Succinate Activation of SUCNR1 Predisposes Severely Injured Patients to Neutrophil-mediated ARDS.
Journal
Annals of surgery
ISSN: 1528-1140
Titre abrégé: Ann Surg
Pays: United States
ID NLM: 0372354
Informations de publication
Date de publication:
01 12 2022
01 12 2022
Historique:
pubmed:
21
11
2020
medline:
11
11
2022
entrez:
20
11
2020
Statut:
ppublish
Résumé
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. 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. 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.
Identifiants
pubmed: 33214479
pii: 00000658-202212000-00060
doi: 10.1097/SLA.0000000000004644
pmc: PMC8128932
mid: NIHMS1676438
doi:
Substances chimiques
Succinic Acid
AB6MNQ6J6L
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e944-e954Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL146442
Pays : United States
Organisme : NIGMS NIH HHS
ID : RM1 GM131968
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008315
Pays : United States
Organisme : NHLBI NIH HHS
ID : UM1 HL120877
Pays : United States
Organisme : NIGMS NIH HHS
ID : P50 GM049222
Pays : United States
Informations de copyright
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
Déclaration de conflit d'intérêts
The authors declare no conflict of interest.
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