| 1. |
- Dold, Stefan, et al.
(författare)
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P-selectin glycoprotein ligand-1-mediated leukocyte recruitment regulates hepatocellular damage in acute obstructive cholestasis in mice.
- 2010
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Ingår i: Inflammation Research. - : Springer Science and Business Media LLC. - 1420-908X .- 1023-3830. ; 59, s. 291-298
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Laschke, Matthias, et al.
(författare)
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Rho-Kinase Inhibitor Attenuates Cholestasis-Induced CXC Chemokine Formation, Leukocyte Recruitment, and Hepatocellular Damage in the Liver.
- 2010
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Ingår i: The Journal of surgical research. - : Elsevier BV. - 1095-8673 .- 0022-4804. ; 159, s. 666-673
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In the present experimental study, we analyzed the role of Rho-kinase during obstructive cholestasis by studying the effect of the Rho-kinase inhibitor Y-27632 on hepatic CXC chemokine formation, leukocyte recruitment and hepatocellular damage. MATERIALS AND METHODS: C57BL/6 mice underwent bile duct ligation (BDL) to induce obstructive cholestasis. Mice were pretreated with Y-27632 (1 and 10mg/kg) or the vehicle PBS. Sham-operated animals served as controls. After 12h, hepatic accumulation of leukocytes and sinusoidal perfusion were determined using intravital fluorescence microscopy. Hepatocellular damage was monitored by measuring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). CXC chemokines in the liver were analyzed by ELISA. RESULTS: Administration of 10mg/kg of Y-27632 protected against cholestasis-induced hepatocellular damage indicated by a more than 87% reduction of ALT and AST in BDL mice. Moreover, this Rho-kinase inhibitor significantly decreased BDL-induced production of CXC chemokines by 44-83% and leukocyte recruitment by 60%. Finally, treatment with Y-27632 restored sinusoidal perfusion in cholestatic animals. CONCLUSIONS: Our findings indicate that the Rho-kinase signaling pathway plays a key role in the pathophysiology of cholestatic liver injury. Thus, targeting Rho-kinase activity may represent a new therapeutic approach in the treatment of inflammation and liver injury in cholestatic liver diseases.
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