After
intravenous administration of bacterial
lipopolysaccharide (LPS) to rats, polymorphonuclear neutrophils (PMNs) rapidly accumulate in the liver, and midzonal hepatic
necrosis is prominent by 6 hr. PMNs are required for the development of hepatic injury in rats. Certain
polychlorinated biphenyls (
PCBs) can activate PMNs, resulting in production of
superoxide anion (O2-.) and release of cytolytic factors from granules. This raises the possibility that PCB exposure might enhance PMN-mediated tissue injury, such as LPS-induced hepatotoxicity. We treated female Sprague-Dawley rats with a minimally toxic dose of LPS in saline (2 mg/kg, intravenous) and 90 min later exposed them to
Aroclor 1248 (50 mg/kg, intraperitoneal), a mixture of
PCBs. The animals were killed 6 hr after LPS administration, and hepatic injury was assessed. Neither LPS nor
Aroclor 1248 alone produced liver injury. Co-treatment with LPS and
Aroclor 1248 resulted in pronounced liver injury as demonstrated from increased activities of
alanine aminotransferase and
isocitrate dehydrogenase in plasma. Histological evaluation indicated increased severity of hepatic
necrosis in rats receiving both LPS and
Aroclor 1248. Hepatic accumulation of PMNs, normally observed after LPS, was not altered by co-exposure to
PCBs.
Aroclor 1248 stimulated rat PMNs in vitro to produce O2-. and to degranulate. In addition, PMN-mediated cytotoxicity to isolated rat hepatocytes in culture was increased upon addition of
Aroclor 1248.
PCBs activate PMNs in vitro and increase PMN-dependent hepatocellular damage in vitro and after LPS treatment in vivo.
PCBs may act in vivo as an additional inflammatory stimulus to activate PMNs to become cytotoxic, resulting in increased tissue injury.