Abstract
BACKGROUND & AIMS:
Intestinal hyper-permeability, impaired peritoneal macrophages (PMs) phagocytosis, and, bacterial translocation (BT) resulting in increased systemic and local infection/inflammation such as spontaneous bacterial peritonitis (SBP), together with increased tumor necrosis factor-α (TNFα) levels, are all implicated in the pathogenesis of cirrhosis-related complications. Manipulation of cannabinoid receptors (CB1R and CB2R), which are expressed on the gut mucosa and PMs, has been reported to modulate intestinal inflammation and systemic inflammatory cytokines release. Our study aims to explore the effects of chronic CB1R/CB2R agonist/antagonist treatments on relevant abnormalities in cirrhotic ascitic rats.
METHODS:
Vehicle, archidonyl-2-chloroethylamide (ACEA, CB1R agonist), JWH133 (CB2R agonist), and AM630 (CB2R antagonist) were given to thioacetamide (TAA)- and common bile duct ligation (BDL)-cirrhotic rats with ascites for 2-weeks and various measurement were performed.
RESULTS:
Compared to sham rats, CB2Rs were down-regulated in cirrhotic rat intestines and PMs. Two-week JWH133 treatment significantly decreased systemic/intestinal oxidative stress, TNFα and inflammatory mediators, infection, intestinal mucosal damage and hyper-permeability, bacterial overgrowth/adhesion, BT and SBP, up-regulating intestinal tight-junctions and down-regulating the PM TNFα receptors/NFκp65 proteins expression in cirrhotic rats. Acute and chronic JWH133 treatment corrected the TNFα -induced suppression of phagocytosis of cirrhotic rat PMs, which then could be reversed by concomitant AM630 treatment.
CONCLUSIONS:
Our study suggests that CB2R agonist have the potential to treat BT and various relevant abnormalities through the inhibition of systemic/intestinal oxidative stress, inflammatory cytokines and TNFα releases in cirrhosis. Overall, chronic CB2R agonist treatment affects multiple approach mechanisms, and the direct effect on hyperdynamic circulation is only minor.
Copyright © 2014. Published by Elsevier B.V.
KEYWORDS:
Bacterial Translocation; Cannabinoid Receptors; Intestinal Hyper-permeability; Peritoneal Macrophages; Spontaneous Bacterial Peritonitis
- PMID:
- 24953022
- [PubMed – as supplied by publisher]
