Cytokines, nitric oxide synthesis and liver regeneration

During the prereplicative period of liver regeneration the changes in the levels of mRNA for tumour necrosis factor-alpha (TNF-alpha) and its receptors were nearly synchronous. The mRNA levels reached their maximum 1-3 h after operation and exceeded the values for intact animals about ten-fold. Lipopolysaccharide stimulation induced an increase in TNF-alpha and TNF receptor production comparable with that occurring during regeneration. Nitric oxide (NO) production in the regenerating liver was determined by electron paramagnetic resonance (EPR) spectroscopy. The first increase in NO production occurred approximately 1 h after partial hepatectomy (PHE). The second and more pronounced peak of NO production was observed about 6 h after PHE when the hepatocytes entered the first cell cycle; it originated mainly from these cells. The consequent minimum of NO synthesis coincided with the maximal rate of DNA synthesis. The third gradual rise of NO production was seen at the transit from the first to the second cell cycle of the hepatocytes and the entrance of the non-parenchymal cells into proliferation. Hepatocytes, Kupffer and endothelial cells were isolated from livers after PHE. They were found to start their main NO production in the described sequence at the times corresponding to their respective entrance into the cell cycle. The maxima of NO synthesis were inversely correlated to the DNA-synthesizing activity of the individual cell type.