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Farnesoid X Receptor Activation Attenuates Intestinal Ischemia Reperfusion Injury in Rats
INTRODUCTION: The farnesoid X receptor (FXR) is abundantly expressed in the ileum, where it exerts an enteroprotective role as a key regulator of intestinal innate immunity and homeostasis, as shown in pre-clinical models of inflammatory bowel disease. Since intestinal ischemia reperfusion injury (I...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5218501/ https://www.ncbi.nlm.nih.gov/pubmed/28060943 http://dx.doi.org/10.1371/journal.pone.0169331 |
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author | Ceulemans, Laurens J. Verbeke, Len Decuypere, Jean-Paul Farré, Ricard De Hertogh, Gert Lenaerts, Kaatje Jochmans, Ina Monbaliu, Diethard Nevens, Frederik Tack, Jan Laleman, Wim Pirenne, Jacques |
author_facet | Ceulemans, Laurens J. Verbeke, Len Decuypere, Jean-Paul Farré, Ricard De Hertogh, Gert Lenaerts, Kaatje Jochmans, Ina Monbaliu, Diethard Nevens, Frederik Tack, Jan Laleman, Wim Pirenne, Jacques |
author_sort | Ceulemans, Laurens J. |
collection | PubMed |
description | INTRODUCTION: The farnesoid X receptor (FXR) is abundantly expressed in the ileum, where it exerts an enteroprotective role as a key regulator of intestinal innate immunity and homeostasis, as shown in pre-clinical models of inflammatory bowel disease. Since intestinal ischemia reperfusion injury (IRI) is characterized by hyperpermeability, bacterial translocation and inflammation, we aimed to investigate, for the first time, if the FXR-agonist obeticholic acid (OCA) could attenuate intestinal ischemia reperfusion injury. MATERIAL AND METHODS: In a validated rat model of intestinal IRI (laparotomy + temporary mesenteric artery clamping), 3 conditions were tested (n = 16/group): laparotomy only (sham group); ischemia 60min+ reperfusion 60min + vehicle pretreatment (IR group); ischemia 60min + reperfusion 60min + OCA pretreatment (IR+OCA group). Vehicle or OCA (INT-747, 2*30mg/kg) was administered by gavage 24h and 4h prior to IRI. The following end-points were analyzed: 7-day survival; biomarkers of enterocyte viability (L-lactate, I-FABP); histology (morphologic injury to villi/crypts and villus length); intestinal permeability (Ussing chamber); endotoxin translocation (Lipopolysaccharide assay); cytokines (IL-6, IL-1-β, TNFα, IFN-γ IL-10, IL-13); apoptosis (cleaved caspase-3); and autophagy (LC3, p62). RESULTS: It was found that intestinal IRI was associated with high mortality (90%); loss of intestinal integrity (structurally and functionally); increased endotoxin translocation and pro-inflammatory cytokine production; and inhibition of autophagy. Conversely, OCA-pretreatment improved 7-day survival up to 50% which was associated with prevention of epithelial injury, preserved intestinal architecture and permeability. Additionally, FXR-agonism led to decreased pro-inflammatory cytokine release and alleviated autophagy inhibition. CONCLUSION: Pretreatment with OCA, an FXR-agonist, improves survival in a rodent model of intestinal IRI, preserves the gut barrier function and suppresses inflammation. These results turn FXR into a promising target for various conditions associated with intestinal ischemia. |
format | Online Article Text |
id | pubmed-5218501 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-52185012017-01-19 Farnesoid X Receptor Activation Attenuates Intestinal Ischemia Reperfusion Injury in Rats Ceulemans, Laurens J. Verbeke, Len Decuypere, Jean-Paul Farré, Ricard De Hertogh, Gert Lenaerts, Kaatje Jochmans, Ina Monbaliu, Diethard Nevens, Frederik Tack, Jan Laleman, Wim Pirenne, Jacques PLoS One Research Article INTRODUCTION: The farnesoid X receptor (FXR) is abundantly expressed in the ileum, where it exerts an enteroprotective role as a key regulator of intestinal innate immunity and homeostasis, as shown in pre-clinical models of inflammatory bowel disease. Since intestinal ischemia reperfusion injury (IRI) is characterized by hyperpermeability, bacterial translocation and inflammation, we aimed to investigate, for the first time, if the FXR-agonist obeticholic acid (OCA) could attenuate intestinal ischemia reperfusion injury. MATERIAL AND METHODS: In a validated rat model of intestinal IRI (laparotomy + temporary mesenteric artery clamping), 3 conditions were tested (n = 16/group): laparotomy only (sham group); ischemia 60min+ reperfusion 60min + vehicle pretreatment (IR group); ischemia 60min + reperfusion 60min + OCA pretreatment (IR+OCA group). Vehicle or OCA (INT-747, 2*30mg/kg) was administered by gavage 24h and 4h prior to IRI. The following end-points were analyzed: 7-day survival; biomarkers of enterocyte viability (L-lactate, I-FABP); histology (morphologic injury to villi/crypts and villus length); intestinal permeability (Ussing chamber); endotoxin translocation (Lipopolysaccharide assay); cytokines (IL-6, IL-1-β, TNFα, IFN-γ IL-10, IL-13); apoptosis (cleaved caspase-3); and autophagy (LC3, p62). RESULTS: It was found that intestinal IRI was associated with high mortality (90%); loss of intestinal integrity (structurally and functionally); increased endotoxin translocation and pro-inflammatory cytokine production; and inhibition of autophagy. Conversely, OCA-pretreatment improved 7-day survival up to 50% which was associated with prevention of epithelial injury, preserved intestinal architecture and permeability. Additionally, FXR-agonism led to decreased pro-inflammatory cytokine release and alleviated autophagy inhibition. CONCLUSION: Pretreatment with OCA, an FXR-agonist, improves survival in a rodent model of intestinal IRI, preserves the gut barrier function and suppresses inflammation. These results turn FXR into a promising target for various conditions associated with intestinal ischemia. Public Library of Science 2017-01-06 /pmc/articles/PMC5218501/ /pubmed/28060943 http://dx.doi.org/10.1371/journal.pone.0169331 Text en © 2017 Ceulemans et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Ceulemans, Laurens J. Verbeke, Len Decuypere, Jean-Paul Farré, Ricard De Hertogh, Gert Lenaerts, Kaatje Jochmans, Ina Monbaliu, Diethard Nevens, Frederik Tack, Jan Laleman, Wim Pirenne, Jacques Farnesoid X Receptor Activation Attenuates Intestinal Ischemia Reperfusion Injury in Rats |
title | Farnesoid X Receptor Activation Attenuates Intestinal Ischemia Reperfusion Injury in Rats |
title_full | Farnesoid X Receptor Activation Attenuates Intestinal Ischemia Reperfusion Injury in Rats |
title_fullStr | Farnesoid X Receptor Activation Attenuates Intestinal Ischemia Reperfusion Injury in Rats |
title_full_unstemmed | Farnesoid X Receptor Activation Attenuates Intestinal Ischemia Reperfusion Injury in Rats |
title_short | Farnesoid X Receptor Activation Attenuates Intestinal Ischemia Reperfusion Injury in Rats |
title_sort | farnesoid x receptor activation attenuates intestinal ischemia reperfusion injury in rats |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5218501/ https://www.ncbi.nlm.nih.gov/pubmed/28060943 http://dx.doi.org/10.1371/journal.pone.0169331 |
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