Document Detail


Intraperitoneal LPS amplifies portal hypertension in rat liver fibrosis.
MedLine Citation:
PMID:  20212458     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Christian J Steib; Anna C Hartmann; Christoph v Hesler; Andreas Benesic; Martin Hennenberg; Manfred Bilzer; Alexander L Gerbes
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-03-08
Journal Detail:
Title:  Laboratory investigation; a journal of technical methods and pathology     Volume:  90     ISSN:  1530-0307     ISO Abbreviation:  Lab. Invest.     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-06-29     Completed Date:  2010-07-19     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0376617     Medline TA:  Lab Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1024-32     Citation Subset:  IM    
Affiliation:
Department of Medicine II (Gastroenterology and Hepatology), Liver Center Munich, University of Munich-Grosshadern, Munich, Germany. christian.steib@med.uni-muenchen.de
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MeSH Terms
Descriptor/Qualifier:
Animals
Cysteine / metabolism
Hypertension, Portal / etiology*,  metabolism
Infusions, Parenteral
Leukotrienes / metabolism
Lipopolysaccharides / administration & dosage*
Liver Cirrhosis / complications*
Male
Myeloid Differentiation Factor 88 / metabolism
Peritonitis / complications*,  metabolism,  physiopathology
Portal Pressure / drug effects*
Rats
Rats, Sprague-Dawley
Thromboxane B2 / metabolism
Toll-Like Receptor 4 / metabolism
Chemical
Reg. No./Substance:
0/Leukotrienes; 0/Lipopolysaccharides; 0/Myd88 protein, rat; 0/Myeloid Differentiation Factor 88; 0/Tlr4 protein, rat; 0/Toll-Like Receptor 4; 0/cysteinyl-leukotriene; 52-90-4/Cysteine; 54397-85-2/Thromboxane B2

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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