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  • Title: Effect of hepatotoxic chemicals and hypoxia on hepatic nonparenchymal cells: impairment of phagocytosis by Kupffer cells and disruption of the endothelium in rat livers perfused with colloidal carbon.
    Author: te Koppele JM, Keller BJ, Caldwell-Kenkel JC, Lemasters JJ, Thurman RG.
    Journal: Toxicol Appl Pharmacol; 1991 Aug; 110(1):20-30. PubMed ID: 1871771.
    Abstract:
    Kupffer cells play an important role in liver function and phagocytosis of foreign particles in the hepatic portal tract. Therefore, the purpose of this study was to investigate the influence of several hepatotoxic chemicals (allyl alcohol, ethylhexanol, and menadione) and hypoxia on phagocytic activity of Kupffer cells in perfused rat liver. A recently developed optical method was used to determine rates of phagocytosis of carbon particles by Kupffer cells in periportal and pericentral regions of the liver lobule based on changes in reflected light from the liver surface (te Koppele, J.M., and Thurman, R.G. 1990. Am. J. Physiol. 259, G814-G821). With all chemicals studied, a rapid (10-30 min) decline in the rate of phagocytosis preceded parenchymal cell death as assessed from release of lactate dehydrogenase. These chemicals impaired parenchymal cell energy status as indicated by inhibition of O2 uptake and bile flow prior to cell death. Livers swell when they are damaged, a process which increases perfusion pressure and could theoretically damage the endothelium and lead to nonspecific uptake of carbon. In perfusions with a hepatotoxic concentration of allyl alcohol (350 microM), carbon particles accumulated in swollen livers after 70 min of perfusion. Histological studies revealed that carbon particles were localized predominantly in periportal regions of the liver lobule in perfusions with all hepatotoxicants studied. When perfusion pressure was elevated to 20 cm H2O in the absence of hepatotoxicants, carbon particles detected optically accumulated in upstream regions of the liver lobule (periportal or pericentral regions in perfusions in the anterograde or retrograde directions, respectively). In scanning electron microscopy of nonswollen livers, the endothelium remained intact. In swollen livers, however, the endothelium was disrupted and carbon was detected bound nonspecifically to parenchymal cells. Fifteen minutes after addition of allyl alcohol, bile canaliculi were dilated and endothelial fenestrations were enlarged. After 2 hr of perfusion with allyl alcohol, hepatic ultrastructure was severely disrupted. Thus, it is concluded that perfusion with hepatotoxic chemicals or hypoxia results in a rapid decrease of particle phagocytosis by Kupffer cells followed by changes in endothelial cell ultrastructure.
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