Intraperitoneal LPS amplifies portal hypertension in rat liver fibrosis
Open accessAbstract
Recent studies have shown that the risk of variceal bleeding in patients with liver cirrhosis increases with infections such as spontaneous bacterial peritonitis (SBP). In this study, we hypothesized that pretreatment with intraperitoneal LPS may escalate portal hypertension. In fibrotic livers (4 weeks after bile duct ligation, BDL), the activation of Kupffer cells (KCs) by zymosan (150 microg/ml) in the isolated non-recirculating liver perfusion system resulted in a transient increase in portal perfusion pressure. Pretreatment with intraperitoneal LPS (1 mg/kg body weight (b.w.) for 3 h) increased basal portal perfusion pressure, and prolonged the zymosan-induced increase from transient to a long-lasting increase that was sustained until the end of the experiments in BDL but not in sham-operated animals. Pretreatment with gadolinium chloride (10 mg/kg b.w.), MK-886 (0.6 mg/kg b.w.), Ly171883 (20 microM) or BM 13.177 (20 microM) reduced the maximal and long-lasting pressure increase in BDL animals by approximately 50-60%. The change in portal perfusion pressure was paralleled by a long-lasting production of cysteinyl leukotriene (Cys-LT) and thromboxane (TX) after LPS pretreatment. However, the response to vasoconstrictors was not altered by intraperitoneal LPS. Western blot analyses showed an increased Toll-like receptor (TLR)4 and MyD88 expression after LPS pretreatment. In vivo experiments confirmed that intraperitoneal LPS increased basal portal pressure, and extended the portal pressure increase produced by intraportal zymosan or by LPS infusion. In conclusion, upregulation of TLR4 and MyD88 expression in fibrotic livers confers hypersensitivity to LPS. This may lead to escalation of portal hypertension by production of TX and Cys-LT after endotoxin-induced KC activation. Therefore, LT inhibitors may represent a promising treatment option in addition to early administration of antibiotics in SBP.
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Targeting the gut-microbiota-liver axis reduces liver fibrosis and portal hypertension in rodents.
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The gut microbiome and liver cancer: mechanisms and clinical translation
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- Authors
- Steib, C. J., Hartmann, A. C., Hesler, C. V., Benesic, A., Hennenberg, M., Bilzer, M., & Gerbes, A. L.
- Affiliations
- Ludwig-Maximilians-Universität München (DE)
- Corresponding author
- Steib, Christian J
- Venue
- Laboratory Investigation
- Publisher
- Elsevier BV
- Published
- 2010-07
- Volume
- 90
- Issue
- 7
- Pages
- 1024-1032
- ISSN
- 0023-6837 (ISSN-L)
- OpenAlex
- W2008153192
- Cited by
- 54
- References
- 36
- Citations by year
- 2025: 4 · 2024: 3 · 2023: 2 · 2022: 3 · 2021: 3 · 2020: 3 · 2019: 4 · 2018: 6 · 2017: 5 · 2016: 4 · 2015: 5 · 2014: 3 · 2013: 3 · 2012: 4
- FWCI
- 1.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Laboratory Investigation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Keywords
- portal hypertension, liver fibrosis, spontaneous bacterial peritonitis, Kupffer cell activation, zymosan, bile duct ligation, cysteinyl leukotrienes, thromboxane, TLR4, MyD88, leukotriene receptor antagonists, gadolinium chloride, MK-886, liver cirrhosis
- MeSH terms
- Animals, Cysteine, Hypertension, Portal, Infusions, Parenteral, Lipopolysaccharides, Liver Cirrhosis, Male, Peritonitis, Thromboxane B2, Leukotrienes, Portal Pressure, Rats, Sprague-Dawley, Toll-Like Receptor 4, Rats, Myeloid Differentiation Factor 88
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