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

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 genetargeted mice, blocking antibodies and a synthetic inhibitor of LFA-1 (LFA703). For this purpose, mice were challenged with lipopolysaccharide (LPS) þ 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.

Attenuation of Inflammation and Apoptosis by Pre- and Posttreatment of Darbepoetin-α in Acute Liver Failure of Mice

“…35 In contrast, TNF-␣ concentrations were already below 100 pg/ml at 4 hours, corresponding to the immediate but very transient rise of TNF-␣ with a maximum at 1.5 to 2 hours on Gal-LPS exposure. 35,36 In line with other reports, 37,38 Gal-LPSexposed livers present with leukocyte accumulation, perfusion failure, as well as apoptotic and necrotic cell death. Hepatotoxicity of leukocytes has mainly been ascribed to the adherence-dependent oxidant stress and degranulation, 39 leading to oncotic necrotic cell death.…”

The HMG-CoA reductase inhibitor simvastatin overcomes cell adhesion–mediated drug resistance in multiple myeloma by geranylgeranylation of Rho protein and activation of Rho kinase

“…19 In our experiments LFA703 significantly reduced CAM-DR. Until today this LFA-1 inhibitor has been supposed primarily for the treatment of inflammation by inhibition of leukocytes. [19][20][21] Considering the importance of CAM-DR in hematologic and solid neoplasms, 16,17 our current study suggests for the first time that LFA703 and its derivatives may be promising compounds in cancer therapy. Although LFA703 is a statin derivative, which completely lacks HMG-CoA reductase inhibition activity, 18 and although statins such as lovastatin have been shown to inhibit integrin interaction, 22 reversal of CAM-DR by LFA703 was not complete and the role of HMG-CoA reductase still had to be evaluated.…”

Long-Term Simvastatin Attenuates Lung Injury and Oxidative Stress in Murine Acute Lung Injury Models Induced by Oleic Acid and Endotoxin

“…[9][10][11] Similarly, there are numerous articles on organ protective effects during sepsis. [31][32][33] There are registered randomized controlled clinical trials underway on statins in sepsis and ALI/ARDS (see http://www.clinicaltrials.gov/ct2/ results?termϭsepsisϩANDϩstatins). 34 However, the available studies on HMG-CoA reductase inhibitors in ALI/ARDS are limited.…”