SEPSIS INCREASES ENDOCYTOSIS OF ENDOTOXIN INTO HEPATOCYTES

Background, Chylomicrons bind endotoxins and accelerate their clearanc e from plasma to the liver This results in reduced mortality from sept ic shock in a rodent model. We hypothesized that the clearance of the LPS-chylomicron (LPS-CM) complex by hepatocytes is due to receptor-med iated endocytosis and that sepsis up-regulates this process. Methods. Three groups of Sprague-Dawley rats; (1) control; (2) pretreated with 10 mu g/kg LPS 24 hours before treatment; and (3) pretreated with 17 p roportional to-ethinyl estradiol (EE, 5 mg/kg subcutaneously for 3 day s), were infused with labeled I-125-LPS alone with I-125-LPS bound to chylomicron. Livers were removed 2.5, 15, and 30 minutes after LPS inj ection and hepatic endosomes were isolated from the liver homogenates by serial ultracentrifugation in sucrose gradients. Results. The injec tion of I-125-LPS-CM complexes resulted in higher levels of endosomal I-125-LPS in all groups, as compared with I-125-LPS alone. In addition , the endosomal uptake of I-125-LPS was markedly increased by both LPS and LE pretreatments. Conclusions, These data strongly suggest a prim ary role for receptor-mediated endocytosis in the increased clearance of LPS when bound to chylomicron. In addition, exposure to LPS appears to increase the accumulation of LPS in endosomes by a mechanism simil ar to that of EE, which is known to up-regulate receptor-mediated lipo protein uptake. This endogenous pathway for the catabolism of endotoxi ns may provide a teleological explanation for the hypertriglyceridemia observed during sepsis.