Abstract
To elucidate the dynamic physiopathologic mechanisms of liver fibrosis by investigating the differential proteome of liver tissue during progression of liver fibrosis in a chemically induced rat model. Following treatment with carbon tetrachloride (CCl4), livers were harvested from rats at various time points. The respective total protein extracts were resolved by two-dimensional gel electrophoresis (2-DE) and compared to identify differentially expressed protein spots, which were then analyzed by matrix-assisted laser desorption/ionization two-stage time-of-flight mass spectrometry (MALDI-TOF/TOF-MS) and identified by database querying. The differential expression of selected proteins was validated by Western blotting and immunohistochemical methods. Statistical analyses were carried out by the least significant difference method of one-way ANOVA for parametric data or by the H test for non-parametric data. The severity scores of liver fibrosis increased in a time-dependent manner following CCl4 exposure (post-induction weeks: 3 less than 6 less than 9). Forty-four protein spots were different on the 2-DE maps for the different time points, among which the CK8 and CK18 proteins were identified and verified as significantly differentially expressed as liver fibrosis progressed. Protein expressions of CK8/CK18 were enhanced upon CCl4 exposure and increased over time (untreated controls: 0.113 ± 0.005/0.170 ± 0.030; CCl4-induced rats at week 3: 0.473 ± 0.046/0.530 ± 0.070, at week 6: 0.682 ± 0.087/0.780 ± 0.080, and at week 9: 0.837 ± 0.096/1.390 ± 0.130). Moreover, the rate of "a" determinant mutations for CK8/CK18 was also significantly differently between weeks 3, 6, and 9 (F = 196.085/74.088, 13.870/16.115, and 75.800/75.900, P less than 0.01). Dynamic proteomic analysis of liver tissue can indicate physiopathologic changes in protein expressions that are related to liver fibrosis induced by CCl4. Proteins with differential expression in CCl4-damaged fibrotic liver are associated with cell growth, development and differentiation, cell proliferation and apoptosis, angiogenesis or reconstitution, oxidative stress, substance metabolism and transport, and signal transduction.
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