title: Metabolomics screening identifies reduced L-carnitine to be associated with progressive emphysema.
abstract: 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.
authors.affiliation: 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.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Conlon
authors.affiliation: Institute of Computational Biology, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Bartel
authors.affiliation: 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.
authors.forename: Korbinian
authors.initials: K
authors.lastname: Ballweg
authors.affiliation: 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.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Günter
authors.affiliation: Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Prehn
authors.affiliation: Institute of Computational Biology, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Krumsiek
authors.affiliation: 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.
authors.forename: Silke
authors.initials: S
authors.lastname: Meiners
authors.affiliation: Institute of Computational Biology, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: Fabian J
authors.initials: FJ
authors.lastname: Theis
authors.affiliation: 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.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
authors.affiliation: 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.
authors.forename: Oliver
authors.initials: O
authors.lastname: Eickelberg
authors.affiliation: 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 oender.yildirim@helmholtz-muenchen.de.
authors.forename: Ali Önder
authors.initials: AÖ
authors.lastname: Yildirim
mesh_terms: D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002331:Carnitine / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D004195:Disease Models, Animal; D015536:Down-Regulation; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D016018:Least-Squares Analysis; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008170:Lung Compliance; D013058:Mass Spectrometry; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D008810:Mice, Inbred C57BL; D010196:Pancreatic Elastase; D011656:Pulmonary Emphysema / Q000097:blood / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors
chemical_list: D015415:Biomarkers; D013481:Superoxides; D010196:Pancreatic Elastase; D002331:Carnitine
keywords: apoptosis; biomarkers; chronic obstructive pulmonary disease (COPD); metabolome