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Polychlorinated biphenyls (PCBs) are ubiquitious lipophilic environmental pollutants. At least some of the PCB congeners and mixtures are hepatic tumor promoters. The mechanisms are not fully understood and might be multifactorial Besides being the most abundant congener in the environment, 2,2,4,4,5,5-hexachlorobiphenyl (PCB-153), has been previously shown to increase hepatocyte proliferation 48h after exposure in rats. The goal of this study was to determine whether hepatic Kupffer cells are important in the promoting activity of PCBs. The hypothesis of this study was that modulation of Kupffer cell activity by PCBs may contribute to PCB-induced liver tumor promotion. The experimental approach consisted on three in vivo models (tumor promotion model and two short term exposure models) and one in vitro model. In the tumor promotion model, glycine inactivation of Kupffer cells did not significantly influence the promoting activity of PCB-77 (3,3,4,4-tetrachlorobiphenyl) or PCB-153. For the short term exposure model, we investigated the effect of Kupffer cell inactivation by glycine and the effect of Kupffer cell depletion on PCB-153s impact on hepatocyte proliferation. The oil used as a vehicle had no significant effect on any of the end points considered. Inhibition of Kupffer cells with glycine or the absence of Kupffer cells did not affect cell proliferation or NF-B activation after PCB treatment compared to the control. In vitro, PCB-153 increased DNA binding activity of NF-B in Kupffer cells but did not significantly increase the TNF- concentration in the medium. In conclusion, PCB-153 increased the number of preneoplastic foci per liver in the casein group but had no significant effect on cell proliferation, and Kupffer cells do not seem to play a role in hepatocyte proliferation.

The liver is a multi-functional organ that regulates major physiological processes and that possesses a remarkable regeneration capacity. After loss of functional liver mass the liver grows back to its original, individual size through hepatocyte proliferation and apoptosis. How does a single hepatocyte ‘know’ when the organ has grown to its final size? This work considers the initial growth phase of liver regeneration after partial hepatectomy in which the mass is restored. There are strong and valid arguments that the trigger of proliferation after partial hepatectomy is mediated through the portal blood flow. It remains unclear, if either or both the concentration of metabolites in the blood or the shear stress are crucial to hepatocyte proliferation and liver size control. A cell-based mathematical model is developed that helps discriminate the effects of these two potential triggers. Analysis of the mathematical model shows that a metabolic load and a hemodynamical hypothesis imply different feedback mechanisms at the cellular scale. The predictions of the developed mathematical model are compared to experimental data in rats. The assumption that hepatocytes are able to buffer the metabolic load leads to a robustness against short-term fluctuations of the trigger which can not be achieved with a purely hemodynamical trigger.

The liver is a multi-functional organ that regulates major physiological processes and that possesses a remarkable regeneration capacity. After loss of functional liver mass the liver grows back to its original, individual size through hepatocyte proliferation and apoptosis. How does a single hepatocyte ‘know’ when the organ has grown to its final size? This work considers the initial growth phase of liver regeneration after partial hepatectomy in which the mass is restored. There are strong and valid arguments that the trigger of proliferation after partial hepatectomy is mediated through the portal blood flow. It remains unclear, if either or both the concentration of metabolites in the blood or the shear stress are crucial to hepatocyte proliferation and liver size control. A cell-based mathematical model is developed that helps discriminate the effects of these two potential triggers. Analysis of the mathematical model shows that a metabolic load and a hemodynamical hypothesis imply different feedback mechanisms at the cellular scale. The predictions of the developed mathematical model are compared to experimental data in rats. The assumption that hepatocytes are able to buffer the metabolic load leads to a robustness against short-term fluctuations of the trigger which can not be achieved with a purely hemodynamical trigger.