Tissue injury and repair as parallel and opposing responses to CCl4 hepatotoxicity: a novel dose-response

Recent studies indicate that the rate and extent of tissue repair, elicited as an endogenous response to toxic insult, are critical determinants in the ultimate outcome of hepatic injury. Therefore, the objective of this study was to develop a dose-response relationship for CCl4 measuring liver injury and tissue repair as two simultaneous but opposing responses. Male Sprague-Dawley rats were injected with a 40-fold dose range of CCl4 (0.1-4 ml/kg i.p.) in corn oil vehicle. Liver injury was assessed by serum enzyme elevations and histopathology, and tissue repair was measured by [3H]thymidine incorporation into hepatonuclear DNA and proliferating cell nuclear antigen immunohistochemistry over a time course of 0 to 96 h. Stimulation of cell division, evident even after a subtoxic dose of CCl4, increased in a dose-dependent manner until a threshold (2 ml/kg) was reached. Doses above this threshold yielded no further increase in tissue repair. Instead, tissue repair response was significantly delayed and diminished. Injury was markedly accelerated above the threshold indicating an unrestrained progression of injury. Although 4 ml CCl4/kg consistently caused 80% lethality by 48 h, tissue repair response in the 20% surviving rats was increased by about 5-fold, aptly demonstrating the critical role of tissue repair in overcoming injury and enabling these animals to survive. This study suggests that, in addition to the extent of tissue repair, the time of onset of tissue repair also determines the extent of hepatic injury and inter-individual differences in the magnitude of tissue repair may contribute significantly to inter-individual differences in susceptibility to toxic chemicals. Thus, while dose-related and prompt stimulation of tissue regeneration leads to recovery, delayed and attenuated repair response, occurring at higher doses, leads to progression of injury and animal mortality. Such dose-response relationships may lead to a better understanding of the underlying cellular mechanisms of injury inflicted by chemical toxicants and aid in fine-tuning risk assessment.