• Geoffrey R Nunns, Navin Vigneshwar, Marguerite R Kelher, Gregory R Stettler, Lajos Gera, Julie A Reisz, Angelo D'Alessandro, Joshua Ryon, Kirk C Hansen, Fabia Gamboni, Ernest E Moore, Erik D Peltz, Mitchell J Cohen, Kenneth L Jones, Angela Sauaia, Xiayuan Liang, Anirban Banerjee, Arsen Ghasabyan, James G Chandler, Sophia Rodawig, Carter Jones, Andrew Eitel, Patrick Hom, and Christopher C Silliman.
• Department of Surgery, School of Medicine University of Colorado, Aurora, Colorado.
• Ann. Surg. 2022 Dec 1; 276 (6): e944e954e944-e954.

ObjectivesIdentify 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.MethodsUntargeted 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.ResultsAfter 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.Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

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