Age-related changes on parameters of experimentally-induced liver injury and regeneration.
Age-dependent changes related to liver injury and regeneration were studied in rats aged 2, 12, and 30 months in a time period of 96 hr following a sublethal dose of thioacetamide (6.6 mmoles/kg body wt). Serum aspartate aminotransferase activity increased earlier in young rats, but the severity of injury was higher in those aged 12 months when compared to young and to old. Microsomal hepatocyte FAD monooxygenase activity was induced earlier in 2-month-old rats following intoxication and the increase was significantly lower both in the youngest and in the oldest groups when compared to adults. As a parameter of hepatocellular postnecrotic regeneration, DNA synthesis (2C --> 4C) was evaluated. The population of hepatocytes in S phase peaked more sharply and earlier in young rat hepatocytes, and was 8 to 12 times higher than the initial in hepatocytes from 2- and 12-month-old rats, while the rise was only 3 times in the oldest group. At 96 hr of intoxication the restoration towards normal in all these parameters was complete in young, incomplete in adult, and slightly detected in the oldest. Serum proliferative activity, assayed on mouse NIH 3T3 fibroblast cultures, increased preceding the necrosis and this increase was higher in 2- and 12-month-old (171% and 224%, respectively), while in the oldest the increase was only 110%. This mitogenic activity decreased in all groups during necrosis, showing a second peak, nondetectable in rats aged 30 months, parallel to regeneration. Serum TNFalpha level was absent in untreated animals and increased markedly following intoxication, the highest values being recorded at 72 hr of intoxication in serum from rats aged 12 months (347 +/- 30 pg/ml) and the lowest at 30 months (4.1 +/- 0.3 pg/ml). The serum ability to induce nitric oxide synthase activity on peritoneal macrophages ex vivo showed significant time- and age-dependent changes in nitric oxide release: a decrease throughout necrosis and an increase during regeneration. We conclude that the main age-related changes in the sequenced process of liver injury and regeneration are the delayed response in the development of cell killing and regeneration and the decreased regenerative ability, which significantly delays the restoration of liver function.
Sanz
N
N
Facultad de Farmacia, Universidad Complutense, Madrid, 28040, USA.
Díez-Fernández
C
C
Alvarez
A M
AM
Fernández-Simón
L
L
Cascales
M
M
D016475:3T3 Cells; D000375:Aging; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002273:Carcinogens; D002455:Cell Division; D056486:Chemical and Drug Induced Liver Injury; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000503:physiopathology*; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D009336:Necrosis; D009569:Nitric Oxide / Q000378:metabolism; D010105:Oxygenases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013853:Thioacetamide; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D002273:Carcinogens; D014409:Tumor Necrosis Factor-alpha; D013853:Thioacetamide; D009569:Nitric Oxide; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D001219:Aspartate Aminotransferases; D005978:Glutathione