabian J. Theis, Jerzy Adamski, Oliver Eickelberg, Ali Önder Yildirim; Metabolomics screening identifies reduced L-carnitine to be associated with progressive emphysema. Clin Sci (Lond) 1 February 2016; 130 (4): 273–287. doi: https://doi.org/10.1042/CS20150438
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