Protective effect of fasudil, a Rho-kinase inhibitor, on chemokine expression, leukocyte recruitment, and hepatocellular apoptosis in septic liver injury.
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.
Thorlacius
Karin
K
Department of Anesthesiology, Lund University, Malmö, Sweden.
Slotta
Jan E
JE
Laschke
Matthias W
MW
Wang
Yusheng
Y
Menger
Michael D
MD
Jeppsson
Bengt
B
Thorlacius
Henrik
H
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000577:Amides / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology; D019743:Chemokines, CXC / Q000276:immunology / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects* / Q000276:immunology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000201:enzymology / Q000276:immunology; D019446:Endotoxemia / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D006499:Hepatic Artery / Q000187:drug effects / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D008107:Liver Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D054460:rho-Associated Kinases
D000577:Amides; D019743:Chemokines, CXC; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; C108830:Y 27632; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; C049347:fasudil