Beneficial Role of ROS in Cell Survival: Moderate Increases in HO Production Induced by Hepatocyte Isolation Mediate Stress Adaptation and Enhanced Survival.

High levels of reactive oxygen species (ROS) can lead to impairment of cell structure, biomolecules' loss of function and cell death and are associated with liver diseases. Cells that survive increased ROS often undergo malignant transformation. Many cancer cells tolerate high levels of ROS. Here we report a transiently increased production of HO and concomitant upregulation of antioxidative enzymes triggered by hepatocyte isolation; the HO levels revert in about two days in culture. Three-day survival rate of the isolated cells in the presence of 2.5-fold increase of HO is almost 80%. Apoptosis activation through the mitochondrial pathway is meanwhile reduced by inhibition of caspase-9 triggering. This reduction depends on the amount of HO production, as decreased production of HO in the presence of an antioxidant results in increased apoptosis triggering. These stress adaptations do not influence urea production, which is unchanged throughout the normal and stress adapted phases. We conclude that hepatocytes' stress adaptation is mediated by increased ROS production. In this case, high ROS improve cell survival.