title: LPS signaling enhances hepatic fibrogenesis caused by experimental cholestasis in mice.
abstract: Although it is clear that bile acid accumulation is the major initiator of fibrosis caused by cholestatic liver disease, endotoxemia is a common side effect. However, the depletion of hepatic macrophages with gadolinium chloride blunts hepatic fibrosis. Because endotoxin is a key activator of hepatic macrophages, this study was designed to test the hypothesis that LPS signaling through CD14 contributes to hepatic fibrosis caused by experimental cholestasis. Wild-type mice and CD14 knockout mice (CD14(-/-)) underwent sham operation or bile duct ligation and were killed 3 wk later. Measures of liver injury, such as focal necrosis, biliary cell proliferation, and inflammatory cell influx, were not significantly different among the strains 3 wk after bile duct ligation. Markers of liver fibrosis such as Sirius red staining, liver hydroxyproline, and alpha-smooth muscle actin expression were blunted in CD14(-/-) mice compared with wild-type mice after bile duct ligation. Despite no difference in lymphocyte infiltration, the macrophage/monocyte activation marker OX42 (CD11b) and the oxidative stress/lipid peroxidation marker 4-hydroxynonenal were significantly upregulated in wild-type mice after bile duct ligation but not in CD14(-/-) mice. Increased profibrogenic cytokine mRNA expression in the liver after bile duct ligation was significantly blunted in CD14(-/-) mice compared with the wild type. The hypothesis that LPS was involved in experimental cholestatic liver fibrosis was tested using mice deficient in LPS-binding protein (LBP(-/-)). LBP(-/-) mice had less liver injury and fibrosis (Siruis red staining and hydroxyproline content) compared with wild-type mice after bile duct ligation. In conclusion, these data demonstrate that endotoxin in a CD14-dependent manner exacerbates hepatic fibrogenesis and macrophage activation to produce oxidants and cytokines after bile duct ligation.
authors.affiliation: Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, University of North Carolina, Chapel Hill, 27599, USA.
authors.forename: Fuyumi
authors.initials: F
authors.lastname: Isayama
authors.forename: Ian N
authors.initials: IN
authors.lastname: Hines
authors.forename: Michael
authors.initials: M
authors.lastname: Kremer
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Milton
authors.forename: Christy L
authors.initials: CL
authors.lastname: Byrd
authors.forename: Ashley W
authors.initials: AW
authors.lastname: Perry
authors.forename: Stephen E
authors.initials: SE
authors.lastname: McKim
authors.forename: Christopher
authors.initials: C
authors.lastname: Parsons
authors.forename: Richard A
authors.initials: RA
authors.lastname: Rippe
authors.forename: Michael D
authors.initials: MD
authors.lastname: Wheeler
mesh_terms: D000818:Animals; D002779:Cholestasis / Q000150:complications / Q000276:immunology* / Q000473:pathology*; D004195:Disease Models, Animal; D018950:Lipopolysaccharide Receptors / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology*; D008099:Liver / Q000276:immunology / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology / Q000276:immunology* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology
chemical_list: D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides