Inhibition of the lectin-like oxidized low-density lipoprotein receptor-1 improves intestinal microcirculation in experimental endotoxaemia

Introduction

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a major endothelial receptor for oxidized low-density lipoprotein [1]. Its expression is induced by pro-atherogenic stimuli as well as by inflammatory cytokines. LOX-1 acts also as an adhesion molecule involved in leukocyte recruitment. The systemic leukocyte activation in sepsis represents a crucial factor in the impairment of the microcirculation of different tissues, causing multiple organ failure and death. The aim of our experimental study was therefore to evaluate the effects of LOX-1 inhibition on the endotoxin-induced leukocyte adherence within the intestinal microcirculation using intravital microscopy.

Methods

Group 1 (n = 10 Lewis rats) remained untreated and served as the control group. In Group 2 (n = 10) endotoxemia was induced by intravenous administration of 2 mg/kg lipopolysaccharide (LPS). In Group 3 (n = 10) endotoxemic animals were treated with 10 mg/kg anti-Lox-1-IgG. Endotoxemic animals of Group 4 (n = 10) were treated with an unspecific IgG. Following 2 hours of endotoxin challenge or placebo administration, intestinal microcirculation was evaluated using intravital microscopy. LOX-1 expression was quantified by western blot and reverse-transcription PCR.

Results

LOX-1 inhibition reduced significantly the leukocyte adherence in the submucosal venules of the intestinal wall (P < 0.05). Functional capillary density of the intestinal muscular layers as well as in the mucosa increased following administration of the LOX-1-antibody in comparison with untreated LPS animals (P < 0.05). At the mRNA level, LOX-1 expression was significantly increased in the untreated LPS group (P < 0.05) whereas animals with LOX-1-antibody administration showed a significant reduction of the expression (P < 0.05).

Conclusion

LOX-1-antibody administration in experimental endotoxaemia significantly reduced leukocyte adherence and increased microvascular perfusion within the intestinal microcirculation. The inhibition of the lectin-like oxidized low-density lipoprotein receptor-1 may represent an attractive target for the modulation of endotoxin-induced impairment of the microcirculation in sepsis.