Effect of pentoxifylline on the fibrogenic functions of cultured rat liver fat-storing cells and myofibroblasts.

The effects of pentoxifylline (PTX) an analogue of the methylxanthine theobromine, on basic fibrogenic reactions of cultured fat-storing cells and myofibroblasts (MFB), the cell types most important for the excessive production of extracellular matrix components in fibrosing liver, were studied. The proliferation of MFB (i.e., activated, transdifferentiated fat-storing cells) was more dose-dependently inhibited by pentoxifylline than that of unactivated fat-storing cells (ED50 50 microgram/mL). In addition, PTX retarded the transdifferentiation of fat-storing cells into smooth muscle alpha-actin positive MFB, a 50% reduction in actin-positive cells being reached with concentrations of 0.5 mg PTX/mL medium. The transdifferentiation-associated decrease in retinyl palmitate of cultured fat-storing cells was delayed by PTX. The synthesis of [35S] sulfate-labeled glycosaminoglycans (GAG) and total and cellular fibronectin was not significantly reduced by treatment of MFB with PTX up to 1.0 mg/mL. It is concluded that PTX reduces the transdifferentiation of fat-storing cells to MFB and the proliferation of MFB, but leaves the synthesis of extracellular matrix components GAG and fibronectin unaffected. The effect of PTX on the former reactions might account for the reported antifibrogenic properties of this drug in experimental hepatic fibrogenesis.

Pharmacological aspects of pentoxifylline with emphasis on its inhibitory actions on hepatic fibrogenesis.

1. Pentoxifylline (PTX), a derivative of the methylxanthine theobromine, has been used for many years in the treatment of peripheral vascular diseases. Increased red blood cell flexibility, reduction of blood viscosity, and decreased potential of platelet aggregation are the basic actions of PTX, resulting in therapeutic benefits due to improved microcirculation and tissue oxygenation. 2. PTX's generally accepted mechanism of action is the inhibition of phosphodiesterases, leading to increased intracellular levels of cyclic adenosine monophosphate (cAMP). 3. A number of studies have shown PTX's effects on the cytokine network. The most relevant clinical results are the therapeutic benefits of PTX in attenuating the effects of tumor necrosis factor-alpha (TNF-alpha) in conditions such as septic shock. 4. PTX also has been found to exert antifibrogenic actions, using cultured fibroblasts or animal models of fibrosis, including liver fibrosis. 5. In hepatic stellate cell culture PTX has been shown to inhibit the basic reactions of liver fibrogenesis, being effective on cytokines and growth factors relevant in fibrogenesis of the liver, too. 6. Therefore, PTX might be an effective drug with few side effects in the treatment of liver fibrosis. Further clinical studies have to be done to establish the real therapeutic benefits of PTX in liver fibrosis and cirrhosis.