The DOI matches its Crossref record; 21 of the 21 references it cites were found in a registry or an index.
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 α-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.
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“Studies in knockout mice have highlighted a key role for TLR4 and other important mediators in the TLR4 signalling pathway, such as CD14 and lipopolysaccharide-binding protein (LBP), in experimental models of toxic and cholestatic liver fibrosis73,74.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [74]
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Metadata
- Authors
- Isayama, F., Hines, I. N., Kremer, M., Milton, R. J., Byrd, C. L., Perry, A. W., McKim, S. E., Parsons, C., Rippe, R. A., & Wheeler, M. D.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Venue
- American Journal of Physiology-Gastrointestinal and Liver Physiology
- Publisher
- American Physiological Society
- Published
- 2006-06
- Volume
- 290
- Issue
- 6
- Pages
- G1318-G1328
- ISSN
- 0193-1857 (ISSN-L)
- 1522-1547
- OpenAlex
- W2020219616
- Cited by
- 123
- References
- 21
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 4 · 2023: 4 · 2022: 5 · 2021: 3 · 2020: 4 · 2019: 2 · 2018: 8 · 2017: 4 · 2016: 2 · 2015: 8 · 2014: 10 · 2013: 8 · 2012: 15
- FWCI
- 4.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Gastrointestinal and Liver Physiology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Keywords
- liver fibrosis, cholestatic liver disease, lipopolysaccharide signaling, CD14, endotoxemia, hepatic macrophages, bile duct ligation, LPS-binding protein, oxidative stress, 4-hydroxynonenal, alpha-smooth muscle actin, liver injury
- MeSH terms
- Animals, Cholestasis, Disease Models, Animal, Lipopolysaccharides, Liver, Liver Cirrhosis, Male, Mice, Inbred C57BL, Signal Transduction, Mice, Knockout, Lipopolysaccharide Receptors, Mice
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