Rao P S, Mangipudy R S, Mehendale H M
Division of Toxicology, College of Pharmacy and Health Sciences, Northeast Louisiana University, Monroe 71209-0470, USA.
Toxicology. 1997 Mar 28;118(2-3):181-93. doi: 10.1016/s0300-483x(97)03617-2.
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.
最近的研究表明，作为对毒性损伤的内源性反应所引发的组织修复速率和程度，是肝损伤最终结果的关键决定因素。因此，本研究的目的是建立四氯化碳的剂量-反应关系，将肝损伤和组织修复作为两种同时发生但相反的反应进行测量。雄性Sprague-Dawley大鼠经腹腔注射溶解于玉米油载体中的40倍剂量范围的四氯化碳（0.1 - 4 ml/kg）。通过血清酶升高和组织病理学评估肝损伤，并在0至96小时的时间过程中，通过将[3H]胸腺嘧啶核苷掺入肝细胞核DNA以及增殖细胞核抗原免疫组织化学来测量组织修复。即使在亚毒性剂量的四氯化碳作用后，细胞分裂的刺激也很明显，并以剂量依赖性方式增加，直至达到阈值（2 ml/kg）。高于此阈值的剂量不会使组织修复进一步增加。相反，组织修复反应明显延迟且减弱。高于阈值时损伤明显加速，表明损伤不受控制地进展。尽管4 ml CCl4/kg在48小时内始终导致80%的致死率，但20%存活大鼠的组织修复反应增加了约5倍，恰当地证明了组织修复在克服损伤并使这些动物存活方面的关键作用。本研究表明，除了组织修复的程度外，组织修复的起始时间也决定了肝损伤的程度，并且组织修复程度的个体差异可能对化学毒物易感性的个体差异有显著贡献。因此，虽然与剂量相关且迅速刺激组织再生会导致恢复，但在较高剂量下发生的延迟和减弱的修复反应会导致损伤进展和动物死亡。这种剂量-反应关系可能有助于更好地理解化学毒物造成损伤的潜在细胞机制，并有助于优化风险评估。
