Lipid mediators derived from arachidonic acid and other precursor polyunsaturated fatty acids, collectively known as oxylipins, are metabolized along different distinct pathways and play important roles in the modulation of inflammation.1,2  Blood oxylipin profiles have been shown to correlate with the survival and development of acute respiratory distress syndrome in patients with sepsis or septic shock.3–5  We aimed to explore serum oxylipin profiles using liquid chromatography coupled to tandem mass spectrometry quantification as previously described6  during the first day of mechanical ventilation in the intensive care unit (ICU). Previously, we have noted elevated plasma concentrations of thromboxane B2, prostaglandin E2, 15-hydroxyeicosatetraenoate, and 11-hydroxyeicosatetraenoate in response to experimental hyperinflation lung injury7  in a large animal model. Based on this, we hypothesized that these metabolites would increase in response to mechanical ventilation in patients. Decreases in a subset of oxylipins have been observed, however, in relation to critical illness.8 

With ethical approval (Linköping, 2010/427-31 and 2018/16-32), all consecutive adult patients (n = 589) with indwelling arterial cannulas after admission to the ICU in Östersund Hospital, Sweden, between February 1, 2012, and January 31, 2013, were screened for inclusion in the study cohort unless transferred from another ICU.9  Blood samples were collected in EDTA tubes during 2012 and 2013. Within 30 min, the samples were spun for 10 min at 2,000g. The plasma was then frozen in aliquots to –70°C, then unfrozen, and analyzed in 2021. In the cohort,9  147 cases with complete data and samples were identified. Of these, 22 men and 3 women with mixed diagnoses were intubated and included in the study with case characteristics in Supplemental Table 1 (https://links.lww.com/ALN/D48). Samples were collected at the time of intubation and on the following morning.

Of 67 oxylipins in the analysis panel, 57 were detected (fig. 1). Of these, 23 were above the limit of quantification in at least 80% of the samples, which was the predetermined limit for oxylipins to be included in formal analysis. The detected metabolites included all major metabolic pathways, cyclooxygenase, lipoxygenase, and cytochrome P450. Complete oxylipin analysis results are given in Supplemental Table 1 (https://links.lww.com/ALN/D48). None of the oxylipins was assumed to be normally distributed. After log transformation, 19 oxylipins were deemed to be normally distributed and were thus evaluated with paired Student’s t test and Hedges’ g. The remaining four oxylipins were compared using the Wilcoxon signed-rank test (table 1). Correction for multiple comparisons was performed with the false discovery rate set to 10% for α = 0.05, yielding a significance level at P < 0.001.

Table 1.

Oxylipins with More Than 80% of Observations above the Limit of Quantification

Oxylipins with More Than 80% of Observations above the Limit of Quantification
Oxylipins with More Than 80% of Observations above the Limit of Quantification
Fig. 1.

Investigated oxylipins grouped according to precursor polyunsaturated fatty acid as well as metabolic pathway. Number of samples above the limit of detection is shown as N. Median (interquartile range) for both sample times together (nanomoles per liter) is shown for metabolites detected in 10% or more of samples. Bold font indicates metabolite included in formal analysis. Italic font indicates uncertain values due to multiple peaks.

Fig. 1.

Investigated oxylipins grouped according to precursor polyunsaturated fatty acid as well as metabolic pathway. Number of samples above the limit of detection is shown as N. Median (interquartile range) for both sample times together (nanomoles per liter) is shown for metabolites detected in 10% or more of samples. Bold font indicates metabolite included in formal analysis. Italic font indicates uncertain values due to multiple peaks.

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For samples after up to 1 day of mechanical ventilation (after intubation), 12-hydroxyeicosatetraenoate showed significantly lower plasma concentrations, and no oxylipin increased (table 1).

The current study supports decreased concentrations of 12-hydroxyeicosatetraenoate in response to mechanical ventilation in contrast to previous reports of 12-hydroxyeicosatetraenoate being considered a proinflammatory mediator.10  Thromboxane B2 and prostaglandin E2 were not among the oxylipins with sufficient detection frequencies for formal analysis. In contrast to the main hypothesis, 15-hydroxyeicosatetraenoate and 11-hydroxyeicosatetraenoate did not increase during the first day of mechanical ventilation.

