title: Reperfusion does not induce oxidative stress but sustained endoplasmic reticulum stress in livers of rats subjected to traumatic-hemorrhagic shock.
abstract: Oxidative stress is believed to accompany reperfusion and to mediate dysfunction of the liver after traumatic-hemorrhagic shock (THS). Recently, endoplasmic reticulum (ER) stress has been suggested as an additional factor. This study investigated whether reperfusion after THS leads to increased oxidative and/or ER stress in the liver. In a rat model, including laparotomy, bleeding until decompensation, followed by inadequate or adequate reperfusion phase, three time points were investigated: 40 min, 3 h, and 18 h after shock. The reactive oxygen and nitrogen species and its scavenging capacity (superoxide dismutase 2), the nitrotyrosine formation in proteins, and the lipid peroxidation together with the status of endogenous antioxidants (alpha-tocopherylquinone-alpha-tocopherol ratio) were investigated as markers for oxidative or nitrosylative stress. Mitochondrial function and cytochrome P450 isoform 1A1 activity were analyzed as representatives for hepatocyte function. Activation of the inositol-requiring enzyme 1/X-box binding protein pathway and up-regulation of the 78-kDa glucose-regulated protein were recorded as ER stress markers. Plasma levels of alanine aminotransferase and Bax/Bcl-XL messenger RNA (mRNA) ratio were used as indicators for hepatocyte damage and apoptosis induction. Oxidative or nitrosylative stress markers or representatives of hepatocyte function were unchanged during and short after reperfusion (40 min, 3 h after shock). In contrast, ER stress markers were elevated and paralleled those of hepatocyte damage. Incidence for sustained ER stress and subsequent apoptosis induction were found at 18 h after shock. Thus, THS or reperfusion induces early and persistent ER stress of the liver, independent of oxidative or nitrosylative stress. Although ER stress was not associated with depressed hepatocyte function, it may act as an early trigger of protracted cell death, thereby contributing to delayed organ failure after THS.
authors.affiliation: Department of Biomedical Sciences, University of Veterinary Medicine, Veterinaerplatz 1, 1210 Vienna, Austria. catharina.duvigneau@vu-wien.ac.at
authors.forename: Johanna Catharina
authors.initials: JC
authors.lastname: Duvigneau
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Kozlov
authors.forename: Clara
authors.initials: C
authors.lastname: Zifko
authors.forename: Astrid
authors.initials: A
authors.lastname: Postl
authors.forename: Romana T
authors.initials: RT
authors.lastname: Hartl
authors.forename: Ingrid
authors.initials: I
authors.lastname: Miller
authors.forename: Lars
authors.initials: L
authors.lastname: Gille
authors.forename: Katrin
authors.initials: K
authors.lastname: Staniek
authors.forename: Rudolf
authors.initials: R
authors.lastname: Moldzio
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Gregor
authors.forename: Susanne
authors.initials: S
authors.lastname: Haindl
authors.forename: Tricia
authors.initials: T
authors.lastname: Behling
authors.forename: Heinz
authors.initials: H
authors.lastname: Redl
authors.forename: Soheyl
authors.initials: S
authors.lastname: Bahrami
mesh_terms: D055371:Acute Lung Injury / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D026361:Reactive Nitrogen Species / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D015424:Reperfusion; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000503:physiopathology*; D012774:Shock, Traumatic / Q000503:physiopathology*; D014157:Transcription Factors / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D026361:Reactive Nitrogen Species; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP