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

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Abstract

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 µg/kg) and D-galactosamine (Gal, 800 mg/kg). HO-1 was induced in vivo by pretreatment with hemin dissolved in DMSO (50 µmol/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.

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Acknowledgments

We appreciate the excellent technical assistance of Janine Becker and Julia Parakenings.

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Authors and Affiliations

  1. Institute for Clinical and Experimental Surgery, University of Saarland, 66421, Homburg/Saar, Germany

    Jonas Roller, Matthias W. Laschke, Claudia Scheuer & Michael D. Menger

Authors
  1. Jonas Roller
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  2. Matthias W. Laschke
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  3. Claudia Scheuer
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  4. Michael D. Menger
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Corresponding author

Correspondence to Jonas Roller.

Additional information

“Best of Abstracts—Chirurgisches Forum 2010, Deutsche Gesellschaft für Chirurgie”

Jonas Roller, Matthias W. Laschke, and Michael D. Menger contributed to the study conception and design; Jonas Roller and Matthias W. Laschke contributed to drafting of the manuscript; Jonas Roller and Claudia Scheuer contributed to acquisition of data; and everyone contributed to the analysis and interpretation of data and the critical revision of the manuscript.

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Roller, J., Laschke, M.W., Scheuer, C. et al. Heme oxygenase (HO)-1 protects from lipopolysaccharide (LPS)-mediated liver injury by inhibition of hepatic leukocyte accumulation and improvement of microvascular perfusion. Langenbecks Arch Surg 395, 387–394 (2010). https://doi.org/10.1007/s00423-010-0603-8

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  • DOI: https://doi.org/10.1007/s00423-010-0603-8

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