Protective effect of fasudil, a Rho-kinase inhibitor, on chemokine expression, leukocyte recruitment, and hepatocellular apoptosis in septic liver injury.

Karin Thorlacius, Jan E Slotta, Matthias W Laschke, Yusheng Wang, Michael D Menger, Bengt Jeppsson, Henrik Thorlacius

Research output: Contribution to journalArticlepeer-review

60 Citations (SciVal)

Abstract

Rho-kinase signaling regulates important features of inflammatory reactions. Herein, we investigated the effect and mechanisms of action of the Rho-kinase inhibitor fasudil in endotoxemic liver injury. C57/BL/6 mice were challenged with lipopolysaccharide (LPS) and D-galactosamine, with or without pretreatment with the Rho-kinase inhibitor fasudil. Six hours after endotoxin challenge, leukocyte-endothelium interactions in the hepatic microvasculature were studied by use of intravital fluorescence microscopy and tumor necrosis factor {alpha} (TNF-{alpha}); CXC chemokines as well as liver enzymes and apoptosis were determined. Administration of fasudil reduced LPS-induced leukocyte adhesion in postsinusoidal venules and sequestration in sinusoids. Moreover, we found that fasudil abolished extravascular infiltration of leukocytes as well as production of TNF-{alpha} and CXC chemokines in the liver of endotoxemic mice. Liver enzymes and hepatocellular apoptosis were markedly reduced, and sinusoidal perfusion was improved significantly in endotoxemic mice pretreated with fasudil. Our novel data document that fasudil is a potent inhibitor of endotoxin-induced expression of TNF-{alpha} and CXC chemokines as well as leukocyte infiltration and hepatocellular apoptosis in the liver. Based on the present findings, it is suggested that inhibition of the Rho-kinase signaling pathway may be a useful target in the treatment of septic liver injury.
Original languageEnglish
Pages (from-to)923-931
JournalJournal of Leukocyte Biology
Volume79
Issue number5
DOIs
Publication statusPublished - 2006

Bibliographical note

The information about affiliations in this record was updated in December 2015.
The record was previously connected to the following departments: Emergency medicine/Medicine/Surgery (013240200), Surgery Research Unit (013242220), Faculty of Medicine (000022000)

Subject classification (UKÄ)

  • Cell and Molecular Biology

Keywords

  • adhesion
  • endotoxin
  • intravital microscopy
  • sepsis

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