Effect of pentoxifylline in rat and swine models of hepatic fibrosis: Role of fibroproliferation in its mechanism

Fibroproliferation was studied in two animal models of liver disease. Oral feeding of yellow phosphorus to pigs reproducibly results in fibrosis after 8 weeks of feeding, extensive fibrosis after 12 weeks and cirrhosis after 16 weeks of yellow phosphorus. Bile duct ligation was used to induce cirrhosis in the rat. Fibroproliferation was assessed as uptake of tritiated thymidine into fibroblasts which had been incubated with monocyte-conditioned medium obtained from monocytes of pigs treated with yellow phosphorus or bile duct-ligated rats and compared to the corresponding controls. Fibrosis was assessed by collagen content of liver sections obtained from the two animal models. The collagen content was determined by quantitation of Sirius red/Fast green-stained liver sections. In both animal models collagen content was significantly elevated at the conclusion of the treatment. Collagen content of liver sections of yellow phosphorus-treated animals were elevated (40 ± 2.7, n = 15) compared to mineral oil-treated controls (23 ± 1.2, n = 12) and collagen levels in the bile duct-ligated rat model liver sections were elevated (31.2 ± 1.6, n = 6) compared to sham-operated controls (21.6 ± 0.7, n = 6). The results of the fibroproliferation assay indicate that monocytes obtained from pigs treated with yellow phosphorus produce fibroproliferative factors during the development of fibrosis. This is in contrast to the bile duct-ligated rat model where no differences were observed in the production of fibroproliferative factors in the bile duct-ligated rats compared to sham operated controls suggesting that this may not be a key event in this model of fibrosis. Pentoxifylline treatment of the yellow phosphorus induced swine model of hepatic fibrosis has been associated with a marked improvement in fibrosis. In this study treatment of fibrotic pigs with pentoxifylline was associated with an improvement in liver function tests, a reduction of collagen content of liver sections, and reduction in fibroproliferation in pigs receiving yellow phosphorus treatment. Fibroproliferative factors were produced during the development of fibrosis in the swine model of fibrosis and their effect was blocked by pentoxifylline administered in vivo. This is in contrast to the bile duct-ligated rat model where pentoxifylline treatment was not associated with improvement in liver function tests or reduction of collagen content of liver sections and did not alter the fibroproliferative activity of monocyte-conditioned media. Taken together these results suggest that fibroproliferation and increased synthesis of collagen are key events in the yellow phosphorus-induced pig model of hepatic fibrosis and that the action of pentoxifylline in this animal model is likely to be related to its effects on fibroproliferation with a subsequent effect on collagen production. This is in contrast to the bile duct-ligated rat model where the results from this study suggest that fibroproliferation per se does not appear to be a key event and where pentoxifylline treatment does not alter fibroproliferative activity nor alter the course of fibrosis in this animal model.