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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Weitz-schmidt, Gabriele Li, Xiang Thorlacius, Henrik Klintman, Daniel Schramm, René |
| Description | Author Affiliation: Li X ( Department of Surgery, Malmö University Hospital, Lund University, Malmo S-205-02, Sweden.) |
| 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. |
| ISSN | 00071188 |
| e-ISSN | 14765381 |
| Journal | British Journal of Pharmacology |
| Issue Number | 4 |
| Volume Number | 141 |
| Language | English |
| Publisher | Wiley Online Library(on behalf of The British Pharmacological Society) |
| Publisher Date | 2004-02-01 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | Open |
| Subject Keyword | Drug-Induced Liver Injury Pathology Prevention & Control Endotoxemia Leukocytes Physiology Lymphocyte Function-Associated Antigen-1 Animals Antibodies, Blocking Pharmacology Apoptosis Drug Effects Capillaries Cell Adhesion Dose-Response Relationship, Drug Gene Targeting Hemodynamics Hepatocytes Leukocyte Count Liver Enzymology Liver Circulation Therapeutic Use Mice Mice, Inbred C57BL Research Support, Non-U.S. Gov't |
| Content Type | Text |
| Resource Type | Article |
| Subject | Pharmacology |
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