Z Gastroenterol 2012; 50 - P1_02
DOI: 10.1055/s-0031-1295732

Induction of heme oxygenase 1 in Mdr2ko mice reduces hepatic inflammation, prevents fibrosis progression and supports fibrolysis

R Barikbin 1, D Neureiter 2, JW Wirth 3, A Erhardt 1, D Schwinge 3, J Kluwe 3, C Schramm 3, G Tiegs 1, G Sass 1
  • 1Institut für Experimentelle Immunologie und Hepatologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg
  • 2Landeskliniken Salzburg, Institut für Pathologie, Salzburg, Austria
  • 3I. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg

Background: Heme oxygenase 1 (HO–1) has been shown to protect mice from acute hepatitis. We now investigated effects of HO–1 induction in a mouse model of chronic liver inflammation (Mdr2 knockout; Mdr2ko; FVB.129P2-Abcb4tm1Bor) with respect to effects on immune cell infiltration and activity and fibrosis formation.

Methods: HO–1 was induced in Mdr2ko mice for 7 consecutive weeks. Liver damage was monitored by alanin aminotranferase (ALT) levels. Leukocyte infiltration, leukocyte subsets (e.g. T cells, macrophages, granulocytes) as well as fibrosis formation (collagen, hepatic stellate cells (HSCs)) was visualized by staining of liver slices. Fibrosis was also quantified by hydroxyproline levels. Activities of MMP–2 and –9 were examined by zymography. Activity of HSCs was determined in in vitro experiments. Real time RT-PCR or Western Blot was used to quantify expression levels of inflammation- and fibrosis markers, e.g. TNF receptors and αSMA.

Results: Induction of HO–1 interfered with liver damage and leucocyte infiltration. HO–1 reduced total levels of CD3+ and foxp3+ cells, while it shifted the ratio to a more suppressive capacity. Numbers of macrophages and neutrophil granulocytes were reduced. Expression levels of TNFR1/2 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 expression. Activity of the gelatinase MMP–9 was increased in CoPP treated mice, whereas MMP–2 activity was unchanged. The amount of quiescent and activated HSCs was reduced. In vitro HSCs showed reduced activation upon HO–1 induction.

Conclusion: Induction of HO–1 reduced chronic inflammation and partially reverted fibrosis in Mdr2ko mice by interference with TNF signaling and regulation of ECM assembly. By interfering with chronic inflammation and fibrosis, HO–1 induction may also delay progression to HCC.

TNF signalling - chronic inflammation - fibrosis - proliferation