A Novel Role for Cytochrome P450 Epoxygenase Metabolites in Septic Shock

Abstract

This is the largest study describing the role of P450 epoxygenase metabolites in septic shock in humans and suggests a novel therapeutic target.

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 versus Norepinephrine as Initial Therapy in Septic Shock trial.

Setting: ICUs in the United Kingdom.

Participants: Adults recruited within 6 hours of onset of septic shock.

Main outcomes and measures: Oxylipin profiling was performed on 404 serum samples from 152 patients using liquid chromatography-mass spectrometry.

Results: Nonsurvivors were found to have higher levels of 14,15-dihydroxyeicosatrienoic acid (DHET) at baseline 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 Sequential Organ Failure Assessment scores that appeared to be accounted for predominantly by the liver component. Measurable 14,15-DHET showed positive correlation with bilirubin (r _s = 0.38; p < 0.001) and lactate (r _s = 0.27; p = 0.001).

Conclusions and relevance: 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.

Keywords: dihydroxyeicosatrienoic acid; eicosanoids; epoxyeicosatrienoic acid; oxylipins; sepsis; septic shock.