title: Hepatocellular heme oxygenase-1: a potential mechanism of erythropoietin-mediated protection after liver ischemia-reperfusion injury.
abstract: Hepatic ischemia-reperfusion (IR) results in progressive injury; initiated by oxidative stress during ischemia and compounded by cytokine-mediated inflammation during reperfusion. Recovery requires strict regulation of these events. Recombinant human erythropoietin (rhEPO) is thought to mitigate hepatocellular IR injury by altering the nonparenchymal liver microenvironment. This study sought to identify additional mechanisms whereby rhEPO is protective after liver IR injury. Mice were treated with rhEPO (4 units/g s.c.) at the onset of partial liver ischemia and assessed for transaminase and histologic injury at intervals after reperfusion. Induction of cytokines, activation of signal transducers and activators of transcription (STATs), suppressors of cytokine signaling (Socs1, Socs3, Cis), caspase-3 activation, and heme oxygenase-1 (HO-1) expression were assessed in postischemic liver. Effects of rhEPO stimulation were further characterized in whole-liver lysates from mice undergoing rhEPO injection alone and in cultured AML-12 hepatocytes. Recombinant human erythropoietin treatment at the onset of severe (90 min) hepatic IR confirmed commensurate biochemical and histological protection without affecting tissue cytokine levels. Although Socs3 and STAT5 activation were induced in normal liver after in vivo rhEPO injection, this treatment did not augment expression beyond that seen with IR alone, and neither was induced in cultured hepatocytes treated with rhEPO. Recombinant human erythropoietin inhibited caspase-3 activation in nonparenchymal cells, whereas hepatocellular HO-1 was rapidly induced both in vivo and in vitro with rhEPO treatment. These data suggest HO-1 as a potent mechanism of rhEPO-mediated protection after liver IR, which involves both direct hepatocellular and nonparenchymal mechanisms.
authors.affiliation: *Department of Surgery, Veterans Administration; and Departments of †Surgery, ‡Pathology, and §Comparative Medicine, University of Washington, Seattle, Washington.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Riehle
authors.forename: Vicki
authors.initials: V
authors.lastname: Hoagland
authors.forename: Whitney
authors.initials: W
authors.lastname: Benz
authors.forename: Jean S
authors.initials: JS
authors.lastname: Campbell
authors.forename: Denny H
authors.initials: DH
authors.lastname: Liggitt
authors.forename: Lorrie A
authors.initials: LA
authors.lastname: Langdale
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004921:Erythropoietin / Q000494:pharmacology / Q000627:therapeutic use*; D051547:Heme Oxygenase-1 / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008565:Membrane Proteins; D011994:Recombinant Proteins; D050791:STAT Transcription Factors; D050826:Suppressor of Cytokine Signaling Proteins; D004921:Erythropoietin; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse