Broad-Spectrum Matrix Metalloproteinase Inhibition Curbs Inflammation and Liver Injury but Aggravates Experimental Liver Fibrosis in Mice by Vincent E de Meijer, Deanna Y. Sverdlov, Yury Popov, Hau D. Le, Jonathan A. Meisel, Vânia Nosé, Detlef Schuppan, Mark Puder.
Liver fibrosis is characterized by excessive synthesis of extracellular matrix proteins, which prevails over their enzymatic degradation, primarily metalloproteinases (MMPs). The effect pharmacological MMP inhibition on fibrogenesis, however, largely unexplored. Inflammation considered a prerequisite and important co-contributor to is, in part, mediated tumor necrosis factor (TNF)-alpha-converting enzyme (TACE). We hypothesized that treatment with broad-spectrum TACE-inhibitor (Marimastat) would ameliorate injury inflammation, leading decreased fibrogenesis during repeated hepatotoxin-induced liver injury.Liver was induced mice carbon tetrachloride (CCl4) administration, the received either Marimastat or vehicle twice daily. A single dose CCl4 administered investigate acute pretreated Marimastat, deficient Mmp9, both TNF-alpha receptors. quantified alanine aminotransferase (ALT) levels confirmed histology. Hepatic collagen determined as hydroxyproline, expression fibrolysis-related transcripts quantitative reverse-transcription polymerase chain reaction. Marimastat-treated animals demonstrated significantly attenuated inflammation but 25% increase deposition. Transcripts related were less upregulated compared vehicle-treated animals, while activity analysis revealed efficient pharmacologic MMP-inhibition fibrolysis following treatment. pre-treatment CCl4-administration, whereas Mmp9 no protection. Mice receptors exhibited an 80% reduction serum ALT, confirming hepatoprotective effects via TNF-signaling pathway.Inhibition TACE chronic administration counterbalanced any beneficial anti-inflammatory effect, resulting positive balance Since effective MMPs accelerates progression, inhibitors should be used caution patients diseases.
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