Differentiation of necrotic cell death with or without lysosomal activation: Application of acute liver injury models induced by carbon tetrachloride(CCL4) and dimethylnitrosamine (DMN)

We investigated the relationship between DNA degradation and lysosome activ ity (loss of lysosomal integrity) in necrotic cell death induced by carbon tetrachloride (CCl4) and dimethylnitrosamine (DMN): coagulation necrosis an d hemorrhagic necrosis, respectively. TdT-mediated dUTP-biotin nick end-lab eling (TUNEL) and enzyme histochemistry for acid phosphatase were performed in both models and results were analyzed by light microscopy, electron mic roscopy, and confocal laser scanning microscopy (CLSM). In the CCl4-injecte d liver, TUNEL staining was closely associated with release of lysosomal en zymes into the cytoplasm, and intranuclear deposition of lysosomal enzymes took place at an early stage of subcellular damage. In the DMN-injected liv er, TUNEL-positive nuclei tended to have well-preserved lysosomes and centr ally localized TUNEL signals. It was assumed that acute hepatocellular dama ge in the CCl4-injected liver would be characterized by necrotic cell death with lysosome activation and that damage in the DMN-injected liver would b e necrotic cell death without lysosome activation. In the DMN-injected live r, DNA degradation may be selectively induced in the nuclear center, in whi ch heterochromatin (including inactive chromatin) is believed to be a targe t. We concluded that necrotic cell death, i.e., DNA degradation, would be a t least divided into two types, with/without association with lysosome acti vation, represented by necrotic cell death in the CCl4-injected liver and t hat in the DMN-injected liver.