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Protective effect of fasudil, a Rho‐kinase inhibitor, on chemokine expression, leukocyte recruitment, and hepatocellular apoptosis in septic liver injury
Author(s) -
Thorlacius Karin,
Slotta Jan E.,
Laschke Matthias W.,
Wang Yusheng,
Menger Michael D.,
Jeppsson Bengt,
Thorlacius Henrik
Publication year - 2006
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0705406
Subject(s) - fasudil , rho kinase inhibitor , intravital microscopy , chemokine , rho associated protein kinase , apoptosis , pharmacology , liver injury , tumor necrosis factor alpha , biology , inflammation , immunology , kinase , cancer research , microbiology and biotechnology , biochemistry , in vivo
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 α (TNF‐α); 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‐α 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‐α 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.