The Influence of Dextran Sulfate on Fibrogenesis in in vivo aud in vitro Experiments. (1975)

Recently, increasing evidence points to the inhibitory effect of dextran sulfate (abbreviated to DS) on the fibrosis of experimental animals. However, the literature dealing with the exact mechanism responsible for this phenomenon is scarce. The aim of the present study was to obtain further information on this problem.In the first experiment, the author has evaluated the inhibitory effect of DS on granulation tissue by measuring its effect upon collagen elaboration in a subcutaneously implanted polyvinyl formal sponge (PVF) in rats. The groups which received intraperitoneal injections of DS for 2 weeks showed a decrease in tissue ingrowth and collagen formation in the PVF sponge implants as compared to controls.Following this study, to evaluate the influence of DS on the formation of pneumoconiosis of rats by the intratracheal injection of a suspended selite solution or fiberous tissue formation in the lung of rabbits induced by the serial i. v. injection of bleomycine, comparative studies between the treated and control groups were made histochemically. From the results of these experiments, it can be shown that the formation of collagen in the lungs of experimental animals was markedly inhibited by the i. p. or i. v. injection of DS.To obtain further information about the effect of DS on the collagen synthesis of fibroblasts, the following experiments were performed on monolayer and suspension cultures of chick embryo fibroblasts. The addition of DS in concentrations from 10 to 1000 μg/ml to the medium of fibroblasts cultures causes a reduction in cell numbers. It was also shown that the incorporation of 3H-deoxyadenosine into DNA synthesized by fibroblast cultures is depressed by the addition of DS.To clarify the lysosomal enzymatic response of cultured fibroblasts to DS treatment, the following histochemical and fluorescencemicroscopic studies were perfomed. When fluorescencemicroscopy is used, the increased lysosomal granules in cultured fibroblasts were demonstrated one hour after the addition of DS. The increased acid phosphatase activities in cultured fibroblasts under treatment with DS was also histochemically demonstrated. Biochemical studies on acid phosphatase and cathepsin D activities show that these enzyme activities were significantly increased at 1 hour after the DS treatment, and then returned to the pretreatment level within 2 hours. The histochemical and biochemical results support the possibilities that the collagenolytic enzyme activity of lysosomal origin may be also induced by DS treatment. From the investigation of the effect of DS on the collagen synthesis of fibroblasts in tissue culture, it was shown that collagen synthesis during DS treatment is significantly inhibited. From the results obtained it can be concluded that inhibition of fibrogenesis in in vivo and in vitro experiments caused by DS can be explained by a reduction in DNA synthesis or by a depression of collagen synthesis. In addition, the increased activity of the lysosomal enzyme induced by DS treatment may also play a role in depression of the intracellular metabolism of fibroblasts.