Lymphocyte function antigen-1 mediates leukocyte adhesion and subsequent liver damage in endotoxemic mice.
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.
Li
Xiang
X
Department of Surgery, Malmö University Hospital, Lund University, Malmo S-205-02, Sweden.
Klintman
Daniel
D
Weitz-Schmidt
Gabriele
G
Schramm
René
R
Thorlacius
Henrik
H
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002196:Capillaries / Q000187:drug effects / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology* / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000473:pathology*; D018390:Gene Targeting; D006439:Hemodynamics / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D007958:Leukocyte Count; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology*; D008099:Liver / Q000201:enzymology; D008102:Liver Circulation / Q000187:drug effects; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
D019138:Antibodies, Blocking; D016169:Lymphocyte Function-Associated Antigen-1