Succinate Activation of SUCNR1 Predisposes Severely Injured Patients to Neutrophil-mediated ARDS.

Autor:	Nunns GR; Department of Surgery, School of Medicine University of Colorado, Aurora, Colorado., Vigneshwar N; Department of Surgery, School of Medicine University of Colorado, Aurora, Colorado., Kelher MR; Department of Surgery, School of Medicine University of Colorado, Aurora, Colorado.; Department of Biochemistry and Molecular Genetics, School of Medicine University of Colorado, Aurora, Colorado., Stettler GR; Department of Surgery, School of Medicine University of Colorado, Aurora, Colorado., Gera L; Department of Pediatrics, School of Medicine, University of Colorado, Aurora, Colorado., Reisz JA; Department of Pediatrics, School of Medicine, University of Colorado, Aurora, Colorado., D'Alessandro A; Department of Pediatrics, School of Medicine, University of Colorado, Aurora, Colorado., Ryon J; Department of Surgery, School of Medicine University of Colorado, Aurora, Colorado., Hansen KC; Department of Pediatrics, School of Medicine, University of Colorado, Aurora, Colorado., Gamboni F; Department of Pediatrics, School of Medicine, University of Colorado, Aurora, Colorado., Moore EE; Department of Surgery, School of Medicine University of Colorado, Aurora, Colorado.; Department of Pathology, School of Medicine, University of Colorado, Aurora, Colorado., Peltz ED; Department of Surgery, School of Medicine University of Colorado, Aurora, Colorado., Cohen MJ; Department of Surgery, School of Medicine University of Colorado, Aurora, Colorado.; Department of Pathology, School of Medicine, University of Colorado, Aurora, Colorado., Jones KL; Department of Surgery, Denver Health Medical Center, Denver, Colorado; School of Public Health, University of Colorado, Aurora, Colorado., Sauaia A; Department of Pathology, School of Medicine, University of Colorado, Aurora, Colorado.; Vitalant Research Institute, Vitalant Denver, Denver, Colorado., Liang X; College of Arts and Letters, University of Notre Dame, Notre Dame, Illinois., Banerjee A; Department of Surgery, School of Medicine University of Colorado, Aurora, Colorado., Ghasabyan A; Department of Surgery, School of Medicine University of Colorado, Aurora, Colorado., Chandler JG; Department of Surgery, School of Medicine University of Colorado, Aurora, Colorado., Rodawig S; Department of Biochemistry and Molecular Genetics, School of Medicine University of Colorado, Aurora, Colorado.; College of Engineering, Georgia Institute of Technology, Atlanta., Jones C; Department of Biochemistry and Molecular Genetics, School of Medicine University of Colorado, Aurora, Colorado.; College of Engineering, Georgia Institute of Technology, Atlanta., Eitel A; Department of Surgery, School of Medicine University of Colorado, Aurora, Colorado., Hom P; Department of Surgery, School of Medicine University of Colorado, Aurora, Colorado., Silliman CC; Department of Surgery, School of Medicine University of Colorado, Aurora, Colorado.; Department of Biochemistry and Molecular Genetics, School of Medicine University of Colorado, Aurora, Colorado.; Department of Surgery, Denver Health Medical Center, Denver, Colorado; School of Public Health, University of Colorado, Aurora, Colorado.
Jazyk:	angličtina
Zdroj:	Annals of surgery [Ann Surg] 2022 Dec 01; Vol. 276 (6), pp. e944-e954. Date of Electronic Publication: 2020 Nov 18.
DOI:	10.1097/SLA.0000000000004644
Abstrakt:	Objectives: Identify the metabolites that are increased in the plasma of severely injured patients that developed ARDS versus severely injured patients that did not, and assay if these increased metabolites prime pulmonary sequestration of neutrophils (PMNs) and induce pulmonary sequestration in an animal model of ARDS. We hypothesize that metabolic derangement due to advanced shock in critically injured patients leads to the PMNs, which serves as the first event in the ARDS. Summary of Background Data: Intracellular metabolites accumulate in the plasma of severely injured patients. Methods: Untargeted metabolomics profiling of 67 critically injured patients was completed to establish a metabolic signature associated with ARDS development. Metabolites that significantly increased were assayed for PMN priming activity in vitro. The metabolites that primed PMNs were tested in a 2-event animal model of ARDS to identify a molecular link between circulating metabolites and clinical risk for ARDS. Results: After controlling for confounders, 4 metabolites significantly increased: creatine, dehydroascorbate, fumarate, and succinate in trauma patients who developed ARDS ( P < 0.05). Succinate alone primed the PMN oxidase in vitro at physiologically relevant levels. Intravenous succinate-induced PMN sequestration in the lung, a first event, and followed by intravenous lipopolysaccharide, a second event, resulted in ARDS in vivo requiring PMNs. SUCNR1 inhibition abrogated PMN priming, PMN sequestration, and ARDS. Conclusion: Significant increases in plasma succinate post-injury may serve as the first event in ARDS. Targeted inhibition of the SUCNR1 may decrease ARDS development from other disease states to prevent ARDS globally. Competing Interests: The authors declare no conflict of interest. (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)
Databáze:	MEDLINE
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