| Cadmium (Cd) is a heavy metal that upon acute administration causes severe hepatotoxicity. The mechanism of Cd-induced toxicity has been extensively studied and appears to be comprised of several components. First, Cd is directly toxic to hepatocytes, most likely by disruption of mitochondrial function and creation of oxidative stress. Second, there also appears to be an indirect component to the mechanism of Cd-induced hepatotoxicity, involving Kupffer cells, the resident macrophages of the liver. However, the role of Kupffer cells in the mechanism of Cd-induced hepatotoxicity is poorly defined. Thus, the overall goal of this dissertation was to investigate and define the role of Kupffer cells in the mechanism of Cd-induced hepatotoxicity. The first study was designed to determine whether GdCl3 prevents Cd-induced hepatotoxicity by depletion of Kupffer cells or induction of metallothionein (MT). GdCl3 produced a dose-related protection against Cd-induced hepatotoxicity, independent of MT induction. However, the dose-related suppression of Kupffer cells did not parallel the dose-related prevention of Cd-induced hepatotoxicity, suggesting that GdCl3 exerts hepatoprotective effects aside from depleting Kupffer cells. The second and third studies in this dissertation were designed to define the role for TNF-α and iNOS, respectively, in the mechanism of Cd-induced hepatotoxicity. The results of these studies indicated that neither TNF-α nor iNOS participated in Cd toxicity. The goal of the final study was two-fold: first, to define and examine the dose- and time-related rat strain difference in sensitivity to Cd-induced hepatotoxicity; and second, to utilize this strain difference to help elucidate the direct versus indirect mechanisms of Cd-induced hepatotoxicity. Fischer 344 rats were shown to be more sensitive to Cd-induced hepatotoxicity than Sprague-Dawley rats. This strain difference was not due to the hepatic disposition of Cd. Although this rat strain difference was clearly established, only minor variations in cytokine and chemokine expression were observed. This study clearly demonstrated that neither the magnitude nor the timing of cytokine and chemokine induction fully accounts for the strain difference in sensitivity to Cd-induced hepatotoxicity. In summary, these studies utilized multiple models and study designs in attempt to specifically define the role of Kupffer cells in the mechanism of Cd-induced hepatotoxicity. The results indicate that Kupffer cells may only have a minor role in the mechanism of Cd-induced hepatotoxicity. |
