Matrix metalloproteinase inhibitor, CTS-1027, attenuates liver injury and fibrosis in the bile duct-ligated mouse

Alisan Kahraman, Steven F. Bronk, Sophie Cazanave, Nathan W. Werneburg, Justin L. Mott, Patricia C. Contreras, Gregory J. Gores

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Aim: 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 (α-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). Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)805-813
Number of pages9
JournalHepatology Research
Volume39
Issue number8
DOIs
StatePublished - Aug 14 2009

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Matrix Metalloproteinase Inhibitors
Bile Ducts
Liver Cirrhosis
Ligation
Wounds and Injuries
Liver
Pharmaceutical Preparations
Caspase 7
Cholestasis
In Situ Nick-End Labeling
Matrix Metalloproteinases
Bilirubin
Bile
Caspase 3
Arthritis
Smooth Muscle Myocytes
Actins
Hepatocytes
Fibrosis
Collagen

Keywords

  • Apoptosis
  • Cholestasis
  • Liver fibrosis
  • Matrix metalloproteinase

ASJC Scopus subject areas

  • Hepatology
  • Infectious Diseases

Cite this

Matrix metalloproteinase inhibitor, CTS-1027, attenuates liver injury and fibrosis in the bile duct-ligated mouse. / Kahraman, Alisan; Bronk, Steven F.; Cazanave, Sophie; Werneburg, Nathan W.; Mott, Justin L.; Contreras, Patricia C.; Gores, Gregory J.

In: Hepatology Research, Vol. 39, No. 8, 14.08.2009, p. 805-813.

Research output: Contribution to journalArticle

Kahraman, Alisan ; Bronk, Steven F. ; Cazanave, Sophie ; Werneburg, Nathan W. ; Mott, Justin L. ; Contreras, Patricia C. ; Gores, Gregory J. / Matrix metalloproteinase inhibitor, CTS-1027, attenuates liver injury and fibrosis in the bile duct-ligated mouse. In: Hepatology Research. 2009 ; Vol. 39, No. 8. pp. 805-813.
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AU - Kahraman, Alisan

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AU - Cazanave, Sophie

AU - Werneburg, Nathan W.

AU - Mott, Justin L.

AU - Contreras, Patricia C.

AU - Gores, Gregory J.

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N2 - Aim: 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 (α-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). Conclusion: 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.

AB - Aim: 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 (α-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). Conclusion: 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.

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