title: Blood-Borne Lipopolysaccharide Is Rapidly Eliminated by Liver Sinusoidal Endothelial Cells via High-Density Lipoprotein.
abstract: During Gram-negative bacterial infections, excessive LPS induces inflammation and sepsis via action on immune cells. However, the bulk of LPS can be cleared from circulation by the liver. Liver clearance is thought to be a slow process mediated exclusively by phagocytic resident macrophages, Kupffer cells (KC). However, we discovered that LPS disappears rapidly from the circulation, with a half-life of 2-4 min in mice, and liver eliminates about three quarters of LPS from blood circulation. Using microscopic techniques, we found that ∼75% of fluor-tagged LPS in liver became associated with liver sinusoidal endothelial cells (LSEC) and only ∼25% with KC. Notably, the ratio of LSEC-KC-associated LPS remained unchanged 45 min after infusion, indicating that LSEC independently processes the LPS. Most interestingly, results of kinetic analysis of LPS bioactivity, using modified limulus amebocyte lysate assay, suggest that recombinant factor C, an LPS binding protein, competitively inhibits high-density lipoprotein (HDL)-mediated LPS association with LSEC early in the process. Supporting the previous notion, 3 min postinfusion, 75% of infused fluorescently tagged LPS-HDL complex associates with LSEC, suggesting that HDL facilitates LPS clearance. These results lead us to propose a new paradigm of LSEC and HDL in clearing LPS with a potential to avoid inflammation during sepsis.
authors.affiliation: Department of Internal Medicine, The Ohio State University, Columbus, OH 43210;
authors.forename: Zhili
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Department of Internal Medicine, The Ohio State University, Columbus, OH 43210;
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Mates
authors.affiliation: Department of Internal Medicine, The Ohio State University, Columbus, OH 43210;
authors.forename: Alana M
authors.initials: AM
authors.lastname: Cheplowitz
authors.affiliation: Department of Internal Medicine, The Ohio State University, Columbus, OH 43210;
authors.forename: Lindsay P
authors.initials: LP
authors.lastname: Hammer
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Maryland, Baltimore, MD 21201;
authors.forename: Andrei
authors.initials: A
authors.lastname: Maiseyeu
authors.affiliation: Department of Biostatistics, The Ohio State University, Columbus, OH 43210;
authors.forename: Gary S
authors.initials: GS
authors.lastname: Phillips
authors.affiliation: Department of Internal Medicine, The Ohio State University, Columbus, OH 43210;
authors.forename: Mark D
authors.identifier: 0000-0002-7079-5633
authors.initials: MD
authors.lastname: Wewers
authors.affiliation: Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210; and.
authors.forename: Murugesan V S
authors.identifier: 0000-0002-1515-1122
authors.initials: MV
authors.lastname: Rajaram
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH 43210.
authors.forename: John M
authors.initials: JM
authors.lastname: Robinson
authors.affiliation: Department of Internal Medicine, The Ohio State University, Columbus, OH 43210;
authors.forename: Clark L
authors.initials: CL
authors.lastname: Anderson
authors.affiliation: Department of Internal Medicine, The Ohio State University, Columbus, OH 43210; Ganesan.Prabha@osumc.edu.
authors.forename: Latha P
authors.identifier: 0000-0002-4236-6620
authors.initials: LP
authors.lastname: Ganesan
mesh_terms: D000209:Acute-Phase Proteins / Q000276:immunology / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology / Q000502:physiology*; D016905:Gram-Negative Bacterial Infections / Q000276:immunology; D006207:Half-Life; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control; D007700:Kinetics; D007728:Kupffer Cells / Q000276:immunology; D008070:Lipopolysaccharides / Q000097:blood* / Q000276:immunology / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000276:immunology / Q000378:metabolism*; D008099:Liver / Q000166:cytology* / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018805:Sepsis / Q000276:immunology; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D008070:Lipopolysaccharides; D008075:Lipoproteins, HDL; D008562:Membrane Glycoproteins; D000099231:Lipopolysaccharide-Binding Protein