title: Bile high-mobility group box 1 contributes to gut barrier dysfunction in experimental endotoxemia.
abstract: Lipopolysaccharide (LPS) is an important factor in sepsis. LPS given by intraperitoneal injection induces intestinal hyperpermeability and bacterial translocation in animals and stimulates hepatic Kupffer cells to release TNF-alpha into the bile. This study aims to test the hypothesis that in response to LPS stimulation, hepatic Kupffer cells and extrahepatic macrophages release a large amount of the inflammatory cytokine high-mobility group box 1 (HMGB1) into the bile and that bile containing HMGB1 contributes to gut barrier dysfunction in experimental endotoxemia. To test this, rat common bile ducts were catheterized and bile flow rate was monitored before and during the LPS administration. Eight hours after LPS challenge, anti-HMGB1 neutralizing antibody or nonimmune (sham) IgG was injected into the duodenal lumen of endotoxemic rats; normal mice were also gavaged with normal or endotoxemic rat bile (bile collected from LPS-treated rats). We found that after LPS challenge, the bile flow rate in rats was significantly decreased at the 4- to 12-h time points, TNF-alpha concentration in the bile was markedly elevated at the 3- to 4-h time points, and bile HMGB1 levels were significantly increased at the 8- to 12-h time points. Duodenal injection with anti-HMGB1 antibody reversed LPS-induced gut barrier dysfunction in rats. In addition, feeding endotoxemic rat bile to normal mice significantly increased both mucosal permeability and bacterial translocation. The increase in permeability and bacterial translocation was reversible following removal of HMGB1 from the endotoxemic rat bile. These findings document that bile HMGB1 mediates gut barrier dysfunction in experimental endotoxemia.
authors.affiliation: Dept. of Critical Care Medicine, Univ. of Pittsburgh Medical School, 1055 Scaife Hall, 3550 Terrace St., Pittsburgh, PA 15261, USA. yangr@ccm.upmc.edu
authors.forename: Runkuan
authors.initials: R
authors.lastname: Yang
authors.forename: Keita
authors.initials: K
authors.lastname: Miki
authors.forename: Niku
authors.initials: N
authors.lastname: Oksala
authors.forename: Atsunori
authors.initials: A
authors.lastname: Nakao
authors.forename: Leena
authors.initials: L
authors.lastname: Lindgren
authors.forename: Meaghan E
authors.initials: ME
authors.lastname: Killeen
authors.forename: Ari
authors.initials: A
authors.lastname: Mennander
authors.forename: Mitchell P
authors.initials: MP
authors.lastname: Fink
authors.forename: Jyrki
authors.initials: J
authors.lastname: Tenhunen
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D001646:Bile / Q000378:metabolism*; D062445:Claudin-1; D003911:Dextrans / Q000378:metabolism; D019446:Endotoxemia / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000378:metabolism; D024243:HMGB1 Protein / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D007082:Ileum / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology / Q000503:physiopathology; D015850:Interleukin-6 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology / Q000503:physiopathology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D062793:Occludin; D010539:Permeability / Q000187:drug effects; D010750:Phosphoproteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D062826:Zonula Occludens-1 Protein
chemical_list: D000906:Antibodies; D062445:Claudin-1; C568113:Cldn1 protein, mouse; C568114:Cldn1 protein, rat; D003911:Dextrans; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D015850:Interleukin-6; D008565:Membrane Proteins; D062793:Occludin; C568986:Ocln protein, mouse; C568987:Ocln protein, rat; D010750:Phosphoproteins; C569043:Tjp1 protein, mouse; C569044:Tjp1 protein, rat; D014409:Tumor Necrosis Factor-alpha; D062826:Zonula Occludens-1 Protein; C015219:fluorescein isothiocyanate dextran; D016650:Fluorescein-5-isothiocyanate