Inhibition of lectin-like oxidized low-density lipoprotein receptor-1 reduces leukocyte adhesion within the intestinal microcirculation in experimental endotoxemia in rats
1 Department of Internal Medicine B, University Hospital Greifswald, Friedrich-Loeffler-Strasse 23 a, D-17475 Greifswald, Germany
2 Research Center of Pharmacology and Experimental Therapeutics, University Hospital Greifswald, Friedrich-Loeffler-Strasse 23 d, D-17475 Greifswald, Germany
3 Department of Anesthesia, Dalhousie University, 1276 South Park St., Halifax, NS, B3 H 2Y9, Canada
4 Department of Anesthesiology and Intensive Care Medicine, University Hospital Greifswald, Friedrich-Loeffler-Strasse 23a, D-17475 Greifswald, Germany
5 Department of Anesthesiology and Intensive Care Medicine, University Hospital Hradec Kralove, Charles University in Prague, Sokolska 581, 500 05 Hradec Kralove, Czech Republic
Critical Care 2010, 14:R223 doi:10.1186/cc9367Published: 10 December 2010
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), the major endothelial receptor for oxidized low-density lipoprotein, is also involved in leukocyte recruitment. Systemic leukocyte activation in sepsis represents a crucial factor in the impairment of the microcirculation of different tissues, causing multiple organ failure and subsequently death. The aim of our experimental study was to evaluate the effects of LOX-1 inhibition on the endotoxin-induced leukocyte adherence and capillary perfusion within the intestinal microcirculation by using intravital microscopy (IVM).
We used 40 male Lewis rats for the experiments. Ten placebo-treated animals served as a control. Thirty animals received 5 mg/kg lipopolysaccharide (LPS) intravenously. Ten endotoxemic rats remained untreated. In 10 LPS animals, we administered additionally 10 mg/kg LOX-1 antibodies. Ten further LPS animals received a nonspecific immunoglobulin (rat IgG) intravenously. After 2 hours of observation, intestinal microcirculation was evaluated by using IVM; the plasma levels of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-α) were determined; and LOX-1 expression was quantified in intestinal tissue with Western blot and reverse-transcription polymerase chain reaction (PCR).
LOX-1 inhibition significantly reduced LPS-induced leukocyte adhesion in intestinal submucosal venules (P < 0.05). At the protein and mRNA levels, LOX-1 expression was significantly increased in untreated LPS animals (P < 0.05), whereas in animals treated with LOX-1 antibody, expression of LOX-1 was reduced (P < 0.05). MCP-1 plasma level was reduced after LOX-1 antibody administration.
Inhibition of LOX-1 reduced leukocyte activation in experimental endotoxemia. LOX-1 represents a novel target for the modulation of the inflammatory response within the microcirculation in sepsis.