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Lymphocyte function antigen-1 mediates leukocyte adhesion and subsequent liver damage in endotoxemic mice

Li, Xiang LU ; Klintman, Daniel LU ; Weitz-Schmidt, G; Schramm, R and Thorlacius, Henrik LU (2004) In British Journal of Pharmacology 141(4). p.709-716
Abstract
1 Sepsis is associated with leukocyte activation and recruitment in the liver. We investigated the role of lymphocyte function antigen-1 (LFA-1) in endotoxin-induced leukocyte-endothelium interactions, microvascular perfusion failure, hepatocellular injury and apoptosis in the liver by use of gene-targeted mice, blocking antibodies and a synthetic inhibitor of LFA-1 (LFA703). For this purpose, mice were challenged with lipopolysaccharide (LPS)+D-galactosamine (Gal), and intravital microscopy of the liver microcirculation was conducted 6 h later. 2 The number of Firmly adherent leukocytes in response to LPS/Gal was reduced by 48% in LFA-1-deficient mice. Moreover, endotoxin-induced increases of apoptosis and enzyme markers of hepatocellular... (More)
1 Sepsis is associated with leukocyte activation and recruitment in the liver. We investigated the role of lymphocyte function antigen-1 (LFA-1) in endotoxin-induced leukocyte-endothelium interactions, microvascular perfusion failure, hepatocellular injury and apoptosis in the liver by use of gene-targeted mice, blocking antibodies and a synthetic inhibitor of LFA-1 (LFA703). For this purpose, mice were challenged with lipopolysaccharide (LPS)+D-galactosamine (Gal), and intravital microscopy of the liver microcirculation was conducted 6 h later. 2 The number of Firmly adherent leukocytes in response to LPS/Gal was reduced by 48% in LFA-1-deficient mice. Moreover, endotoxin-induced increases of apoptosis and enzyme markers of hepatocellular injury were decreased by 64 and 69-90%, respectively, in LFA-1-deficient mice. Furthermore, sinusoidal perfusion was improved in endotoxemic mice lacking LFA-1. 3 A similar protective pattern was observed in endotoxemic mice pretreated with an antibody against LFA-1. Thus, immunoneutralization of LFA-1 reduced endotoxin-induced leukocyte adhesion by 55%, liver enzymes by 64-66% and apoptosis by 42%, in addition to the preservation of microvascular perfusion. 4 Administration of a novel statin-derived inhibitor of LFA-1, LFA703, significantly decreased leukocyte adhesion (more than 56%) and the subsequent liver injury in endotoxemic mice. 5 Thus, this study demonstrates a pivotal role of LFA-1 in supporting leukocyte adhesion in the liver. Moreover, interference with LFA-1-mediated leukocyte adhesion protects against endotoxemic liver damage, and may constitute a potential therapeutic strategy in sepsis. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
statins, sepsis, LFA703, intravital microscopy, integrin, adhesion, endotoxin
in
British Journal of Pharmacology
volume
141
issue
4
pages
709 - 716
publisher
The British Pharmacological Society
external identifiers
  • wos:000220379200019
  • pmid:14744817
  • scopus:1842506199
ISSN
1476-5381
DOI
10.1038/sj.bjp.0705634
language
English
LU publication?
yes
id
ffc644b2-7a7b-4263-966f-ff60f68736d0 (old id 284722)
date added to LUP
2007-10-24 18:31:23
date last changed
2018-01-07 09:20:20
@article{ffc644b2-7a7b-4263-966f-ff60f68736d0,
  abstract     = {1 Sepsis is associated with leukocyte activation and recruitment in the liver. We investigated the role of lymphocyte function antigen-1 (LFA-1) in endotoxin-induced leukocyte-endothelium interactions, microvascular perfusion failure, hepatocellular injury and apoptosis in the liver by use of gene-targeted mice, blocking antibodies and a synthetic inhibitor of LFA-1 (LFA703). For this purpose, mice were challenged with lipopolysaccharide (LPS)+D-galactosamine (Gal), and intravital microscopy of the liver microcirculation was conducted 6 h later. 2 The number of Firmly adherent leukocytes in response to LPS/Gal was reduced by 48% in LFA-1-deficient mice. Moreover, endotoxin-induced increases of apoptosis and enzyme markers of hepatocellular injury were decreased by 64 and 69-90%, respectively, in LFA-1-deficient mice. Furthermore, sinusoidal perfusion was improved in endotoxemic mice lacking LFA-1. 3 A similar protective pattern was observed in endotoxemic mice pretreated with an antibody against LFA-1. Thus, immunoneutralization of LFA-1 reduced endotoxin-induced leukocyte adhesion by 55%, liver enzymes by 64-66% and apoptosis by 42%, in addition to the preservation of microvascular perfusion. 4 Administration of a novel statin-derived inhibitor of LFA-1, LFA703, significantly decreased leukocyte adhesion (more than 56%) and the subsequent liver injury in endotoxemic mice. 5 Thus, this study demonstrates a pivotal role of LFA-1 in supporting leukocyte adhesion in the liver. Moreover, interference with LFA-1-mediated leukocyte adhesion protects against endotoxemic liver damage, and may constitute a potential therapeutic strategy in sepsis.},
  author       = {Li, Xiang and Klintman, Daniel and Weitz-Schmidt, G and Schramm, R and Thorlacius, Henrik},
  issn         = {1476-5381},
  keyword      = {statins,sepsis,LFA703,intravital microscopy,integrin,adhesion,endotoxin},
  language     = {eng},
  number       = {4},
  pages        = {709--716},
  publisher    = {The British Pharmacological Society},
  series       = {British Journal of Pharmacology},
  title        = {Lymphocyte function antigen-1 mediates leukocyte adhesion and subsequent liver damage in endotoxemic mice},
  url          = {http://dx.doi.org/10.1038/sj.bjp.0705634},
  volume       = {141},
  year         = {2004},
}