Evidence for a Negative Feedback System Controlling Liver Regeneration 149 



Figure 1 illustrates the application of the classical method for plasma 

 dilution, plasmapheresis, and the results obtained. Normal adult male rats 

 were used. Blood was withdrawn every twelve hours corresponding to 31 to 

 38 per cent of the initial total blood volume of the animals in the first group 



Fig. 1. Induction of cell division in the resting liver by plasmapheresis. 

 A total of eighteen adult male rats was used. 

 The rate of plasmapheresis is expressed as the percentage of the initial total blood 

 volume of the animal replaced by saline per 12 hours. In the control group 

 rate refers to the fact that blood was merely withdrawn and re-injected, with the 

 animals submitted to the same stressful conditions of restriction, anesthesia, 

 venipuncture etc. as the experimental groups. The mitotic activity was obtained 

 by counting 50,000 cells, and expressed as the per cent mitotic index. When no 

 mitosis was found, the mitotic index was recorded as <0.002. 



and 39 to 46 per cent in the second. The bleedings were followed by re-injections 

 of the blood cells suspended in an equal volume of saline. Under such conditions 

 cell division was induced in the resting liver of adult rats and was intensified 

 with increasing dilution of the plasma. In this experiment, then, the evidence 

 obtained satisfies the first condition for a negative feedback system. 



With respect to the second condition, the method used to achieve plasma 

 concentration was restriction of fluid intake as illustrated in Fig. 2. Two experi- 

 mental groups were used, differing with regard to the weight of the animals 

 and the extent of the partial hepatectomy. All animals were partially hepatec- 

 tomized and tube-fed an identical isocaloric fluid diet containing 3 per cent 

 water. The controls were given drinking water ad libitum but the experimental 

 animals were deprived of water for the duration of the experiment, which was 

 sixty-four hours, starting sixteen hours prior to the operation and continuing 

 for forty-eight hours postoperatively, at which time the animals were sacrificed. 

 A measure of total body-water loss obtained by this regimen is given by the 

 difference in weight change between experimental and control animals in each 

 group. A measure of the plasma concentration achieved is given by the difference 

 in total protein change. In both the experimental groups an effective inhibition 

 of cell division in the liver was obtained; this inhibition became greater with 

 increasing concentration of the serum. On the other hand mitosis in the 

 intestinal epithelium was not affected. The evidence obtained in this experiment, 

 then, satisfies the second condition for a negative feedback system. 



The smaller extent of total body-water loss and plasma concentration in 

 the first group can be ascribed to the greater initial weight of the animals in 



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