Original article

Blood Transfusion - 5 2019 (September-October)

Selective organ ischaemia/reperfusion identifies liver as the key driver of the post-injury plasma metabolome derangements

Authors

Key words: metabolism, succinate, UHPLC-MS, trauma/haemorrhagic shock
Publication Date: 2018-12-13

Abstract

Background. Understanding the molecular mechanisms in perturbation of the metabolome following ischaemia and reperfusion is critical in developing novel therapeutic strategies to prevent the sequelae of post-injury shock. While the metabolic substrates fueling these alterations have been defined, the relative contribution of specific organs to the systemic metabolic reprogramming secondary to ischaemic or haemorrhagic hypoxia remains unclear.
Materials and methods. A porcine model of selected organ ischaemia was employed to investigate the relative contribution of liver, kidney, spleen and small bowel ischaemia/reperfusion to the plasma metabolic phenotype, as gleaned through ultra-high performance liquid chromatography-mass spectrometry-based metabolomics.
Results. Liver ischaemia/reperfusion promotes glycaemia, with increases in circulating carboxylic acid anions and purine oxidation metabolites, suggesting that this organ is the dominant contributor to the accumulation of these metabolites in response to ischaemic hypoxia. Succinate, in particular, accumulates selectively in response to the hepatic ischemia, with levels 6.5 times spleen, 8.2 times small bowel, and 6 times renal levels. Similar trends, but lower fold-change increase in comparison to baseline values, were observed upon ischaemia/reperfusion of kidney, spleen and small bowel.
Discussion. These observations suggest that the liver may play a critical role in mediating the accumulation of the same metabolites in response to haemorrhagic hypoxia, especially with respect to succinate, a metabolite that has been increasingly implicated in the coagulopathy and pro-inflammatory sequelae of ischaemic and haemorrhagic shock.

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Authors

Nathan Clendenen - Department of Anesthesiology, University of Colorado Denver, Aurora, CO

Geoffrey R. Nunns - Department of Surgery, University of Colorado Denver, Aurora, CO

Ernest E. Moore - Department of Surgery, University of Colorado Denver, Aurora, CO; Denver Health Medical Center, Denver, CO

Eduardo Gonzalez - Department of Surgery, University of Colorado Denver, Aurora, CO

Michael Chapman - Department of Surgery, University of Colorado Denver, Aurora, CO

Julie A. Reisz - Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO

Erik Peltz - Department of Surgery, University of Colorado Denver, Aurora, CO

Miguel Fragoso - Denver Health Medical Center, Denver, CO

Travis Nemkov - Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO

Matthew J. Wither - Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO

Angela Sauaia - Department of Surgery, University of Colorado Denver, Aurora, CO

Christopher C. Silliman - Bonfils Blood Center, Denver, CO, United States of America

Kirk Hansen - Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO

Anirban Banerjee - Department of Surgery, University of Colorado Denver, Aurora, CO

Angelo D'Alessandro - Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO

Hunter B. Moore - Department of Surgery, University of Colorado Denver, Aurora, CO

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