In conclusion, this study demonstrates that several oxylipins may be detected in intensive care patients and that plasma concentration of 12-hydroxyeicosatetraenoate decreases during the first day of mechanical ventilation in the ICU.

This work was supported by the Swedish Research Council VR (2014–6354; Stockholm, Sweden), Marie Sklodowska Curie Actions, Cofund, Project INCA 600398 (European Union), Åke Wiberg’s Foundation (M17-0219; Stockholm, Sweden), research funding from Umeå University (Umeå, Sweden), and the ALF-LUA cooperative Region Västerbotten-Umeå University (Umeå, Sweden) intramural research funding system.

Dr. Larsson has received speaker fees for lecturing in clinical symposia sponsored by Dräger Medical (Götesburg, Sweden), and not related to this specific topic. We do not consider this relevant to the report. The authors declare no other conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Supplemental Digital Content, https://links.lww.com/ALN/D48

1.
Shearer
G
,
Walker
R
:
An overview of the biologic effects of omega-6 oxylipins in humans.
Prostaglandins Leukot Essent Fatty Acids
.
2018
;
137
:
26
38
2.
Morisseau
C
,
Hammock
BD
:
Impact of soluble epoxide hydrolase and epoxyeicosanoids on human health.
Annu Rev Pharmacol Toxicol
.
2013
;
53
:
37
58
3.
Dalli
J
,
Colas
RA
,
Quintana
C
,
Barragan-Bradford
D
,
Hurwitz
S
,
Levy
BD
,
Choi
AM
,
Serhan
CN
,
Baron
RM
:
Human sepsis eicosanoid and proresolving lipid mediator temporal profiles: correlations with survival and clinical outcomes.
Crit Care Med
.
2017
;
45
:
58
68
4.
Hamaguchi
M
,
Wu
HN
,
Tanaka
M
,
Tsuda
N
,
Tantengco
OAG
,
Matsushima
T
,
Nakao
T
,
Ishibe
T
,
Sakata
I
,
Yanagihara
I
:
A case series of the dynamics of lipid mediators in patients with sepsis.
Acute Med Surg
.
2019
;
6
:
413
8
5.
Jones
TN
,
Janani
L
,
Gordon
AC
,
Al-Beidh
F
,
Antcliffe
DB
:
A novel role for cytochrome P450 epoxygenase metabolites in septic shock.
Crit Care Explor
.
2022
;
4
:
e0622
6.
Späth
J
,
Brodin
T
,
Cerveny
D
,
Lindberg
R
,
Fick
J
,
Nording
M
:
Oxylipins at intermediate larval stages of damselfly Coenagrion hastulatum as biochemical biomarkers for anthropogenic pollution.
Environ Sci Pollut Res Int
.
2021
;
28
:
27629
38
7.
Larsson
N
,
Lehtipalo
S
,
Gouveia-Figueira
S
,
Claesson
J
,
Pourazar
J
,
Isaksson Mettävainio
M
,
Haney
M
,
Nording
ML
:
Plasma and bronchoalveolar lavage fluid oxylipin levels in experimental porcine lung injury.
Prostaglandins Other Lipid Mediat
.
2022
;
160
:
106636
8.
Biagini
D
,
Franzini
M
,
Oliveri
P
,
Lomonaco
T
,
Ghimenti
S
,
Bonini
A
,
Vivaldi
F
,
Macera
L
,
Balas
L
,
Durand
T
,
Oger
C
,
Galano
J-M
,
Maggi
F
,
Celi
A
,
Paolicchi
A
,
Di Francesco
F
:
MS-based targeted profiling of oxylipins in COVID-19: A new insight into inflammation regulation.
Free Radical Biol Med
.
2022
;
180
:
236
43
9.
Tydén
J
,
Herwald
H
,
Sjöberg
F
,
Johansson
J
:
Increased plasma levels of heparin-binding protein on admission to intensive care are associated with respiratory and circulatory failure.
PLoS One
.
2016
;
11
:
e0152035
10.
Kulkarni
A
,
Nadler
JL
,
Mirmira
RG
,
Casimiro
I
:
Regulation of tissue inflammation by 12-lipoxygenases.
Biomolecules
.
2021
;
11
:
717