Time-course of changes in fibrous components in a thioacetamide-induced liver fibrosis model in cynomolgus monkeys.

Abstract

In liver fibrosis, the possible causes of irreversibility include the accumulation of collagen I during extracellular matrix remodeling, together with the deposition of elastic fibers in later stages. Drug development targeting liver fibrosis should preferably employ models that closely mimic human diseases. To better understand the progress of fibrosis in a cynomolgus monkey liver fibrosis model, we evaluated the time-course of changes in the fibrosis score, collagens, and elastic fibers. The animals were subcutaneously administered thioacetamide twice a week (experiment 1) or once every 2 weeks (experiment 2). Liver tissues were collected at 8 and 16 (experiment 1) or 10 and 20 (experiment 2) weeks of administration, and 12 weeks after withdrawal (experiments 1 and 2). The fibrosis score was evaluated by Masson's trichrome staining. Immunohistochemistry for collagen Ia1, III, and IV, and Elastica van Gieson staining were also performed. Fibrosis was observed from week 8 (experiment 1) or 10 (experiment 2), and in most animals, it progressed during the administration period. After withdrawal, the fibrosis scores tended to decrease. Collagen IV was predominant in the early stage but was replaced by collagen I after 20 weeks in both experiments. Collagen III distributed mostly along with collagen I throughout the study period. The elastic fibers deposition was markedly limited throughout the experiment. Fibrous component examination showed that the main collagen type contributing to fibrosis shifted from collagen IV to I after 20 weeks or later and revealed that the fibrosis status is not fully reflected in the fibrosis score.