NMR metabolomic analysis is a potentially useful technique for diagnosis of sepsis. The concentrations of metabolites involved in energy metabolism and in the inflammatory response change in this model of sepsis.
A significant glycolytic shift in the cells of the pulmonary vasculature and right ventricle during pulmonary arterial hypertension (PAH) has been recently described. Due to the late complications and devastating course of any variant of this disease, there is a great need for animal models that reproduce potential metabolic reprograming of PAH. Our objective is to study, in situ, the metabolic reprogramming in the lung and the right ventricle of a mouse model of PAH by metabolomic profiling and molecular imaging. PAH was induced by chronic hypoxia exposure plus treatment with SU5416, a vascular endothelial growth factor receptor inhibitor. Lung and right ventricle samples were analyzed by magnetic resonance spectroscopy. In vivo energy metabolism was studied by positron emission tomography. Our results show that metabolomic profiling of lung samples clearly identifies significant alterations in glycolytic pathways. We also confirmed an upregulation of glutamine metabolism and alterations in lipid metabolism. Furthermore, we identified alterations in glycine and choline metabolism in lung tissues. Metabolic reprograming was also confirmed in right ventricle samples. Lactate and alanine, endpoints of glycolytic oxidation, were found to have increased concentrations in mice with PAH. Glutamine and taurine concentrations were correlated to specific ventricle hypertrophy features. We demonstrated that most of the metabolic features that characterize human PAH were detected in a hypoxia plus SU5416 mouse model and it may become a valuable tool to test new targeting treatments of this severe disease.
The aim of this study is the identification of metabolomic biomarkers of sepsis and sepsis-induced acute kidney injury (AKI) in an experimental model. Pigs were anesthetized and monitored to measure mean arterial pressure (MAP), systemic blood flow (QT), mean pulmonary arterial pressure, renal artery blood flow (QRA), renal cortical blood flow (QRC), and urine output (UO). Sepsis was induced at t = 0 min by the administration of live Escherichia coli ( n = 6) or saline ( n = 8). At t = 300 min, animals were killed. Renal tissue, urine, and serum samples were analyzed by nuclear magnetic resonance (NMR) spectroscopy. Principal component analyses were performed on the processed NMR spectra to highlight kidney injury biomarkers. Sepsis was associated with decreased QT and MAP and decreased QRA, QRC, and UO. Creatinine serum concentration and neutrophil gelatinase-associated lipocalin (NGAL) serum and urine concentrations increased. NMR-based metabolomics analysis found metabolic differences between control and septic animals: 1) in kidney tissue, increased lactate and nicotinuric acid and decreased valine, aspartate, glucose, and threonine; 2) in urine, increased isovaleroglycine, aminoadipic acid, N-acetylglutamine, N-acetylaspartate, and ascorbic acid and decreased myoinositol and phenylacetylglycine; and 3) in serum, increased lactate, alanine, pyruvate, and glutamine and decreased valine, glucose, and betaine concentrations. The concentration of several metabolites altered in renal tissue and urine samples from septic animals showed a significant correlation with markers of AKI (i.e., creatinine and NGAL serum concentrations). NMR-based metabolomics is a potentially useful tool for biomarker identification of sepsis-induced AKI.
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