Matrix metalloproteinase inhibitor, CTS-1027, attenuates liver injury and fibrosis in the bile duct-ligated mouse.
OBJECTIVE
Excessive matrix metalloproteinase (MMP) activity has been implicated in the pathogenesis of acute and chronic liver injury. CTS-1027 is an MMP inhibitor, which has previously been studied in humans as an anti-arthritic agent. Thus, our aim was to assess if CTS-1027 is hepato-protective and anti-fibrogenic during cholestatic liver injury.


METHODS
C57/BL6 mice were subjected to bile duct ligation (BDL) for 14 days. Either CTS-1027 or vehicle was administered by gavage.


RESULTS
BDL mice treated with CTS-1027 demonstrated a threefold reduction in hepatocyte apoptosis as assessed by the TUNEL assay or immunohistochemistry for caspase 3/7-positive cells as compared to vehicle-treated BDL animals (P < 0.01). A 70% reduction in bile infarcts, a histological indicator of liver injury, was also observed in CTS-1027-treated BDL animals. These differences could not be ascribed to differences in cholestasis as serum total bilirubin concentrations were nearly identical in the BDL groups of animals. Markers for stellate cell activation (alpha-smooth muscle actin) and hepatic fibrogenesis (collagen 1) were reduced in CTS-1027 versus vehicle-treated BDL animals (P < 0.05). Overall animal survival following 14 days of BDL was also improved in the group receiving the active drug (P < 0.05).


CONCLUSIONS
The BDL mouse, liver injury and hepatic fibrosis are attenuated by treatment with the MMP inhibitor CTS-1027. This drug warrants further evaluation as an anti-fibrogenic drug in hepatic injury.
Kahraman
Alisan
A
Miles and Shirley Fitterman Center for Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Bronk
Steven F
SF
Cazanave
Sophie
S
Werneburg
Nathan W
NW
Mott
Justin L
JL
Contreras
Patricia C
PC
Gores
Gregory J
GJ