Rho-kinase signalling mediates endotoxin hypersensitivity after partial hepatectomy.
BACKGROUND
Excessive loss of functional liver mass results in hepatic dysfunction and is associated with an increased sensitivity to infection. This experimental study investigated the role of Rho-kinase in hepatectomy-induced sensitization to endotoxin.


METHODS
Male C57BL/6J mice underwent 68 per cent hepatectomy and were injected 24 h later with 100 microg Escherichia coli lipopolysaccharide (LPS). Simultaneously, animals received either fasudil or Y-27632 for Rho-kinase inhibition, or phosphate-buffered saline. Untreated hepatectomized animals served as positive controls and sham-operated animals as negative controls. Liver injury and inflammatory parameters were assessed 6 h after LPS challenge by serum alanine aminotransferase (ALT) levels, histomorphology and enzyme-linked immunosorbent assay.


RESULTS
Hepatectomy resulted in a significant susceptibility to LPS, as indicated by inflammatory leucocyte recruitment (mean(s.e.m.) 10(1) leucocytes per high-power field), hepatocellular disintegration (ALT 22.4(3.1) microkat/l) and apoptotic cell death (3.8(0.2) per cent). Rho-kinase inhibition reduced leucocytic infiltration by more than 33 per cent, abolished hepatocellular apoptosis entirely, and reduced tumour necrosis factor alpha expression by more than 48 per cent and CXC chemokine expression by more than 36 per cent.


CONCLUSIONS
Hepatectomy increased susceptibility to LPS by Rho-kinase-dependent mechanisms. Blocking Rho-kinase signalling decreased LPS-induced liver injury in hepatectomized mice.
Department of Surgery, Malmö University Hospital, Lund University, Malmö, Sweden.
J E
JE
Slotta
M W
MW
Laschke
M D
MD
Menger
H
H
Thorlacius
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000410:Alanine Transaminase / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli; D006498:Hepatectomy / Q000009:adverse effects*; D006505:Hepatitis / Q000209:etiology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D008099:Liver / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology
D000577:Amides; D016207:Cytokines; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C108830:Y 27632; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000410:Alanine Transaminase; D054460:rho-Associated Kinases; C049347:fasudil