title: HbG200-mediated preinduction of heme oxygenase-1 improves bile flow and ameliorates pericentral downregulation of Bsep and Mrp2 following experimental liver ischemia and reperfusion.
abstract: We studied the downregulation of hepatobiliary transport systems and the effect of pharmacological heme oxygenase-1 (HO-1) preinduction by Hemoglobin-Glutamer 200 (HbG200) in cold ischemia-reperfused rat liver (I/R). Cold I/R reduced bile flow in the reperfusion period from 3.10±0.10 ml/3 h to 0.54±0.20 ml/3 h (p<0.05) and biliary taurocholate excretion from 45.9±13.81 μmol/3 h to 1.87±0.46 μmol/3 h (p<0.05). Mrp2, Bsep and Ntcp peak immunofluorescence in pericentral hepatocytes decreased to 79.0±2.6% (p<0.001), 80.6±8.4% (p<0.05) and 65.8±5.0% (p<0.01), respectively. Pre-induction of HO-1 by HbG200 was largely confined to pericentral hepatocytes. HO-1 induction attenuated the decreased bile flow (0.91±0.16 ml/3 h, p<0.05) and canalicular taurocholate secretion (4.33±1.71 μmol/3 h, p<0.05). Bsep and Mrp2 peak immunofluorescence in pericentral hepatocytes was largely restored. Activation of JNK and Fyn by cold I/R was significantly attenuated by HO-1. Inhibiting HO activity by tin protoporphyrin IX after HbG200 administration reversed the effect on bile flow and canalicular transporter expression. In conclusion, pericentral downregulation of Bsep and Mrp2 following cold I/R is ameliorated by inducing HO-1 and was associated with diminished hepatocellular JNK and Fyn signaling. HO-1 may serve as a therapeutic target to attenuate hepatocellular cholestasis following I/R injury.
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, Germany. Markus.Donner@med.uni-duesseldorf.de
authors.forename: Markus G
authors.initials: MG
authors.lastname: Donner
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Topp
authors.forename: Patricia
authors.initials: P
authors.lastname: Cebula
authors.forename: Anna
authors.initials: A
authors.lastname: Krienen
authors.forename: Thor
authors.initials: T
authors.lastname: Gehrmann
authors.forename: Annika
authors.initials: A
authors.lastname: Sommerfeld
authors.forename: Roland
authors.initials: R
authors.lastname: Reinehr
authors.forename: Arne
authors.initials: A
authors.lastname: Macher
authors.forename: Diran
authors.initials: D
authors.lastname: Herebian
authors.forename: Ertan
authors.initials: E
authors.lastname: Mayatepek
authors.forename: Benedikt H
authors.initials: BH
authors.lastname: Pannen
authors.forename: Wolfram T
authors.initials: WT
authors.lastname: Knoefel
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001646:Bile / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism*; D007511:Ischemia / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000201:enzymology / Q000378:metabolism*
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; C490548:Abcb11 protein, rat; C423013:Abcc2 protein, rat; D006454:Hemoglobins; C402601:hemoglobin glutamer-200; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat