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dc.contributor.authorWieser, Verenaen
dc.contributor.authorAdolph, Timon Een
dc.contributor.authorEnrich, Barbaraen
dc.contributor.authorKuliopulos, Athanen
dc.contributor.authorKaser, Arthuren
dc.contributor.authorTilg, Herberten
dc.contributor.authorKaneider, Nicole Cen
dc.date.accessioned2015-12-08T16:42:31Z
dc.date.available2015-12-08T16:42:31Z
dc.date.issued2016-02-08en
dc.identifier.citationWeiser et al. Gut (2016). doi: 10.1136/gutjnl-2015-310344en
dc.identifier.issn0017-5749
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/252901
dc.description.abstractObjective Alcoholic steatohepatitis is a life-threatening condition with short-term mortality up to 40%. It features hepatic neutrophil infiltration and blood neutrophilia, and may evolve from ethanol-induced breakdown of the enteric barrier and consequent bacteraemia. Signalling through CXCR1/2 G-protein-coupled-receptors (GPCRs), the interleukin (IL)-8 receptors, is critical for the recruitment and activation of neutrophils. We have developed short lipopeptides (pepducins), which inhibit post-ligand GPCR activation precisely targeting individual GPCRs. Design Experimental alcoholic liver disease was induced by administering alcohol and a Lieber–DeCarli high-fat diet. CXCR1/2 GPCRs were blocked via pepducins either from onset of the experiment or after disease was fully established. Hepatic inflammatory infiltration, hepatocyte lipid accumulation and overall survival were assessed as primary outcome parameters. Neutrophil activation was assessed by myeloperoxidase activity and liver cell damage by aspartate aminotransferase and alanine aminotransferase plasma levels. Chemotaxis assays were performed to identify chemoattractant signals derived from alcohol-exposed hepatocytes. Results Here, we show that experimental alcoholic liver disease is driven by CXCR1/2-dependent activation of neutrophils. CXCR1/2-specific pepducins not only protected mice from liver inflammation, weight loss and mortality associated with experimental alcoholic liver disease, but therapeutic administration cured disease and prevented further mortality in fully established disease. Hepatic neutrophil infiltration and triglyceride accumulation was abrogated by CXCR1/2 blockade. Moreover, CXCL-1 plasma levels were decreased with the pepducin therapy as was the transcription of hepatic IL-1β mRNA. Conclusions We propose that high circulating IL-8 in human alcoholic hepatitis may cause pathogenic overzealous neutrophil activation, and therapeutic blockade via pepducins merits clinical study.
dc.description.sponsorshipWellcome Trust Career Re-entry Fellowship (103077/Z/13/Z) to NCK, Christian Doppler Research Society to HT and European Research Council (FP7/2007- 2013) to AK
dc.languageEnglishen
dc.language.isoenen
dc.publisherBMJ Group
dc.rightsAttribution 2.0 UK: England & Wales
dc.rights.urihttp://creativecommons.org/licenses/by/2.0/uk/
dc.subjectCXCR2en
dc.subjectalcoholic liver injuryen
dc.subjectpepducinen
dc.subjectCXCL1en
dc.subjectrecepotor modulationen
dc.titleReversal of murine alcoholic steatohepatitis by pepducin-based functional blockade of interleukin-8 receptorsen
dc.typeArticle
dc.description.versionThis is the final version of the article. It first appeared from the BMJ Group via http://dx.doi.org/10.1136/gutjnl-2015-310344en
prism.publicationDate2016en
prism.publicationNameGuten
dcterms.dateAccepted2015-12-07en
rioxxterms.versionofrecord10.1136/gutjnl-2015-310344en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2016-02-08en
dc.identifier.eissn1468-3288
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (103077/Z/13/Z)
cam.orpheus.successThu Jan 30 12:55:30 GMT 2020 - The item has an open VoR version.*
rioxxterms.freetoread.startdate2300-01-01


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Attribution 2.0 UK: England & Wales
Except where otherwise noted, this item's licence is described as Attribution 2.0 UK: England & Wales