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

Thorlacius, Karin LU ; Slotta, Jan E ; Laschke, Matthias W ; Wang, Yusheng LU ; Menger, Michael D ; Jeppsson, Bengt LU and Thorlacius, Henrik LU (2006) In Journal of Leukocyte Biology 79(5). p.923-931
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... (More)
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. (Less)
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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
adhesion, endotoxin, intravital microscopy, sepsis
in
Journal of Leukocyte Biology
volume
79
issue
5
pages
923 - 931
publisher
John Wiley and Sons
external identifiers
  • wos:000243015200007
  • pmid:16624932
  • scopus:33745326435
ISSN
1938-3673
DOI
10.1189/jlb.0705406
language
English
LU publication?
yes
additional info
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)
id
0650b539-c81d-405a-9be0-df2b1841a0ef (old id 155691)
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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16641138&dopt=Abstract
date added to LUP
2016-04-01 12:20:36
date last changed
2021-01-10 05:11:12
@article{0650b539-c81d-405a-9be0-df2b1841a0ef,
  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.},
  author       = {Thorlacius, Karin and Slotta, Jan E and Laschke, Matthias W and Wang, Yusheng and Menger, Michael D and Jeppsson, Bengt and Thorlacius, Henrik},
  issn         = {1938-3673},
  language     = {eng},
  number       = {5},
  pages        = {923--931},
  publisher    = {John Wiley and Sons},
  series       = {Journal of Leukocyte Biology},
  title        = {Protective effect of fasudil, a Rho-kinase inhibitor, on chemokine expression, leukocyte recruitment, and hepatocellular apoptosis in septic liver injury.},
  url          = {http://dx.doi.org/10.1189/jlb.0705406},
  doi          = {10.1189/jlb.0705406},
  volume       = {79},
  year         = {2006},
}