Endotoxin-induced mortality in bile duct-ligated rats after administrationof reconstituted high-density lipoprotein

Cholestatic patients have substantial morbidity because of increased suscep tibility to endotoxin (lipopolysaccharide [LPS]). Although reconstituted hi gh-density lipoprotein (rHDL) can bind and neutralize LPS, cholestasis is a ssociated with a near complete absence of HDL. Effects of rHDL infusion on the outcome of LPS-induced inflammatory responses in cholestatic rats were determined. Bile duct-ligated (BDL) and sham rats were treated with rHDL or saline and challenged with LPS. Distribution of cholesterol over the lipop rotein subclasses changed by ligation: levels in low-density lipoprotein (L DL) and very low-density lipoprotein (VLDL) were increased 2-fold and 5-fol d, respectively, and were decreased in HDL 2-fold. rHDL treatment did not a ffect cholesterol distribution. LPS was mainly found in the HDL fraction, a nd ligation affected only levels of HDL-bound LPS (50% decrease; P <.05). A lthough rHDL infusion effectively normalized the lipoprotein-bound LPS dist ribution, it resulted in increased sensitivity (mortality: 88% in the ligat ion+ rHDL group versus 44% in the ligation + saline group, 25% in the sham + saline group, and 0% in the sham + rHDL group, P <.05). In accordance wit h these results, plasma tumor necrosis factor (TNF) was significantly highe st in the BDL + rHDL group at several hours after LPS challenge as well as the accumulation of LPS in the liver (P <.05). rHDL infusion leads to incre ased LPS-induced mortality in cholestatic rats. These results sharply contr ast with the protective effects of rHDL suppletion in experimental endotoxe mia in animals and human volunteers without biliary obstruction and suggest that there may be danger in administration of rHDL to cholestatic patients .