METHODOLOGY/PRINCIPAL FINDINGS:
Liver fibrosis was induced in mice by repeated
carbon tetrachloride (CCl4) administration, during which the mice received either
Marimastat or vehicle twice daily. A single dose of CCl4 was administered to investigate acute liver injury in mice pretreated with
Marimastat, mice deficient in Mmp9, or mice deficient in both
TNF-alpha receptors. Liver injury was quantified by
alanine aminotransferase (ALT) levels and confirmed by histology. Hepatic
collagen was determined as
hydroxyproline, and expression of fibrogenesis and fibrolysis-related transcripts was determined by quantitative reverse-transcription polymerase chain reaction.
Marimastat-treated animals demonstrated significantly attenuated liver injury and
inflammation but a 25% increase in
collagen deposition. Transcripts related to fibrogenesis were significantly less upregulated compared to vehicle-treated animals, while
MMP expression and activity analysis revealed efficient pharmacologic
MMP-inhibition and decreased fibrolysis following
Marimastat treatment.
Marimastat pre-treatment significantly attenuated liver injury following acute CCl4-administration, whereas Mmp9 deficient animals demonstrated no protection. Mice deficient in both
TNF-alpha receptors exhibited an 80% reduction of serum ALT, confirming the hepatoprotective effects of
Marimastat via the TNF-signaling pathway.
CONCLUSIONS/SIGNIFICANCE: Inhibition of
MMP and TACE activity with
Marimastat during chronic CCl4 administration counterbalanced any beneficial anti-inflammatory effect, resulting in a positive balance of
collagen deposition. Since effective inhibition of
MMPs accelerates
fibrosis progression,
MMP inhibitors should be used with caution in patients with chronic
liver diseases.