Quantitative Relation of Cell Proliferation and Fibrogenesis in the Liver^*

To study qualitative and quantitative relations between proliferation of bile ductules and hepatic fibrogenesis, experimental hepatic fibrosis was produced in rats by subacute ethionine intoxication, bile duct ligation, administration of α-naphthylisothiocyanate, and by a high fat-low protein diet. Regression of fibrosis was produced in ethionine-intoxicated animals by treatment with methionine, and the lesion was modified by cortisone treatment and simultaneous methionine administration. Hepatic protein, RNA, DNA, and hydroxyproline as a measure of collagen were correlated with the histologic changes in cell population determined by differential cell counts. After 7 weeks of ethionine administration, collagen and DNA content increased 4–5 times. The liver weight and protein almost doubled. In the same period the total number of ductular cells increased about 50-fold, and mesenchymal cells doubled. After substitution of methionine for ethionine after 7 weeks, the liver catabolized about 3 times the collagen content of the control liver, and the number of ductular cells decreased precipitously. The hydroxyproline/DNA ratio, i.e., the ratio of collagen to total cell number, remained constant in all stages of fibrogenesis induced by ethionine, modifications of ethionine intoxication, α-naphthylisothiocyanate intoxication, bile duct ligation, and in control animals. During recovery from ethionine intoxication, DNA content decreased more rapidly than did hydroxyproline content. It is suggested that the increase in total hepatic protein during ethionine intoxication is a reflection of the proliferation of ductules rather than the formation of an abnormal protein. This cellular proliferation seems to act as a stimulus for fibrogenesis, the ductular cells apparently forming a framework around which fibers are laid down by mesenchymal cells. The disappearance of this framework results in the removal of collagen with mesenchymal cells possibly playing a role in the rapid fibroclasia.