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A novel role for cytochrome P450 epoxygenase metabolites in septic shock

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Title: A novel role for cytochrome P450 epoxygenase metabolites in septic shock
Authors: Jones, T
Janani, L
Gordon, A
Al-Beidh, F
Antcliffe, D
Item Type: Journal Article
Abstract: Objectives Oxylipins are oxidative breakdown products of cell membrane fatty acids. Animal models have demonstrated that oxylipins generated by the P450 epoxygenase pathway may be implicated in septic shock pathology. However, these mediators are relatively unexplored in humans with septic shock. We aimed to determine if there were patterns of oxylipins that were associated with 28-day septic shock mortality and organ dysfunction. Design Retrospective analysis of samples collected during the Vasopressin vs. Norepinephrine as Initial Therapy in Septic Shock trial. Setting Intensive Care Units in the United Kingdom Patients Adults recruited within six hours of onset of septic shock. Interventions Trial interventions were not considered in this analysis. Measurements and Main Results Oxylipin profiling was performed on 404 serum samples from 152 patients using liquid chromatography-mass spectrometry. Non-survivors were found to have higher levels of 14,15-dihydroxyeicosatrienoic acid at baseline (DHET) than survivors (p=0.02). Patients with 14,15-DHET levels above the lower limit of quantification of the assay were more likely to die than patients with levels below this limit (Hazard Ratio 2.3, 95% CI 1.2-4.5). Patients with measurable 14,15-DHET had higher levels of organ dysfunction and fewer renal failure free days than those in whom it was unmeasurable. Considering samples collected over the first week of intensive care stay, measurable levels of DHET species were associated with higher daily SOFA scores which appeared to be accounted for predominantly by the liver component. Measurable 14,15-DHET showed positive correlation with bilirubin (rs=0.38, p<0.001) and lactate (rs=0.27, p=0.001). Conclusions The P450 epoxygenase-derived DHET species of oxylipins were associated with organ, particularly liver, dysfunction in septic shock and 14,15-DHET was associated with septic shock mortality. These results support further investigation into the role of the P450 epoxygenase-derived oxylipins in sepsis and suggest that this pathway may offer a novel therapeutic strategy in septic shock.
Date of Acceptance: 16-Dec-2021
URI: http://hdl.handle.net/10044/1/93525
DOI: 10.1097/CCE.0000000000000622
ISSN: 2639-8028
Publisher: Lippincott, Williams & Wilkins
Journal / Book Title: Critical Care Explorations
Volume: 4
Issue: 1
Copyright Statement: © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBYNC- ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
Sponsor/Funder: National Institute for Health Research
National Institute for Health Research
Imperial College Healthcare NHS Trust
NIHR -RfPB
NIHR
Funder's Grant Number: NIHR/CS/009/007
NIHR Fellowship
RDB17 79560
RD305
Keywords: dihydroxyeicosatrienoic acid
eicosanoids
epoxyeicosatrienoic acid
oxylipins
sepsis
septic shock
Publication Status: Published online
Appears in Collections:Department of Surgery and Cancer
Faculty of Medicine
School of Public Health



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