P-selectin glycoprotein ligand-1-mediated leukocyte recruitment regulates hepatocellular damage in acute obstructive cholestasis in mice.
OBJECTIVE
Leukocytes mediate hepatocellular injury in obstructive cholestasis. The aim of the present study was to define the role of P-selectin glycoprotein ligand-1 (PSGL-1) in cholestasis-induced leukocyte recruitment and liver damage.


METHODS
C57BL/6 mice were pre-treated with an anti-PSGL-1 antibody or a control antibody prior to bile duct ligation (BDL) for 12 h. Hepatic recruitment of leukocytes and sinusoidal perfusion were determined by means of intravital fluorescence microscopy. Liver damage was monitored by measuring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Hepatic levels of CXC chemokines were determined by ELISA.


RESULTS
BDL caused significant hepatocellular damage indicated by increased serum activities of ALT and AST as well as decreased sinusoidal perfusion and clear-cut hepatic infiltration of leukocytes. Administration of the anti-PSGL-1 antibody reduced BDL-induced levels of ALT by 78% and AST by 77%. Inhibition of PSGL-1 decreased BDL-provoked leukocyte rolling and adhesion in post-sinusoidal venules by more than 81%. Moreover, we found that immunoneutralisation of PSGL-1 restored sinusoidal perfusion and decreased hepatic formation of CXC chemokines in cholestatic mice.


CONCLUSIONS
Our novel data show that PSGL-1 plays an important role in cholestatic liver damage by regulating leukocyte rolling in post-sinusoidal venules. Consequently, interference with PSGL-1 attenuates cholestasis-provoked leukocyte adhesion and extravasation in the liver. Thus, inhibition of PSGL-1 may help to protect against hepatocellular damage in cholestatic diseases.
Dold
Stefan
S
Department of Surgery, Malmö University Hospital, Lund University, Malmö, Sweden.
Laschke
Matthias W
MW
Zhau
Yilin
Y
Schilling
Martin
M
Menger
Michael D
MD
Jeppsson
Bengt
B
Thorlacius
Henrik
H
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001652:Bile Ducts / Q000502:physiology; D054426:Chemokine CXCL2 / Q000378:metabolism; D019743:Chemokines, CXC / Q000378:metabolism; D002779:Cholestasis / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D022781:Hepatocytes / Q000473:pathology*; D007962:Leukocytes / Q000187:drug effects*; D008099:Liver / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D009504:Neutrophils / Q000187:drug effects; D010976:Platelet Count
D054426:Chemokine CXCL2; D019743:Chemokines, CXC; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase