Polyunsaturated Fatty Acid Metabolism Signature in Ischemia Differs from Reperfusion in Mouse Intestine

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.

Alpha-2-macroglobulin loaded microcapsules enhance human leukocyte functions and innate immune response

“…Quantification of Protectin DX (PDX), Leukotriene B 4 (LTB 4 ), Prostaglandin E 2 (PGE 2 ), 5-Hydroxy Eicosatetraenoic acid (5-HETE), 15-Hydroxy Eicosatetraenoic acid (15-HETE), 14-Hydroxy Docosahexaenoic Acid (14-HDoHE), 17-Hydroxy Docosahexaenoic Acid (17-HDoHE), and 18-Hydroxy Eicosapentaenoic acid (18-HEPE) in peritoneal lavages, after phagocytosis assay, was achieved by LC–MS/MS measurements as described [15] . For each standard, calibration curves were built using 10 solutions at concentration ranging from 0.95 ng/ml to 500 ng/ml.…”

Protective effects of n‐6 fatty acids‐enriched diet on intestinal ischaemia/reperfusion injury involve lipoxin A4 and its receptor

“…The recent development of new techniques of high sensitivity LC‐MS/MS allows a better comprehension of disease‐associated lipidic metaboloma detecting simultaneously the presence of a number of PUFA metabolites in tissues. In our previous study, we characterized, by LC‐MS/MS, the tissue profile of n‐6 and n‐3 PUFA metabolites in an experimental model of murine intestinal I/R (Gobbetti et al ., ). We identified temporal and quantitative differences in n‐3 and n‐6 PUFA metabolite production, which correlated with inflammatory damage.…”

Association between serum n-3 polyunsaturated fatty acids and quadriceps weakness immediately after total knee arthroplasty

“…It has been observed that n-3 PUFA metabolites peak approximately 24 hours after IR [26]. In addition, the increased amount of n-3 PUFA after IR is enhanced by n-3 PUFA supplementation taken prior to IR, contributing to the resolution of IR-induced acute inflammation [19].…”