Gadolinium Chloride Inhibits the Spontaneous Resolution of Fibrosis in CCL4-Induced Cirrhosis

Abstract

Current evidence indicates that liver fibrosis is dynamic and can be bidirectional, involving phases of progression and regression, and that in addition to increased matrix synthesis, this pathological process involves major changes in the regulation of matrix degradation. There is also evidence that Kupffer cells participate in both fibrogenesis and fibrolysis. Therefore, the aim of the present work was to study the participation of Kupffer cells on the spontaneous resolution of hepatic fibrosis. Cirrhosis was produced by 3 months of chronic CCl4 intoxication in male Wistar rats, and then CCl4 was discontinued and two groups were formed: One group received gadolinium chloride (10 mg/kg, IP, daily) and the other received the vehicle (water) only for 2 months. Serum enzyme activities of alkaline phosphatase and alanine aminotransferase and liver lipid peroxidation increased by CCl4 treatment but returned to normal by discontinuation of CCl4. GSH, GSH/GSSG, and GSH+GSSG decreased significantly by CCl4, but withdrawal of CCl4 restored normal glutathione parameters. Fibrosis increased five-fold and glycogen decreased significantly by CCl4 treatment, while discontinuation of CCl4 reversed completely glycogen depletion and partially fibrosis. Gadolinium chloride showed effects only in the content of glycogen and collagen; the former was decreased further and the latter remained elevated despite discontinuation of the toxic agent. Persistent fibrosis induced by gadolinium chloride, a selective inhibitor of Kupffer cells, indicates that these cells play a pivotal role in fibrolysis.