Z Gastroenterol 2011; 49 - P1_05
DOI: 10.1055/s-0030-1269455

Induction of HEME Oxygenase 1 reduces inflammation and fibrosis in a mouse model of chronic hepatitis

R Barikbin 1, D Schwinge 2, C Schramm 2, G Tiegs 1, G Sass 1
  • 1Institut für Experimentelle Immunologie und Hepatologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg
  • 2I. Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg

Aims: Heme oxygenase 1 (HO-1) is an essential enzyme in heme catabolism and has been shown to protect from acute inflammation induced liver damage. We now investigated effects of HO-1 induction in a mouse model of chronic hepatitis (Mdr2 knockout; Mdr2ko; FVB.129P2-Abcb4tm1Bor), characterized by fibrosis and progression to hepatocellular carcinoma (HCC).

Methods: 5 or 12 weeks old Mdr2ko mice were treated with the HO-1 inducer cobalt protoporphyrin IX (CoPP) twice a week for 7 consecutive weeks. Liver damage was monitored by alanin aminotranferase (ALT) levels. Leukocyte infiltrations were visualized by H&E staining of liver slices. Fibrosis was quantified by hydroxyproline assay and Chromothrope Anilin Blue (CAB) staining. Activities of MMP-2 and -9 were examined by zymography. Expression levels of inflammation- (TNF, TNFR1,-2), fibrosis- (collagen I; III, TGFbeta2), cell cycle progression (cyclinD1, E1) and tumor-markers (AFP) were quantified by real time RT-PCR.

Results: Induction of HO-1 reduced liver damage and leucocyte infiltrations. Expression levels of hepatic TNFR1 and 2 were reduced and plasma levels were elevated upon higher shedding activity. Fibrosis was significantly reduced upon HO-1 induction by less connective tissue assembly, reduced hydroxyproline levels and decreased collagen I and III expressions. Activity of MMP-9 was increased in CoPP treated mice, whereas MMP-2 activity was not altered. Cell cycle regulating genes CyclinD1/E1 and proliferation markers PCNA and TGFbeta2 were down-regulated after CoPP treatment. Expression of the tumor marker AFP was reduced by HO-1 induction.

Conclusion: Induction of HO-1 reduces chronic inflammation and fibrosis in Mdr2ko mice by interference with TNF signaling and regulation of ECM assembly. By reducing expression levels of proliferation-, cell cycle- and tumor markers, HO-1 induction may have beneficial effects on progression to HCC.

AFP - CoPP - HCC - HO-1 - MDR2 - fibrosis - inflammation