SUPPRESSION OF KUPFFER CELL-FUNCTION PREVENTS CADMIUM-INDUCED HEPATOCELLULAR NECROSIS IN THE MALE SPRAGUE-DAWLEY RAT

Exposure of humans to toxic metals and metalloids is a major environme ntal problem. Many metals, such as cadmium, can be hepatotoxic. Howeve r, the mechanisms by which metals cause acute hepatic injury are in ma ny cases unknown. Previous reports suggest a major role for inflammati on in acute cadmium induced hepatotoxicity. In initial experiments we found that a non-hepatotoxic dose of cadmium chloride (CdCl2; 2.0 mg/k g, i.v.) markedly increased the clearance rate of colloidal carbon fro m the blood, which is indicative of enhanced phagocytic activity by Ku pffer cells (resident hepatic macrophages). Thus, the objective these studies was to determine the involvement of Kupffer cells in cadmium i nduced liver injury by inhibiting their function with gadolinium chlor ide (GdCl3). Male Sprague-Dawley rats were administered GdCl3 (10 mg/k g, i.v.) followed 24 h later by a single dose of CdCl2 (3.0 and 4.0 mg /kg, i.v.). Twenty four hours after CdCl2 administration animals were killed and the degree of liver toxicity was assessed using plasma alan ine aminotransferase (ALT), as well as light microscopy. Cadmium chlor ide administration produced multifocal hepatocellular necrosis and inc reased plasma ALT activity. Pretreatment with GdCl3 significantly redu ced both the morphological changes and hepatic ALT release caused by C dCl2. However, the protection was specific to the liver, and did not a lter CdCl2 induced testicular injury, as determined by histopathologic al damage. In many cases, the inducible cadmium-binding protein, metal lothionein (MT) is often an essential aspect of the acquisition of cad mium tolerance in the liver. Although cadmium caused a dramatic induct ion of hepatic MT (32-fold), GdCl3 caused only a minor increase (2-fol d). Combined CdCl2 and GdCl3 treatment did not induce levels to an ext ent greater than CdCl2 alone. As expected, GdCl3 also caused a slight increase in the amount of cadmium associated with the liver. In cultur ed hepatocytes isolated from GdCl3 pretreated rats, CdCl2 induced cyto toxicity was not significantly altered compared to control hepatocytes , indicating that the mechanism of tolerance required the presence of other cell types. Thus, GdCl3 attenuation of CdCl2 induced hepatotoxic ity does not appear to be caused by increased tissue MT content or a d ecreased susceptibility of hepatocytes to cadmium. From these data, we concluded that tolerance to cadmium induced hepatotoxicity involves t he inhibition of Kupffer cell function which results in a decreased in flammatory response and an altered progression of hepatic injury. Thes e data further indicate that Kupffer cell function is critical to cadm ium induced hepatocellular necrosis. (C) 1997 Elsevier Science Ireland Ltd.