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 fibr osis after 8 weeks of feeding, extensive fibrosis after 12 weeks and c irrhosis after 16 weeks of yellow phosphorus, Bile duct ligation was u sed to induce cirrhosis in the rat. Fibroproliferation was assessed as uptake of tritiated thymidine into fibroblasts which had been incubat ed with monocyte-conditioned medium obtained from monocytes of pigs tr eated 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 c ontent was determined by quantitation of Sirius red/Fast green-stained liver sections, In both animal models collagen content was significan tly elevated at the conclusion of the treatment. Collagen content of l iver 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 s ections 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 p hosphorus produce fibroproliferative factors during the development of fibrosis. This is in contrast to the bile duct-ligated rat model wher e no differences were observed in the production of fibroproliferative factors in the bile duct-ligated rats compared to sham operated contr ols suggesting that this may not be a key event in this model of fibro sis. Pentoxifylline treatment of the yellow phosphorus induced swine m odel of hepatic fibrosis has been associated with a marked improvement in fibrosis, In this study treatment of fibrotic pigs with pentoxifyl line was associated with an improvement in liver function tests, a red uction of collagen content of liver sections, and reduction in fibropr oliferation in pigs receiving yellow phosphorus treatment. Fibroprolif erative factors were produced during the development of fibrosis in th e swine model of fibrosis and their effect was blocked by pentoxifylli ne administered in vivo. This is in contrast to the bile duct-ligated rat model where pentoxifylline treatment was not associated with impro vement in liver function tests or reduction of collagen content of liv er sections and did not alter the fibroproliferative activity of monoc yte-conditioned media. Taken together these results suggest that fibro proliferation and increased synthesis of collagen are key events in th e 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 coll agen production. This is in contrast to the bile duct-ligated rat mode l where the results from this study suggest that fibroproliferation pe r se does not appear to be a key event and where pentoxifylline treatm ent does not alter fibroproliferative activity nor alter the course of fibrosis in this animal model.