Platelet-dependent accumulation of leukocytes in sinusoids mediates hepatocellular damage in bile duct ligation-induced cholestasis
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1141849
- author
- Laschke, MW ; Dold, Stefan LU ; Menger, MD ; Jeppsson, Bengt LU and Thorlacius, Henrik LU
- organization
- publishing date
- 2008
- type
- Contribution to journal
- publication status
- published
- subject
- in
- British Journal of Pharmacology
- volume
- 153
- issue
- 1
- pages
- 148 - 156
- publisher
- Wiley
- external identifiers
-
- pmid:18026126
- wos:000252128400016
- scopus:37849053583
- pmid:18026126
- 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
- 2016-04-01 13:54:18
- date last changed
- 2022-01-27 21:43:51
@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 = {{Wiley}},
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}},
doi = {{10.1038/sj.bjp.0707578}},
volume = {{153}},
year = {{2008}},
}