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.
Conclusion
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.
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Article info
Publication history
Published online: July 21, 2008
Accepted:
May 14,
2008
Footnotes
Supported by research grants from the Swedish Medical Research Council (2006–4889), Crafoordska stiftelsen, Einar och Inga Nilssons stiftelse, Harald och Greta Jaenssons stiftelse, Greta och Johan Kocks stiftelser, Fröken Agnes Nilssons stiftelse, Franke och Margareta Bergqvists stiftelse för främjande av cancerforskning, Magnus Bergvalls stiftelse, Mossfelts stiftelse, Nanna Svartz stiftelse, Ruth och Richard Julins stiftelse, Svenska Läkaresällskapet, Allmäna sjukhusets i Malmö stiftelse för bekämpande av cancer, MAS fonder, Malmö University Hospital and Lund University.
Identification
Copyright
© 2008 Mosby, Inc. Published by Elsevier Inc. All rights reserved.
