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Sepsis-associated cholestasis is critically dependent on P-selectin-dependent leukocyte recruitment in mice.

Laschke, Mattias W; Menger, Michael D; Wang, Yusheng LU ; Lindell, Gert LU ; Jeppsson, Bengt LU and Thorlacius, Henrik LU (2007) In American Journal of Physiology: Gastrointestinal and Liver Physiology 292. p.1396-1402
Abstract
Cholestasis is a major complication in sepsis although the underlying mechanisms remain elusive. The aim of this study was to evaluate the role of P-selectin and leukocyte recruitment in endotoxemia- associated cholestasis. C57BL/6 mice were challenged intraperitoneally with endotoxin ( 0.4 mg/ kg), and 6 h later the common bile duct was cannulated for determination of bile flow and biliary excretion of bromosulfophthalein. Mice were pretreated with an anti-P-selectin antibody or an isotype- matched control antibody. Leukocyte infiltration was determined by measuring hepatic levels of myeloperoxidase. Tumor necrosis factor-alpha and CXC chemokines in the liver was determined by ELISA. Liver damage was monitored by measuring serum levels of... (More)
Cholestasis is a major complication in sepsis although the underlying mechanisms remain elusive. The aim of this study was to evaluate the role of P-selectin and leukocyte recruitment in endotoxemia- associated cholestasis. C57BL/6 mice were challenged intraperitoneally with endotoxin ( 0.4 mg/ kg), and 6 h later the common bile duct was cannulated for determination of bile flow and biliary excretion of bromosulfophthalein. Mice were pretreated with an anti-P-selectin antibody or an isotype- matched control antibody. Leukocyte infiltration was determined by measuring hepatic levels of myeloperoxidase. Tumor necrosis factor-alpha and CXC chemokines in the liver was determined by ELISA. Liver damage was monitored by measuring serum levels of alanine aminotransferase and aspartate aminotransferase. Apoptosis was quantified morphologically by nuclear condensation and fragmentation using Hoechst 33342 staining. Endotoxin induced a significant inflammatory response with increased TNF-alpha and CXC chemokine concentrations, leukocyte infiltration, liver enzyme release, and apoptotic cell death. This response was associated with pronounced cholestasis indicated by a > 70% decrease of bile flow and biliary excretion of bromosulfophthalein. Immunoneutralization of P-selectin significantly attenuated endotoxin- induced leukocyte infiltration reflected by a > 60% reduction of hepatic myeloperoxidase levels. Interference with P-selectin decreased endotoxin- mediated hepatocellular apoptosis and necrosis, but did not affect hepatic levels of tumor necrosis factor-alpha and CXC chemokines. Of interest, inhibition of P- selectin restored bile flow and biliary excretion of bromosulfophthalein to normal levels in endotoxin- challenged animals. Our study demonstrates for the first time that P-selectin-mediated recruitment of leukocytes, but not the local production of proinflammatory mediators, is the primary cause of cholestasis in septic liver injury. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
liver, inflammation, apoptosis, chemokines, bile
in
American Journal of Physiology: Gastrointestinal and Liver Physiology
volume
292
pages
1396 - 1402
publisher
American Physiological Society
external identifiers
  • wos:000247935800023
  • scopus:34347388241
ISSN
1522-1547
DOI
10.1152/ajpgi.00539.2006
language
English
LU publication?
yes
id
28e483c7-b433-4ee5-89df-81c508398de6 (old id 164633)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17255363&dopt=Abstract
date added to LUP
2007-07-25 10:37:28
date last changed
2017-01-01 04:46:10
@article{28e483c7-b433-4ee5-89df-81c508398de6,
  abstract     = {Cholestasis is a major complication in sepsis although the underlying mechanisms remain elusive. The aim of this study was to evaluate the role of P-selectin and leukocyte recruitment in endotoxemia- associated cholestasis. C57BL/6 mice were challenged intraperitoneally with endotoxin ( 0.4 mg/ kg), and 6 h later the common bile duct was cannulated for determination of bile flow and biliary excretion of bromosulfophthalein. Mice were pretreated with an anti-P-selectin antibody or an isotype- matched control antibody. Leukocyte infiltration was determined by measuring hepatic levels of myeloperoxidase. Tumor necrosis factor-alpha and CXC chemokines in the liver was determined by ELISA. Liver damage was monitored by measuring serum levels of alanine aminotransferase and aspartate aminotransferase. Apoptosis was quantified morphologically by nuclear condensation and fragmentation using Hoechst 33342 staining. Endotoxin induced a significant inflammatory response with increased TNF-alpha and CXC chemokine concentrations, leukocyte infiltration, liver enzyme release, and apoptotic cell death. This response was associated with pronounced cholestasis indicated by a > 70% decrease of bile flow and biliary excretion of bromosulfophthalein. Immunoneutralization of P-selectin significantly attenuated endotoxin- induced leukocyte infiltration reflected by a > 60% reduction of hepatic myeloperoxidase levels. Interference with P-selectin decreased endotoxin- mediated hepatocellular apoptosis and necrosis, but did not affect hepatic levels of tumor necrosis factor-alpha and CXC chemokines. Of interest, inhibition of P- selectin restored bile flow and biliary excretion of bromosulfophthalein to normal levels in endotoxin- challenged animals. Our study demonstrates for the first time that P-selectin-mediated recruitment of leukocytes, but not the local production of proinflammatory mediators, is the primary cause of cholestasis in septic liver injury.},
  author       = {Laschke, Mattias W and Menger, Michael D and Wang, Yusheng and Lindell, Gert and Jeppsson, Bengt and Thorlacius, Henrik},
  issn         = {1522-1547},
  keyword      = {liver,inflammation,apoptosis,chemokines,bile},
  language     = {eng},
  pages        = {1396--1402},
  publisher    = {American Physiological Society},
  series       = {American Journal of Physiology: Gastrointestinal and Liver Physiology},
  title        = {Sepsis-associated cholestasis is critically dependent on P-selectin-dependent leukocyte recruitment in mice.},
  url          = {http://dx.doi.org/10.1152/ajpgi.00539.2006},
  volume       = {292},
  year         = {2007},
}