Polyunsaturated fatty acid metabolism signature in ischemia differs from reperfusion in mouse intestine

PLoS One. 2013 Sep 20;8(9):e75581. doi: 10.1371/journal.pone.0075581. eCollection 2013.

Abstract

Polyunsaturated fatty acid (PUFA) metabolites are bioactive autoacoids that play an important role in the pathogenesis of a vast number of pathologies, including gut diseases. The induction and the resolution of inflammation depend on PUFA metabolic pathways that are favored. Therefore, understanding the profile of n-6 (eicosanoids)/n-3 (docosanoids) PUFA-derived metabolites appear to be as important as gene or protein array approaches, to uncover the molecules potentially implicated in inflammatory diseases. Using high sensitivity liquid chromatography tandem mass spectrometry, we characterized the tissue profile of PUFA metabolites in an experimental model of murine intestinal ischemia reperfusion. We identified temporal and quantitative differences in PUFA metabolite production, which correlated with inflammatory damage. Analysis revealed that early ischemia induces both pro-inflammatory and anti-inflammatory eicosanoid production. Primarily, LOX- (5/15/12/8-HETE, LTB4, LxA4) and CYP- (5, 6-EET) metabolites were produced upon ischemia, but also PGE3, and PDx. This suggests that different lipids simultaneously play a role in the induction and counterbalance of ischemic inflammatory response from its onset. COX-derived metabolites were more present from 2 to 5 hours after reperfusion, fitting with the concomitant inflammatory peaks. All metabolites were decreased 48 hours post-reperfusion except for to the pro-resolving RvE precursor 18-HEPE and the PPAR-γαμμα agonist, 15d-PGJ2. Data obtained through the pharmacological blockade of transient receptor potential vanilloid-4, which can be activated by 5, 6-EET, revealed that the endogenous activation of this receptor modulates post-ischemic intestinal inflammation. Altogether, these results demonstrate that different lipid pathways are involved in intestinal ischemia-reperfusion processes. Some metabolites, which expression is severely changed upon intestinal ischemia-reperfusion could provide novel targets and may facilitate the development of new pharmacological treatments.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromatography, Liquid
  • Cytokines / metabolism
  • Fatty Acids, Unsaturated / metabolism*
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Inflammation Mediators / metabolism
  • Intestine, Small / metabolism*
  • Intestine, Small / pathology
  • Ischemia / metabolism*
  • Ischemia / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Peroxidase / metabolism
  • Reperfusion Injury / metabolism*
  • Reperfusion Injury / pathology
  • Survival Rate
  • Tandem Mass Spectrometry

Substances

  • Cytokines
  • Fatty Acids, Unsaturated
  • Inflammation Mediators
  • Peroxidase

Grant support

This research was supported by the Agence Nationale de la Recherche (to NV and to NC) and by the region Midi-Pyrenees (to NV). TG was the recipient of an award from the 10th World Congress of Inflammation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.