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Critical role of CXC chemokines in endotoxemic liver injury in mice.

Li, Xiang LU ; Klintman, Daniel LU ; Liu, Qing LU ; Sato, Tohru; Jeppsson, Bengt LU and Thorlacius, Henrik LU (2004) In Journal of Leukocyte Biology 75(3). p.443-452
Abstract
Tissue accumulation of leukocytes constitutes a rate-limiting step in endotoxin-induced tissue injury. Chemokines have the capacity to regulate leukocyte trafficking. However, the role of CXC chemokines, i.e., macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (KC), in leukocyte recruitment, microvascular perfusion failure, cellular injury, and apoptosis in the liver remains elusive. Herein, mice were challenged with lipopolysaccharide (LPS) in combination with D-galactosamine, and intravital microscopy of the liver microcirculation was conducted 6 h later. It was found that immunoneutralization of MIP-2 and KC did not reduce LPS-induced leukocyte rolling and adhesion in postsinusoidal venules. In... (More)
Tissue accumulation of leukocytes constitutes a rate-limiting step in endotoxin-induced tissue injury. Chemokines have the capacity to regulate leukocyte trafficking. However, the role of CXC chemokines, i.e., macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (KC), in leukocyte recruitment, microvascular perfusion failure, cellular injury, and apoptosis in the liver remains elusive. Herein, mice were challenged with lipopolysaccharide (LPS) in combination with D-galactosamine, and intravital microscopy of the liver microcirculation was conducted 6 h later. It was found that immunoneutralization of MIP-2 and KC did not reduce LPS-induced leukocyte rolling and adhesion in postsinusoidal venules. In contrast, pretreatment with monoclonal antibodies against MIP-2 and KC abolished (83% reduction) extravascular recruitment of leukocytes in the livers of endotoxemic mice. Notably, endotoxin challenge increased the expression of CXC chemokines, which was mainly confined to hepatocytes. Moreover, endotoxin-induced increases of liver enzymes and hepatocellular apoptosis were decreased by more than 82% and 68%, respectively, and sinusoidal perfusion was restored in mice passively immunized against MIP-2 and KC. In conclusion, this study indicates that intravascular accumulation of leukocytes in the liver is independent of CXC chemokines in endotoxemic mice. Instead, our novel data suggest that CXC chemokines are instrumental in regulating endotoxin-induced transmigration and extravascular tissue accumulation of leukocytes. Indeed, these findings demonstrate that interference with MIP-2 and KC functions protects against septic liver damage and may constitute a potential therapeutic strategy to control pathological inflammation in endotoxemia. (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
endotoxin, adhesion, transmigration, sepsis, intravital microscopy
in
Journal of Leukocyte Biology
volume
75
issue
3
pages
443 - 452
publisher
Society for Leukocyte Biology
external identifiers
  • wos:000220076500010
  • pmid:14673016
  • scopus:1542343956
ISSN
1938-3673
DOI
10.1189/jlb.0603297
language
English
LU publication?
yes
id
a677252a-9d0f-475d-a4c1-7c37abb32aa2 (old id 119633)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14673016&dopt=Abstract
date added to LUP
2007-07-25 13:55:51
date last changed
2017-05-28 03:32:59
@article{a677252a-9d0f-475d-a4c1-7c37abb32aa2,
  abstract     = {Tissue accumulation of leukocytes constitutes a rate-limiting step in endotoxin-induced tissue injury. Chemokines have the capacity to regulate leukocyte trafficking. However, the role of CXC chemokines, i.e., macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (KC), in leukocyte recruitment, microvascular perfusion failure, cellular injury, and apoptosis in the liver remains elusive. Herein, mice were challenged with lipopolysaccharide (LPS) in combination with D-galactosamine, and intravital microscopy of the liver microcirculation was conducted 6 h later. It was found that immunoneutralization of MIP-2 and KC did not reduce LPS-induced leukocyte rolling and adhesion in postsinusoidal venules. In contrast, pretreatment with monoclonal antibodies against MIP-2 and KC abolished (83% reduction) extravascular recruitment of leukocytes in the livers of endotoxemic mice. Notably, endotoxin challenge increased the expression of CXC chemokines, which was mainly confined to hepatocytes. Moreover, endotoxin-induced increases of liver enzymes and hepatocellular apoptosis were decreased by more than 82% and 68%, respectively, and sinusoidal perfusion was restored in mice passively immunized against MIP-2 and KC. In conclusion, this study indicates that intravascular accumulation of leukocytes in the liver is independent of CXC chemokines in endotoxemic mice. Instead, our novel data suggest that CXC chemokines are instrumental in regulating endotoxin-induced transmigration and extravascular tissue accumulation of leukocytes. Indeed, these findings demonstrate that interference with MIP-2 and KC functions protects against septic liver damage and may constitute a potential therapeutic strategy to control pathological inflammation in endotoxemia.},
  author       = {Li, Xiang and Klintman, Daniel and Liu, Qing and Sato, Tohru and Jeppsson, Bengt and Thorlacius, Henrik},
  issn         = {1938-3673},
  keyword      = {endotoxin,adhesion,transmigration,sepsis,intravital microscopy},
  language     = {eng},
  number       = {3},
  pages        = {443--452},
  publisher    = {Society for Leukocyte Biology},
  series       = {Journal of Leukocyte Biology},
  title        = {Critical role of CXC chemokines in endotoxemic liver injury in mice.},
  url          = {http://dx.doi.org/10.1189/jlb.0603297},
  volume       = {75},
  year         = {2004},
}