Brown A P, Schultze A E, Holdan W L, Buchweitz J P, Roth R A, Ganey P E
Department of Pharmacology/Toxicology, Michigan State University, East Lansing 48824, USA.
Environ Health Perspect. 1996 Jun;104(6):634-40. doi: 10.1289/ehp.96104634.
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.
给大鼠静脉注射细菌脂多糖（LPS）后，多形核中性粒细胞（PMN）迅速在肝脏中积聚，到6小时时肝中区坏死明显。PMN是大鼠肝损伤发生所必需的。某些多氯联苯（PCB）可激活PMN，导致超氧阴离子（O2-.）的产生以及颗粒中细胞溶解因子的释放。这增加了PCB暴露可能增强PMN介导的组织损伤（如LPS诱导的肝毒性）的可能性。我们用生理盐水（2mg/kg，静脉注射）中最小毒性剂量的LPS处理雌性Sprague-Dawley大鼠，90分钟后给它们腹腔注射Aroclor 1248（50mg/kg），一种PCB混合物。在给予LPS 6小时后处死动物，并评估肝损伤情况。单独给予LPS或Aroclor 1248均未产生肝损伤。LPS与Aroclor 1248联合处理导致明显的肝损伤，血浆中丙氨酸转氨酶和异柠檬酸脱氢酶活性增加即证明了这一点。组织学评估表明，同时接受LPS和Aroclor 1248的大鼠肝坏死严重程度增加。通常在LPS后观察到的PMN在肝脏中的积聚，并未因同时暴露于PCB而改变。Aroclor 1248在体外刺激大鼠PMN产生O2-.并脱颗粒。此外，加入Aroclor 1248后，培养的分离大鼠肝细胞的PMN介导的细胞毒性增加。PCB在体外激活PMN，并在体外以及LPS处理后的体内增加PMN依赖性肝细胞损伤。PCB在体内可能作为一种额外的炎症刺激物，激活PMN使其具有细胞毒性，从而导致组织损伤增加。
