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.