Modulation of thioacetamide‐induced hepatocellular necrosis by prostaglandins is associated with novel histologic changes

Abstract

Cytoprotective effects of the prostaglandins 16, 16-dimethyl PGE₂ (dmPGE₂) and PGF₂ α tromethamine (PGF₂ α) were evaluated in the rat model of acute hepatocellular necrosis induced by thioacetamide (TAA). dmPGE₂ (100 μg/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 μg/kg SC 30 min before TAA) reduced TAA-induced elevations in serum ALT (684 ± 68 (SEM) vs 274 ± 135 IU/1, p>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>0.01), and, as assessed by stereology, less hepatocellular necrosis and degenerative changes. PGF₂ α, 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. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.