Severity-Dependent Long-Term Post-Traumatic Changes in the Circulating Oxylipin Profile

Abstract

Trauma causes the breakdown of membrane phospholipids and the subsequent degradation of the released polyunsaturated fatty acids (PUFAs) to partially bioactive oxylipins. Here, we screened for circulating PUFAs and oxylipins in patients (n = 34) differing from those of uninjured controls (n = 25) and analyzed their diagnostic potential. Patients were followed up for 1 to 240 h after minor/moderate, severe, and very severe injuries. Of the targeted oxylipins, 13 out of 80 (13/80) were detected in almost all patients and controls. Injury caused a long-term decrease in 9- and 13-hydroxyoctadecadienoic acids and in several dihydroxyeicosatetraenoic acids, the stable derivatives of bioactive anti-inflammatory epoxyeicosatrienoic acids, compared to controls. Frequently, these oxylipins correlated inversely to injury severity, days in the intensive care unit and hospital, and/or procalcitonin and pro-inflammatory cytokine levels 48 up to 240 h after trauma. Notably, 20/80 oxylipins were detected in some patients but not or less often in controls. Many of these oxylipins increased transiently immediately after injury. Their level is partly correlated with adverse clinical parameters at this early time point. The circulating oxylipidome was markedly affected by trauma. Several oxylipins showed injury-dependent alterations at different time points in the post-traumatic course.

Keywords: arachidonic acid; injury; oxylipin; polytrauma; polyunsaturated fatty acid.

Figure 1

Post-traumatic time course of circulating PUFAs. (A) Comparison of the PUFA levels between controls and all patients (one-way ANOVA). (B) Comparison of the PUFA levels between patient groups (mixed effect model). (C) Ratio of the concentration of ω6 PUFA/ω PUFA in controls and all patients (one-way ANOVA). * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001.

Figure 2

PUFA-derived oxylipins detectable in injured patients PUFAs are encircled. The metabolites are arranged mainly according to the pathway in which they are generated (cyclooxygenases, COX; lipoxygenases, LOX; cytochrome P450 mixed function oxidase enzymes, CYP; nonenzymatic free-radical mechanisms, non). Metabolites in black: present in almost all patients, metabolites in blue: present in some patients; metabolites in grey: not detected at any time point in patients. *, **, *** these PUFAs/metabolites were quantified together.

Figure 3

Comparison of the frequencies of controls and patients for those oxylipins that were detected in some (less than 90%) of the patients at any time point. At each time point after trauma the frequency (%) of controls (ctr), all patients, and of the 3 patient groups are indicated. * Only significant differences between controls and all patients at 1 h after injury are noted (Fisher’s exact test, p-value). Oxylipins present at each time point in almost all patients are not included in this figure.

Figure 4

Post-traumatic time course of circulating LA-derived 9- and 13-HODE (A) and ARA-derived DHETs (B). Comparison between controls and all patients: one-way ANOVA; comparison between the indicated patient groups: mixed effect model; * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001.

Figure 5

Correlation of patient’s clinical parameters with PUFA and oxylipin levels 1 to 240 h after trauma. In the correlation matrix, the square color indicates the magnitude of correlation (Spearman). Only oxylipins with significant correlations are shown. Oxylipins with less than 50% of the patients with detected values at the indicated time point were not analyzed (grey lines in the respective fields). In this analysis, values not detected in a present sample were not imputed.