Modulation of thioacetamide-induced hepatocellular necrosis by prostaglandins is associated with novel histologic changes.
Cytoprotective effects of the prostaglandins 16,16-dimethyl PGE2 (dmPGE2) and PGF2 alpha tromethamine (PGF2 alpha) were evaluated in the rat model of acute hepatocellular necrosis induced by thioacetamide (TAA). dmPGE2 (100 micrograms/kg SC 8 hourly) did not induce a significant increase in survival when started after the onset of TAA-induced fulminant hepatic failure. However, priming with dmPGE2 (100 micrograms/kg SC 30 min before TAA) reduced TAA-induced elevations in serum ALT (684 +/- 68 (SEM) vs 274 +/- 135 IU/1, p less than 0.01). This phenomenon did not occur if dmPGE2 was administered after TAA or by the IP route. Modulation of TAA-induced centrizonal hepatocellular necrosis by dmPGE2 was associated with a striking increase in centrizonal ballooning of hepatocytes (p less than 0.01), and, as assessed by stereology, less hepatocellular necrosis and degenerative changes. PGF2 alpha, which in contrast to dmPGE2 does not act via cAMP, had no effect on TAA-induced changes in serum ALT or hepatic histology. These findings suggest that dmPGE2 decreases hepatocellular necrosis by activating surface membrane adenylate cyclase and consequently stimulating cAMP. Ballooning of hepatocytes could occur secondary to these membrane events and appears to be a marker of dmPGE2-induced cytoprotection in this model.
Bergasa
N V
NV
Liver Diseases Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
Borque
M J
MJ
Wahl
L M
LM
Rabin
L
L
Jones
E A
EA
D015064:16,16-Dimethylprostaglandin E2 / Q000627:therapeutic use*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006501:Hepatic Encephalopathy / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008297:Male; D009336:Necrosis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013853:Thioacetamide
D013853:Thioacetamide; D015237:Dinoprost; C010714:dinoprost tromethamine; D000410:Alanine Transaminase; D015064:16,16-Dimethylprostaglandin E2