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PROTEOSOME INHIBITOR ENHANCES ANTI-FIBROTIC EFFICACY OF TLR3-STIMULATING AGENT IN HEPATIC FIBROSIS

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Authors
Yang, J. I.; Yoon, J. -H.; Myung, S. J.; Kim, D.; Kim, B. H.; Jung, E. U.; Lee, H. -S.; Lee, Y. J.; Lee, J. S.; Kim, Y. J.; Lee, J. -H.; Kim, H. Y.
Issue Date
2009
Publisher
ELSEVIER SCIENCE BV
Citation
JOURNAL OF HEPATOLOGY; Vol.50 ; S119-S119
Abstract
Background and Aims: Activated hepatic Natural Killer (NK) cells can
attenuate hepatic fibrosis by killing activated hepatic stellate cells (HSCs)
in a TRAIL-dependent manner. Since proteosome inhibitors can induce
TRAIL receptor expression and TLR3 stimulation can activate NK cells,
we attempted to examine if simultaneous treatment of proteosome inhibitor
may enhance anti-fibrotic efficacy of TLR3 stimulating agent in hepatic
fibrosis.
Methods: Hepatic fibrosis in vivo model was established in 8 BALB/c
mice in each group by injecting thioacetamide intraperitoneally three
times per week for 6 weeks. Polyinosinic:polycytidylic acid (poly I:C)
was used as an NK cell-activating agent, which is mediated via TLR3
stimulation, and Bortezomib was used as a proteosome inhibitor. Poly I:C
and Bortezomib were administered intraperitoneally for 5 weeks. Hepatic
fibrosis was assessed by morphometric analysis of histological findings.
HSC apoptosis was assessed by double staining for TUNEL and a smooth
muscle actin.
Results: There were no differences in mortality: 3 died in control mice,
mice treated with poly I:C and mice treated with poly I:C + Bortezomib,
and 2 died in mice treated with Bortezomib. There were no significant
differences in mean body weight among 4 groups. AST and ALT were
higher in control mice and mice treated with Bortezomib than in mice
treated with poly I:C and mice treated with poly I:C + Bortezomib. The
extent of collagen deposition was significantly decreased in mice treated
with poly I:C + Bortezomib as compared to control or single compoundtreated
mice (Figure 1, *p<0.001). The number of TUNEL-positive HSCs
was markedly increased in mice treated with poly I:C + Bortezomib as
compared to control or single compound-treated mice.
Conclusions: These results demonstrate that proteosome inhibitor enhances
anti-fibrotic efficacy of TLR3-stimulating agent in in vivo model of
hepatic fibrosis. Therefore, this combination strategy may therapeutically
be implicated in hepatic fibrosis.
ISSN
0168-8278
Language
English
URI
https://hdl.handle.net/10371/77714
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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