Bailie M B, Pearson J M, Fink G D, Roth R A
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, 48824, USA.
Toxicol Lett. 1996 Feb;84(2):89-95. doi: 10.1016/0378-4274(95)03620-2.
Alpha-naphthylisothiocyanate (ANIT) is a cholangiolitic hepatotoxicant that causes periportal edema, hepatic parenchymal and biliary epithelial cell necrosis, and cholestasis in the rat. A hallmark of ANIT hepatotoxicity is periportal inflammation that includes neutrophil infiltration. Neutrophils are requisite for the expression of ANIT-induced liver injury; however, the mechanism(s) of neutrophil accumulation in the liver and the role of these cells in ANIT hepatotoxicity is incompletely understood. Platelet activating factor (PAF) is a proinflammatory agent that is both a chemoattractant for and an activator of neutrophils. Therefore, we evaluated the role of PAF in ANIT-induced liver injury. Rats were treated with the PAF receptor antagonist, WEB 2086 (WEB), to determine if it afforded protection from ANIT hepatotoxicity. In a separate study, a combination of WEB and the leukotriene synthesis inhibitor, Zileuton (ZIL), was used to address the possible interaction of PAF and leukotrienes in ANIT-induced liver injury. Treatment of rats with WEB, alone or in combination with Zileuton, did not attenuate ANIT-induced liver injury as assessed by increases in plasma alanine aminotransferase or gamma-glutamyl transferase activities. In addition, neither treatment ameliorated ANIT-induced cholestasis assessed as increased plasma bilirubin concentration. These results suggest that PAF, alone or in combination with products of 5-lipoxygenase, does not contribute to ANIT-induced liver injury.
α-萘基异硫氰酸酯（ANIT）是一种引起胆管炎的肝毒性物质，可导致大鼠门静脉周围水肿、肝实质和胆管上皮细胞坏死以及胆汁淤积。ANIT肝毒性的一个标志是门静脉周围炎症，包括中性粒细胞浸润。中性粒细胞是ANIT诱导的肝损伤表达所必需的；然而，中性粒细胞在肝脏中积累的机制以及这些细胞在ANIT肝毒性中的作用尚未完全了解。血小板活化因子（PAF）是一种促炎剂，既是中性粒细胞的趋化剂又是其激活剂。因此，我们评估了PAF在ANIT诱导的肝损伤中的作用。用PAF受体拮抗剂WEB 2086（WEB）处理大鼠，以确定它是否能保护大鼠免受ANIT肝毒性的影响。在另一项研究中，使用WEB和白三烯合成抑制剂齐留通（ZIL）的组合来探讨PAF和白三烯在ANIT诱导的肝损伤中可能的相互作用。单独或与齐留通联合使用WEB处理大鼠，通过血浆丙氨酸氨基转移酶或γ-谷氨酰转移酶活性的增加评估，并未减轻ANIT诱导的肝损伤。此外，两种处理均未改善以血浆胆红素浓度升高评估的ANIT诱导的胆汁淤积。这些结果表明，PAF单独或与5-脂氧合酶产物联合使用，对ANIT诱导的肝损伤没有作用。
