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, eli cited as an endogenous response to toxic insult, are critical determin ants in the ultimate outcome of hepatic injury. Therefore, the objecti ve of this study was to develop a dose-response relationship for CCl4 measuring liver injury and tissue repair as two simultaneous but oppos ing responses. Male Sprague-Dawley rats were injected with a 40-fold d ose 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 tissu e repair was measured by [H-3]thymidine incorporation into hepatonucle ar DNA and proliferating cell nuclear antigen immunohistochemistry ove r a time course of 0 to 96 h. Stimulation of cell division, evident ev en after a subtoxic dose of CCl4, increased in a dose-dependent manner until a threshold (2 ml/kg) was reached. Doses above this threshold y ielded no further increase in tissue repair. Instead, tissue repair re sponse was significantly delayed and diminished. Injury was markedly a ccelerated 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 b y about 5-fold, aptly demonstrating the critical role of tissue repair in overcoming injury and enabling these animals to survive. This stud y 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 ma y contribute significantly to inter-individual differences in suscepti bility to toxic chemicals. Thus, while dose-related and prompt stimula tion of tissue regeneration leads to recovery, delayed and attenuated repair response, occurring at higher doses, leads to progression of in jury and animal mortality. Such dose-response relationships may lead t o a better understanding of the underlying cellular mechanisms of inju ry inflicted by chemical toxicants and aid in fine-tuning risk assessm ent. (C) 1997 Elsevier Science Ireland Ltd.