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Platelet-dependent accumulation of leukocytes in sinusoids mediates hepatocellular damage in bile duct ligation-induced cholestasis

Laschke, MW; Dold, Stefan LU ; Menger, MD; Jeppsson, Bengt LU and Thorlacius, Henrik LU (2008) In British Journal of Pharmacology 153(1). p.148-156
Abstract
Background:Although it is well known that extrahepatic cholestasis induces liver damage, the mechanisms are still not completely understood. The aim of the present study was to evaluate the role of platelets and P-selectin in cholestasis-induced liver injury.Experimental approach:C57BL/6 mice underwent bile duct ligation (BDL) and pretreatment with an anti-GP1balpha antibody, which depletes platelets, an anti-P-selectin antibody or a control antibody. Hepatic platelet and leukocyte recruitment as well as microvascular perfusion were determined by intravital fluorescence microscopy.Key results:BDL caused significant liver damage and sinusoidal perfusion failure. BDL further induced hepatic platelet accumulation with widespread intravascular... (More)
Background:Although it is well known that extrahepatic cholestasis induces liver damage, the mechanisms are still not completely understood. The aim of the present study was to evaluate the role of platelets and P-selectin in cholestasis-induced liver injury.Experimental approach:C57BL/6 mice underwent bile duct ligation (BDL) and pretreatment with an anti-GP1balpha antibody, which depletes platelets, an anti-P-selectin antibody or a control antibody. Hepatic platelet and leukocyte recruitment as well as microvascular perfusion were determined by intravital fluorescence microscopy.Key results:BDL caused significant liver damage and sinusoidal perfusion failure. BDL further induced hepatic platelet accumulation with widespread intravascular platelet aggregates, increased platelet adhesion in postsinusoidal venules and massive platelet accumulation in liver sinusoids. Administration of the anti-GP1balpha antibody reduced systemic platelet count by 90%. Depletion of platelets in BDL mice not only abolished accumulation and adhesion of platelets in sinusoids and venules but also restored sinusoidal perfusion and reduced liver enzymes by more than 83%. Platelet depletion further reduced BDL-associated sinusoidal leukocyte accumulation by 48% although leukocyte-endothelium interactions in venules were not affected. Immunoneutralization of P-selectin also inhibited hepatic microvascular accumulation of platelets and leukocytes, and protected against cholestasis-provoked hepatocellular damage.Conclusions and implications:Platelets play an important role in BDL-induced liver injury by promoting leukocyte recruitment and deteriorating microvascular perfusion. Moreover, our findings demonstrate that cholestasis-induced accumulation of platelets is mediated by P-selectin. Thus, targeting platelet accumulation may be a useful strategy against liver damage associated with obstructive jaundice.British Journal of Pharmacology advance online publication, 19 November 2007; doi:10.1038/sj.bjp.0707578. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
in
British Journal of Pharmacology
volume
153
issue
1
pages
148 - 156
publisher
The British Pharmacological Society
external identifiers
  • pmid:18026126
  • wos:000252128400016
  • scopus:37849053583
ISSN
1476-5381
DOI
10.1038/sj.bjp.0707578
language
English
LU publication?
yes
id
a5d0d438-c98f-48bd-807d-82ded37704c8 (old id 1141849)
date added to LUP
2008-08-04 15:58:59
date last changed
2017-02-26 03:53:35
@article{a5d0d438-c98f-48bd-807d-82ded37704c8,
  abstract     = {Background:Although it is well known that extrahepatic cholestasis induces liver damage, the mechanisms are still not completely understood. The aim of the present study was to evaluate the role of platelets and P-selectin in cholestasis-induced liver injury.Experimental approach:C57BL/6 mice underwent bile duct ligation (BDL) and pretreatment with an anti-GP1balpha antibody, which depletes platelets, an anti-P-selectin antibody or a control antibody. Hepatic platelet and leukocyte recruitment as well as microvascular perfusion were determined by intravital fluorescence microscopy.Key results:BDL caused significant liver damage and sinusoidal perfusion failure. BDL further induced hepatic platelet accumulation with widespread intravascular platelet aggregates, increased platelet adhesion in postsinusoidal venules and massive platelet accumulation in liver sinusoids. Administration of the anti-GP1balpha antibody reduced systemic platelet count by 90%. Depletion of platelets in BDL mice not only abolished accumulation and adhesion of platelets in sinusoids and venules but also restored sinusoidal perfusion and reduced liver enzymes by more than 83%. Platelet depletion further reduced BDL-associated sinusoidal leukocyte accumulation by 48% although leukocyte-endothelium interactions in venules were not affected. Immunoneutralization of P-selectin also inhibited hepatic microvascular accumulation of platelets and leukocytes, and protected against cholestasis-provoked hepatocellular damage.Conclusions and implications:Platelets play an important role in BDL-induced liver injury by promoting leukocyte recruitment and deteriorating microvascular perfusion. Moreover, our findings demonstrate that cholestasis-induced accumulation of platelets is mediated by P-selectin. Thus, targeting platelet accumulation may be a useful strategy against liver damage associated with obstructive jaundice.British Journal of Pharmacology advance online publication, 19 November 2007; doi:10.1038/sj.bjp.0707578.},
  author       = {Laschke, MW and Dold, Stefan and Menger, MD and Jeppsson, Bengt and Thorlacius, Henrik},
  issn         = {1476-5381},
  language     = {eng},
  number       = {1},
  pages        = {148--156},
  publisher    = {The British Pharmacological Society},
  series       = {British Journal of Pharmacology},
  title        = {Platelet-dependent accumulation of leukocytes in sinusoids mediates hepatocellular damage in bile duct ligation-induced cholestasis},
  url          = {http://dx.doi.org/10.1038/sj.bjp.0707578},
  volume       = {153},
  year         = {2008},
}