Abstract

Background: Hepatic fibrosis is characterized by intense tissue remodeling, mainly driven by matrix metalloproteinases. We previously identified CO3-610, a type III collagen neoepitope generated by matrix metalloproteinase (MMP)-9, and tested its performance as a fibrosis marker in rats with bile-duct ligation. In this study, we assessed whether CO3-610 could be used as a surrogate biomarker of liver fibrosis and portal hypertension in carbon tetrachloride-induced experimental fibrosis. Results: For this study, 68 Wistar rats were used. Serum CO3-610 was measured by ELISA. Liver fibrosis was quantified by Sirius red staining. Serum hyaluronic acid (HA) was measured with a binding-protein assay. Gene expression of collagens I and III, Mmp2 and Mmp9, and tissue inhibitors of matrix metalloproteinase 1 (Timp1) and 2(Timp2) was quantified by PCR. Hemodynamic measurements were taken in a subgroup of animals. A close direct relationship was found between serum CO3-610 and hepatic collagen content (r = 0.78; P < 0.001), superior to that found for serum HA (r = 0.49; P < 0.05). CO3-610 levels in rats with severe fibrosis (43.5 ± 3.3 ng/mL, P < 0.001) and cirrhosis (60.6 ± 4.3 ng/mL, P < 0.001) were significantly higher than those in control animals (26.6 ± 1.3 ng/mL). Importantly, a highly significant relationship was found between serum CO3-610 and portal hypertension (r = 0.84; P < 0.001). Liver Mmp9 expression increased significantly in fibrotic animals but decreased to control levels in cirrhotic ones. Conclusions: Circulating CO3-610 behaves as a reliable indicator of hepatic remodeling and portal hypertension in experimental fibrosis. This peptide could ultimately be a useful marker for the management of liver disease in patients.

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