Heme oxygenase (HO)-1 protects from lipopolysaccharide (LPS)-mediated liver injury by inhibition of hepatic leukocyte accumulation and improvement of microvascular perfusion.

PURPOSE

Lipopolysaccharide (LPS) represents a highly toxic substance which may aggravate morbidity and mortality in septic diseases. A recent study has reported that the induction of heme oxygenase (HO)-1 protects from LPS-induced liver injury. The mechanisms of action however, have not been clarified yet. Therefore, we analyzed in vivo the effects of HO-1 on the liver microcirculation under conditions of LPS exposure.

METHODS

In C57BL/6 mice, endotoxemia was induced by intraperitoneal (i.p.) administration of LPS (500 microg/kg) and D-galactosamine (Gal, 800 mg/kg). HO-1 was induced in vivo by pretreatment with hemin dissolved in DMSO (50 micromol/kg i.p.). Animals treated with DMSO only served as controls. Six hours after LPS exposure the hepatic microcirculation and leukocyte-endothelial cell interaction were analyzed by intravital fluorescence microscopy. HO-1 expression was determined by Western blot analysis. Hepatocellular damage was assessed by measuring the serum levels of aspartate aminotransferase and alanine aminotransferase. In addition, leukocyte transmigration and hepatocellular apoptosis were analyzed by histology and immunohistochemistry.

RESULTS

In controls, LPS/Gal caused severe liver injury, as indicated by increased liver enzyme levels and apoptotic cell death. This was associated with distinct sinusoidal perfusion failure and microvascular intrahepatic leukocyte accumulation. Of interest, induction of HO-1 significantly reduced numbers of adherent and extravascular leukocytes when compared to controls. Moreover, microvascular perfusion was significantly improved, resulting in a decrease of AST and ALT and a reduction of hepatocellular apoptosis.

CONCLUSIONS

Our novel data indicate that induction of HO-1 protects the liver from LPS-mediated injury by reducing leukocytic inflammation and improving intrahepatic microcirculation.