title: Apolipoprotein E protects against bacterial lipopolysaccharide-induced lethality. A new therapeutic approach to treat gram-negative sepsis.
abstract: Septic shock is the most common cause of death in intensive care units and no effective treatment is available at present. Lipopolysaccharide (LPS) is the primary mediator of Gram-negative sepsis by inducing the production of macrophage-derived cytokines. Previously, we showed that apolipoprotein E (apoE), an established modulator of lipid metabolism, can bind LPS, thereby redirecting LPS from macrophages to hepatocytes in vivo. We now report that intravenously administered LPS strongly increases the serum levels of apoE. In addition, apoE can prevent the LPS-induced production of cytokines and subsequent death in rodents. Finally, apoE-deficient mice show a significantly higher sensitivity toward LPS than control wild-type mice. These findings indicate that apoE may have a physiological role in the protection against sepsis, and recombinant apoE may be used therapeutically to protect against LPS-induced endotoxemia.
authors.affiliation: Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, University of Leiden, Sylvius Laboratories, P. O. Box 9503, 2300 RA Leiden, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Van Oosten
authors.forename: P C
authors.initials: PC
authors.lastname: Rensen
authors.forename: E S
authors.initials: ES
authors.lastname: Van Amersfoort
authors.forename: M
authors.initials: M
authors.lastname: Van Eck
authors.forename: A M
authors.initials: AM
authors.lastname: Van Dam
authors.forename: J J
authors.initials: JJ
authors.lastname: Breve
authors.forename: T
authors.initials: T
authors.lastname: Vogel
authors.forename: A
authors.initials: A
authors.lastname: Panet
authors.forename: T J
authors.initials: TJ
authors.lastname: Van Berkel
authors.forename: J
authors.initials: J
authors.lastname: Kuiper
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017208:Rats, Wistar; D012475:Salmonella / Q000472:pathogenicity*; D018805:Sepsis / Q000382:microbiology / Q000628:therapy*
chemical_list: D001057:Apolipoproteins E; D008070:Lipopolysaccharides