title: Induction of heme oxygenase 1 prevents progression of liver fibrosis in Mdr2 knockout mice.
abstract: Induction or overexpression of the heme-degrading enzyme, heme oxygenase 1 (HO-1), has been shown to protect mice from liver damage induced by acute inflammation. We have investigated the effects of HO-1 induction in a mouse model of chronic liver inflammation and fibrogenesis with progression to hepatocellular carcinoma (HCC) (Mdr2ko; FVB.129P2-Abcb4(tm1Bor)). HO-1 was induced in vivo by treatment with cobalt protoporphyrin IX, starting at week 5 or 12 of mice lifespan, and continued for 7 weeks. Our results showed that HO-1 induction reduced liver damage and chronic inflammation by regulating immune cell infiltration or proliferation as well as tumor necrosis factor receptor signaling. Fibrosis progression was significantly reduced by HO-1 induction in mice with mild, as well as established, portal and lobular fibrosis. HO-1 induction significantly suppressed hepatic stellate cell activation. During established fibrosis, HO-1 induction was able to revert portal inflammation and fibrosis below levels observed at the start of treatment. Moreover, hepatocellular proliferation and signs of dysplasia were decreased after HO-1 induction.
  
  
  CONCLUSIONS
  Induction of HO-1 interferes with chronic inflammation and fibrogenesis and, in consequence, might delay progression to HCC.
authors.affiliation: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Roja
authors.initials: R
authors.lastname: Barikbin
authors.forename: Daniel
authors.initials: D
authors.lastname: Neureiter
authors.forename: Jan
authors.initials: J
authors.lastname: Wirth
authors.forename: Annette
authors.initials: A
authors.lastname: Erhardt
authors.forename: Dorothee
authors.initials: D
authors.lastname: Schwinge
authors.forename: Johannes
authors.initials: J
authors.lastname: Kluwe
authors.forename: Christoph
authors.initials: C
authors.lastname: Schramm
authors.forename: Gisa
authors.initials: G
authors.lastname: Tiegs
authors.forename: Gabriele
authors.initials: G
authors.lastname: Sass
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000818:Animals; D049109:Cell Proliferation; D018450:Disease Progression; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000201:enzymology* / Q000276:immunology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011524:Protoporphyrins; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D048049:Extracellular Signal-Regulated MAP Kinases; D051547:Heme Oxygenase-1; D008565:Membrane Proteins; D011524:Protoporphyrins; D018124:Receptors, Tumor Necrosis Factor; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C007095:cobaltiprotoporphyrin; C496542:Hmox1 protein, mouse