Abstract

alpha-Naphthylisothiocyanate (ANIT) causes cholestasis and injury to bile duct epithelium and hepatic parenchymal cells in rats. The mechanism of toxicity is unknown. Neutrophils (PMNs) infiltrate periportal regions of the liver after ANIT intoxication. Because PMNs play a causal role in other extrahepatic models of tissue injury, we determined whether PMNs might be involved in ANIT-induced liver injury in rats by reducing circulating PMN numbers with a polyclonal antibody (antineutrophil serum). ANIT treatment caused cholestasis and elevations in serum of total bilirubin concentration, total bile acid concentration, aspartate amino-transferase activity, gamma-glutamyltransferase activity and histologic lesions consistent with acute, neutrophilic cholangiohepatitis. Cotreatment of rats with antineutrophil serum reduced circulating PMN numbers, prevented ANIT-induced cholestasis and attenuated other markers of liver injury elevated by ANIT. In addition, antineutrophil serum treatment attenuated the severity of histologic lesions within the liver and reduced the number of PMNs in periportal regions. Numbers of PMNs in liver sections correlated positively with markers of liver injury, histologic evidence of cholangiohepatitis and numbers of circulating PMNs in peripheral blood. The protection afforded by antineutrophil serum appeared to result from a specific reduction of PMNs and not lymphocytes, because administration of an antilymphocyte serum reduced circulating lymphocyte numbers without offering protection. Inasmuch as ANIT stimulates PMNs in vitro to release O2- and since PMN-derived oxygen species may cause tissue injury, we determined whether administration of agents which degrade oxygen radicals afforded protection against the liver injury caused by ANIT.(ABSTRACT TRUNCATED AT 250 WORDS)