Platelet-derived growth factor and pentoxifylline modulation of collagen synthesis in myofibroblasts

Fibroblast proliferation and extracellular matrix accumulation are two major events occurring in fibrosis. Hepatic stellate cells are the major collagen-producing cells of the liver and are transformed into proliferative myofibroblasts following activation. Whether proliferation and extracellular matrix production are regulated by the same cytokines is not known. Monocyte-conditioned medium obtained from pigs with yellow phosphorus-induced hepatic fibrosis increased the collagen production by cultured porcine myofibroblasts. Liver biopsies from these same fibrotic animals had increased levels of collagen α1(I) and α1(III) mRNA compared to control animals. Preincubation with platelet-derived growth factor (PDGF) B/B antibody significantly reduced the collagen-stimulating ability of the monocyte-conditioned medium. Recombinant PDGF stimulated proliferation in nonconfluent myofibroblasts and stimulated collagen production in confluent cultures of myofibroblasts without increasing cell number, suggesting that these events can occur independent of each other. Pentoxifylline and one of its active metabolites (metabolite-1) inhibited PDGF-stimulated collagen production in cultured porcine myofibroblasts. These results demonstrate the importance of PDGF in the pathogenesis of liver fibrosis and provide evidence that pentoxifylline interferes with PDGF-mediated events during experimental liver fibrosis.