RESUMO
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.
Assuntos
Fígado/metabolismo , Metaboloma , Traumatismo por Reperfusão/metabolismo , Animais , Fígado/patologia , Masculino , Oxirredução , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/patologia , Ácido Succínico/sangue , Ácido Succínico/metabolismo , SuínosRESUMO
BACKGROUND: Trauma is the leading cause of mortality under the age of 40 years. Recent observations on metabolic reprogramming during hypoxia and ischemia indicate that hypoxic mitochondrial uncoupling promotes the generation of succinate, which in turn mediates reperfusion injury and inflammatory sequelae upon reoxygenation. Plasma levels of succinate significantly increase in response to trauma and hemorrhage in experimental models and clinical samples, suggesting that succinate may represent a candidate marker of systemic perfusion in trauma. METHODS: Quantitative mass spectrometry-based metabolomics was used to quantify succinate and lactate in 595 plasma samples from severely injured patients enrolled at the Denver Health Medical Center, a Level I trauma center in Denver, Colorado. RESULTS: A total of 95 severely injured patients were sampled for up to 10 time points (595 total samples), from field blood to 7 days postinjury. Results indicate that plasma levels of succinate increased up to 25.9-fold in deceased patients versus the median of the surviving patients (p = 2.75e-100; receiver operating characteristic area under the curve, 0.911). On the other hand, only 2.4-fold changes increases in lactate were observed (p = 5.8e-21; area under the curve, 0.874). CONCLUSION: Succinate represents a uniquely sensitive biomarker of postshock metabolic derangement and may be an important mediator of sequelae. LEVEL OF EVIDENCE: Prognostic study, level III.