Lymphocyte function antigen-1 mediates leukocyte adhesion and subsequent liver damage in endotoxemic mice
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/284722
- author
- Li, Xiang LU ; Klintman, Daniel LU ; Weitz-Schmidt, G ; Schramm, R and Thorlacius, Henrik LU
- organization
- publishing date
- 2004
- 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
- Wiley
- external identifiers
-
- wos:000220379200019
- pmid:14744817
- scopus:1842506199
- pmid:14744817
- ISSN
- 1476-5381
- DOI
- 10.1038/sj.bjp.0705634
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Surgery Research Unit (013242220), Emergency medicine/Medicine/Surgery (013240200)
- id
- ffc644b2-7a7b-4263-966f-ff60f68736d0 (old id 284722)
- date added to LUP
- 2016-04-01 16:31:02
- date last changed
- 2022-01-28 20:17:41
@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}},
keywords = {{statins; sepsis; LFA703; intravital microscopy; integrin; adhesion; endotoxin}},
language = {{eng}},
number = {{4}},
pages = {{709--716}},
publisher = {{Wiley}},
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}},
doi = {{10.1038/sj.bjp.0705634}},
volume = {{141}},
year = {{2004}},
}