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Am J Transl Res. 2013 May 24;5(4):465-9. Print 2013.

Peptidyl arginine deiminase inhibitor effect on hepatic fibrogenesis in a CCl4 pre-clinical model of liver fibrosis.

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Assay Development, Nordic Bioscience Copenhagen, Denmark ; Department of Endocrinology, University of Southern Denmark Odense, Denmark.


Having previously shown that levels of the citrullinated vimentin peptide VICM are raised in liver fibrosis in rats, we aimed to investigate whether inhibition of citrullination as measured by VICM levels could affect fibrogenesis.


Fibrogenesis was evaluated by quantitative histology and circulating levels of collagen type III in a carbon tetrachloride (CCl4) rat model of liver fibrosis for 6 weeks (n=40+10 untreated controls). The first treatment group (n=20) was treated exclusively with CCl4 for the duration of the study.The second treatment group (n=20) was additionally treated, for the same period, with N-a-benzoyl-N5-(2 Chloro-1-iminoethyl)-L-Ornithine amide, a known PAD inhibitor.


All 40 CCl4 treated animals showed a statistically significant increase in total collagen (p<0.0001) and C3M levels (p<0.001) compared with controls assessed by quantitative histology. Animals additionally treated with the PAD inhibitor showed a statistically significant increase when compared with controls for both total collagen (p<0.001) and C3M levels (p<0.0001) but no statistically difference when compared with animals treated only with CCl4. The mean systemic level of VICM in control animals was 115 ng/ml at 6 weeks. In CCl4-treated animals, mean systemic VICM levels increased 324% at week 6 (p<0.001). The mean level of the marker in CCl4-treated rats was not statistically significant from that in controls (P>0.05). In PAD-treated animals VICM levels were 51% (P<0.05) lower than in non-PAD CCl4-treated animals.


The PAD inhibitor did not reduce fibrogenesis in this preclinical model. However circulating VICM marker levels were decreased in the presence of the PAD inhibitor.


Biomarker; CCl4; PAD inhibitor; VICM; citrulline; liver fibrosis; vimentin

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