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Conlon, T.M. ; Bartel, J. ; Ballweg, K. ; Günter, S. ; Prehn, C. ; Krumsiek, J. ; Meiners, S. ; Theis, F.J. ; Adamski, J. ; Eickelberg, O. ; Yildirim, A.Ö.

Metabolomics screening identifies reduced L-carnitine to be associated with progressive emphysema.

Clin. Sci. 130, 273-287 (2016)

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Chronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitis, small airway remodeling 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 mass spectrometry-based approaches to quantitate 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 to PBS controls. Partial Least Square 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 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 to PBS treated controls (lung compliance; 0.067±0.008ml/cmH20 vs 0.035±0.005ml/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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