Oral Treatment with PBI-4425 Decreases Fibrosis
in Carbon Tetrachloride (CCl4)-Induced Hepatic Fibrosis Model
Brigitte Grouix, François Sarra-Bournet, Kathy Hince, Alexandra Felton, Mikaël Tremblay,
Shaun Abbott, Jean-Simon Duceppe, Boulos Zacharie, Pierre Laurin and Lyne Gagnon
PROMETIC BIOSCIENCES INC., LAVAL, QUÉBEC, CANADA
BACKGROUND AND AIM
PBI-4425 reduces CCl4-induced fibrosis in liver
Control
Histomorphometric analysis
CCl4
CCl4 + PBI-4425 (100 mg/kg)
CCl4 + PBI-4425 (200 mg/kg)
Collagen
1.00
% of Collagen
Chronic liver diseases are a major cause of mortality
and morbidity worldwide. Liver fibrosis is characterized by progressive accumulation of extracellular
matrix (ECM) proteins, including collagens, resulting
in destruction of the hepatic architecture.
The purpose of this study was to investigate the effect
of PBI-4425, an anti-inflammatory/fibrotic compound,
on hepatic fibrosis induced by administration of carbon
tetrachloride (CCl4) in C57BL/6 mice.
RESULTS
0.75
*
0.50
0.25
****
0.00
Sham
CCl4
Photomicrographs of liver tissue (100X).
****
0.25
Sham
CCl4
CCl4 +
CCl4 +
PBI-4425
PBI-4425
(100 mg/kg) (200 mg/kg)
***
0.75
0.50
0.25
0.00
**
0.00
CCl4
CCl4 +
CCl4 +
PBI-4425
PBI-4425
(100 mg/kg) (200 mg/kg)
*
1.00
0.75
0.50
****
0.25
CCl4
CCl4 +
CCl4 +
PBI-4425
PBI-4425
(100 mg/kg) (200 mg/kg)
CCl4 +
CCl4 +
PBI-4425
PBI-4425
(100 mg/kg) (200 mg/kg)
TIMP-1
1.25
0.00
Sham
1.00
0.75
0.50
0.25
0.00
Sham
CCl4
CCl4 +
CCl4 +
PBI-4425
PBI-4425
(100 mg/kg) (200 mg/kg)
Sham
CCl4
CCl4 +
CCl4 +
PBI-4425
PBI-4425
(100 mg/kg) (200 mg/kg)
PBI-4425 restores PPARγ gene expression
****
2.0
***
****
1.5
1.0
0.5
0.0
Sham
Statistics: *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. (Student’s
t-test), compared to CCl4 group.
**
0.25
2.5
*
*
0.50
HGF
1.25
1.00
1.00
0.75
MMP-2
1.25
Relative Quantitation
0.50
PBI-4425 improves liver regeneration
Relative Quantitation
Fibrosis in mouse liver was evaluated by mRNA
expression of fibrotic, remodeling and EMT markers
using mouse TaqMan® Gene Expression Assays, and
collagen was measured by histomorphometric analysis
of liver tissue stained by Masson’s Trichrome.
**
0.75
0.00
DAY 59
Euthanasia and
fibrosis evaluation
Relative Quantitation
C57BL6/J male
1.00
α-SMA
1.25
Relative Quantitation
IP injection of 2 ml/kg of CCl4 10% in
olive oil, twice a week for 8 weeks
Relative Quantitation
CCl4-INDUCED LIVER FIBROSIS STUDY DESIGN
DAY 1
Oral administration
of vehicle or PBI-4425
(100 or 200 mg/kg, day 1 to 58)
Collagen 1
1.25
PBI-4425 reduces remodeling markers
Relative Quantitation
PBI-4425 reduces fibrotic and EMT markers
METHODS
*
Sham
CCl4
CCl4 +
CCl4 +
PBI-4425
PBI-4425
(100 mg/kg) (200 mg/kg)
CONCLUSIONS
PBI-4425:
► Reduces pro-fibrotic markers
► Reduces collagen deposition in liver
► Improves liver regeneration
► Restores PPARγ gene expression
Taken together, these results suggest
that PBI-4425 offers the potential as
a novel therapy for hepatic fibrosis.