title: Role of reactive oxygen species for hepatocellular injury and heme oxygenase-1 gene expression after hemorrhage and resuscitation.
abstract: Reactive oxygen species (ROS) generated during hemorrhage and subsequent resuscitation (H/R) may contribute to cellular injury but may also regulate an adaptive cellular response to stress. Heme oxygenase (HO)-1 has been recognized as an important stress-inducible gene conferring protection after H/R. The aim of this study was to determine the contribution of ROS to hepatocellular injury and to induction of HO-1 in parenchymal and nonparenchymal cells after H/R. Anesthetized Sprague-Dawley rats were subjected to reversible H/R with or without coadministration of the potent antioxidant Trolox (6 mg/kg body wt). HO-1 gene expression was determined at baseline, at the end of hemorrhagic hypotension, and after 1, 3, and 5 h of resuscitation on the messenger ribonucleic acid (mRNA) and protein level. Assessment of hepatocellular injury by alpha-glutathione-S-transferase serum levels showed a significant increase after H/R that was attenuated by Trolox (sham: 38 (26-42); H/R: 286 (150-696); Trolox: 14 (2-227) microg/L; median (25th/75th percentile) P<0.05). Injury correlated with induction of HO-1 mRNA (r2 = 0.97) on the whole organ level and with the expression pattern of HO-1-immunoreactive protein in pericentral hepatocytes after H/R. Trolox attenuated H/R-induced increase of HO-1 in hepatocytes. In contrast, nonparenchymal cells showed high constitutive levels of HO-1 mRNA and protein that were increased by sham operation and H/R to a similar extent. HO-1 steady-state transcripts in nonparenchymal cells were not modulated by Trolox. These results suggest a differential regulation of HO-1 gene expression in hepatocytes and nonparenchymal cells. ROS formation seems to contribute to early hepatocellular injury but also serves as an important trigger for HO-1 gene expression in parenchymal cells, which confers delayed protection after H/R.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, University of the Saarland, Homburg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Rensing
authors.forename: I
authors.initials: I
authors.lastname: Bauer
authors.forename: I
authors.initials: I
authors.lastname: Peters
authors.forename: T
authors.initials: T
authors.lastname: Wein
authors.forename: M
authors.initials: M
authors.lastname: Silomon
authors.forename: H
authors.initials: H
authors.lastname: Jaeschke
authors.forename: M
authors.initials: M
authors.lastname: Bauer
mesh_terms: D000818:Animals; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics*; D051547:Heme Oxygenase-1; D006439:Hemodynamics / Q000502:physiology; D006470:Hemorrhage / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012151:Resuscitation
chemical_list: D017382:Reactive Oxygen Species; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1