And for our friends at DNA to consider.......................
>>Br J Pharmacol. 2004 Feb;141(4):709-16. Epub 2004 Jan 26. Related Articles, Links
Lymphocyte function antigen-1 mediates leukocyte adhesion and subsequent liver damage in endotoxemic mice.
Li X, Klintman D, Weitz-Schmidt G, Schramm R, Thorlacius H.
Department of Surgery, Malmo University Hospital, Lund University, Malmo S-205-02, Sweden.
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. 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. 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. 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. 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.British Journal of Pharmacology (2004) 141, 709-716. doi:10.1038/sj.bjp.0705634 |
