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Lipopolysaccharide-induced hepatic injury is enhanced by polychlorinated biphenyls
A P Brown1, A E Schultze, W L Holdan
1Department of Pharmacology/Toxicology, Michigan State University, East Lansing 48824, USA.
Abstract:
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.
Insights
Polychlorinated biphenyls (PCBs) worsen liver injury by activating polymorphonuclear neutrophils (PMNs). This study shows PCBs enhance PMN-mediated damage, increasing liver toxicity when combined with bacterial lipopolysaccharide (LPS).
Area of Science:
- Toxicology
- Immunology
- Hepatology
Background:
- Bacterial lipopolysaccharide (LPS) induces liver injury in rats, mediated by polymorphonuclear neutrophils (PMNs).
- Certain polychlorinated biphenyls (PCBs) activate PMNs, leading to superoxide anion production and release of cytolytic factors.
- The potential for PCBs to exacerbate PMN-mediated tissue injury, such as LPS-induced hepatotoxicity, remains to be fully elucidated.
Purpose of the Study:
- To investigate whether PCB exposure enhances PMN-mediated liver injury induced by LPS.
- To determine the effects of co-exposure to LPS and Aroclor 1248 on hepatic injury in rats.
Main Methods:
- Female Sprague-Dawley rats were administered LPS intravenously, followed by intraperitoneal injection of Aroclor 1248.
- Hepatic injury was assessed by measuring plasma enzyme activities (alanine aminotransferase, isocitrate dehydrogenase) and histological evaluation.
- In vitro experiments assessed PCB effects on PMN activation (superoxide anion production, degranulation) and PMN-mediated cytotoxicity to isolated hepatocytes.
Main Results:
- Neither LPS nor Aroclor 1248 alone caused liver injury.
- Co-administration of LPS and Aroclor 1248 resulted in significant liver injury, evidenced by elevated plasma enzyme levels and increased hepatic necrosis.
- PCB exposure did not alter LPS-induced PMN accumulation in the liver but enhanced PMN activation and cytotoxicity in vitro, and increased PMN-dependent hepatocellular damage in vivo.
Conclusions:
- PCBs can act as an additional inflammatory stimulus, activating PMNs to become cytotoxic.
- This activation of PMNs by PCBs contributes to enhanced liver injury following LPS challenge.
- PCBs potentiate PMN-mediated hepatocellular damage, highlighting a mechanism for increased tissue injury in co-exposed individuals.