Modulation of endotoxin-induced endothelial cell toxicity by low density lipoprotein.
Bacterial endotoxins (lipopolysaccharides (LPS] have been reported to the toxic to endothelial cells in vivo. In vitro they have been shown to be toxic to bovine endothelial cells but not to human endothelial cells. In this report we demonstrate that the presence of plasma low density lipoprotein (LDL) protected bovine endothelial cells from LPS-induced toxicity whereas the presence of LDL actually promoted LPS-induced toxicity to human endothelial cells. These effects of LPS were independent of its source or method of preparation. High density lipoprotein also inhibited LPS-induced toxicity to bovine endothelial cells but unlike LDL, did not enhance LPS-induced toxicity to human cells. The toxicity of LPS to human endothelial cells in the presence of LDL required the oxidation of LDL by free radicals produced by the endothelial cells. LDL modified by acetylation enhanced LPS-induced toxicity to both human and bovine endothelial cells. The toxicity to human endothelial cells of LPS plus either LDL (after endothelial cell-mediated oxidation) or acetyl-LDL was inhibited by fucoidin and polyinosinic acid, blockers of the acetyl-LDL (scavenger) receptor. Polymyxin B, a specific LPS antagonist, inhibited the toxicity of LPS to bovine endothelial cells but not the toxicity of LPS plus LDL to human endothelial cells. These results are consistent with our hypothesis that LDL prevents the toxicity of LPS to bovine endothelial cells by binding the LPS and making it less accessible to the cells. Human endothelial cells are not directly susceptible to LPS-induced toxicity but, unlike bovine cells, produce oxygen free radicals in sufficient quantity to oxidize LDL and render the LDL-LPS complex recognizable for uptake by a scavenger receptor-like process similar to that for acetyl-LDL. LPS thus enters the human endothelial cells via this complex and kills the cells. These findings may have important implications for the study of LPS-induced toxicity to endothelial cells in vitro and for understanding the phenomenon in vivo.
D000818:Animals; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004727:Endothelium / Q000187:drug effects*; D004731:Endotoxins / Q000633:toxicity*; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011112:Polymyxin B / Q000494:pharmacology; D013045:Species Specificity
D004731:Endotoxins; D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D011112:Polymyxin B