Macrophage Populations, Myofibroblastic Cells, and Extracellular Matrix Accumulation in Chronically-Developing Rat Liver Cirrhosis Induced by Repeated Injection of Thioacetamide.

Abstract

In order to clarify the cellular and molecular aspects in cirrhotic lesions, we investigated the response of macrophage populations, myofibroblastic cell development, and deposition of extracellular matrices (ECMs), as well as expression patterns of fibrogenic factors, in chronically-developing hepatic cirrhosis induced in rats by thioacetamide (TAA). As an animal model, male F344 rats were rendered cirrhotic by repeated intraperitoneal injection of TAA (100 mg/kg BW; twice a week), and were examined at post-first injection (PFI) weeks 1, 3, 5, 7, 10, 15, and 20. Histologically, hepatocyte degeneration became evident in the perivenular and periportal areas with time, and from PFI weeks 10 micronodular lesions separated by fibrous septa were developed. ECMs (collagen types I, III, and IV, fibronectin and laminin) deposited with advancing lesions. ED1-immunopositive exudate macrophages showed an increased number for 20 weeks. ED2-immunopositive Kupffer cells and antigen-presenting macrophages reacting to OX6 (MHC class II-recognized antibody) revealed a transiently increased number at PFI weeks 1 and 3; interestingly, Kupffer cells became hypertrophic with time. The number of myofibroblastic cells reacting to α-smooth muscle actin was increased from PFI week 1, with a peak at PFI week 10. The semiquantitative analysis by the reverse transcription polymerase chain reaction revealed that expressions of transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α) mRNAs could be increased for 20 weeks. These results indicated that different macrophage populations participated in chronically-developing rat hepatic cirrhosis with different kinetics patterns, and that these macrophages might be related to myofibroblastic cell development through the production of fibrogenic factors such as TGF-β1 and TNF-α.