Cholestatic liver damage is mediated by lymphocyte function antigen-1-dependent recruitment of leukocytes.
BACKGROUND
The role of specific adhesion molecules in cholestasis-induced leukocyte recruitment in the liver is not known. Therefore, the aim of our experimental study was to evaluate the role of lymphocyte function antigen-1 (LFA-1) in cholestatic liver injury.


METHODS
C57BL/6 mice underwent bile duct ligation for 12 hours. Mice were pretreated with an anti-LFA-1 antibody or control antibody. Subsequently, hepatic accumulation of leukocytes and sinusoidal perfusion were determined by means of intravital fluorescence microscopy. Hepatocellular damage was monitored by measuring serum levels of alanine aminotransferase and aspartate aminotransferase. CXC chemokines in the liver were determined by enzyme-linked immunosorbent assay.


RESULTS
Bile duct ligation provoked clear-cut recruitment of leukocytes and liver damage, as indicated by increased serum activities of liver enzymes and sinusoidal perfusion failure. Neutrophils expressed greater levels of LFA-1 and inhibition of LFA-1 significantly decreased serum activity of alanine aminotransferase and aspartate aminotransferase levels in cholestatic mice. Immunoneutralization of LFA-1 reduced leukocyte adhesion in postsinusoidal venules that had been induced by bile duct ligation, whereas leukocyte rolling and sinusoidal accumulation were not changed. Moreover, blocking LFA-1 function restored sinusoidal perfusion in cholestatic animals.


CONCLUSIONS
These findings demonstrate an important role of LFA-1 in supporting cholestasis-induced leukocyte recruitment in the liver. Thus, targeting LFA-1 may help to protect against pathologic inflammation and liver damage in cholestatic liver diseases.
Dold
Stefan
S
Department of Surgery, Malmö University Hospital, Lund University, Malmö, Sweden.
Laschke
Matthias W
MW
Lavasani
Shahram
S
Menger
Michael D
MD
Thorlacius
Henrik
H
D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D002779:Cholestasis / Q000276:immunology*; D004195:Disease Models, Animal; D008107:Liver Diseases / Q000276:immunology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL
D016169:Lymphocyte Function-Associated Antigen-1