Temporal Changes in Tissue Repair Permit Survival of Diet-Restricted Rats from an Acute Lethal Dose of Thioacetamide

Although, diet restriction (DR) has been shown to substantiallyincrease longevity while reducing or delaying the onset of agerelateddiseases, little is known about the mechanisms underlying thebeneficial effects of DR on acute toxic outcomes. An earlierstudy (S. K. Ramaiah et al., 1998, Toxicol. Appl. Pharmacol.150, 12–21) revealed that a 35% DR compared to ad libitum(AL) feeding leads to a substantial increase in liver injuryof thioacetamide (TA) at a low dose (50 mg/kg, ip). Higher liverinjury was accompanied by enhanced survival. A prompt and enhancedtissue repair response in DR rats at the low dose (sixfold higherliver injury) occurred, whereas at equitoxic doses (50 mg/kgin DR and 600 mg/kg in AL rats) tissue repair in AL rats wassubstantially diminished and delayed. The extent of liver injurydid not appear to be closely related to the extent of stimulatedtissue repair response. The purpose of the present study wasto investigate the time course (0–120 h) of liver injuryand liver tissue repair at the high dose (600 mg TA/kg, ip,lethal in AL rats) in AL and DR rats. Male Sprague-Dawley rats(225–275 g) were 35% diet restricted compared to theirAL cohorts for 21 days and on day 22 they received a singledose of TA (600 mg/kg, ip). Liver injury was assessed by plasmaALT and by histopathological examination of liver sections.Tissue repair was assessed by ³H]thymidine incorporation intohepatonuclear DNA and proliferating cell nuclear antigen (PCNA)immunohistochemistry during 0–120 h after TA injection.In AL-fed rats hepatic necrosis was evident at 12 h, peakedat 60 h, and persisted thereafter until mortality (3 to 6 days).Peak liver injury was approximately twofold higher in DR ratscompared to that seen in AL rats. Hepatic necrosis was evidentat 36 h, peaked at 48 h, persisted until 96 h, and returnedto normal by 120 h. Light microscopy of liver sections revealedprogression of hepatic injury in AL rats whereas injury regressedcompletely leading to recovery of DR rats by 120 h. Progressionof injury led to 90% mortality in AL rats vs 30% mortality inDR group. In the surviving AL rats, S-phase DNA synthesis wasevident at 60 h, peaked at 72 h, and declined to base levelby 120 h, whereas in DR rats S-phase DNA synthesis was evidentat 36 h and was consistently higher until 96 h reaching controllevels by 120 h. PCNA studies showed a corresponding increasein cells in S and M phase in the AL and DR groups. DR resultedin abolition of the delay in tissue repair associated with thelethal dose of TA in ad libitum rats. Temporal changes and highertissue repair response in DR rats (earlier and prolonged) arethe conduits that allow a significant number of diet restrictedrats to escape lethal consequence.