Bailie M B, Pearson J M, Lappin P B, Killam A L, Roth R A
Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824.
Toxicol Appl Pharmacol. 1994 Dec;129(2):207-13. doi: 10.1006/taap.1994.1245.
Administration of alpha-naphthylisothiocyanate (ANIT) to rats results in periportal cholangiolitic hepatopathy. Inflammation is a hallmark of the liver injury, and expression of toxicity is dependent on blood neutrophils. The role of other cellular mediators of inflammation in ANIT-induced hepatic insult is unknown. We hypothesized that platelets participate in the expression of ANIT hepatotoxicity. To test this, circulating platelets were decreased by administration of anti-rat platelet serum (PAb) prior to treatment of rats with ANIT. The PAb treatment regimen effectively reduced circulating thrombocytes over the course of the experiment. Twenty-four hours after oral ANIT administration, rats were euthanized and liver injury was estimated by increases in serum alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) activities. Cholestasis was assessed by measurement of serum total bilirubin concentration and bile flow. Reduction in platelet numbers was associated with attenuation of the increases in plasma ALT activity and bilirubin concentration seen after ANIT administration. However, PAb treatment did not attenuate the increase in plasma GGT, a marker of biliary epithelial cell injury. ANIT-induced changes in platelet function were assessed by evaluating platelet aggregation responses in platelet-rich plasma from rats treated with ANIT in vivo. ANIT treatment modestly decreased ex vivo platelet aggregation in response to ADP and collagen stimuli. To address further the role of platelet-derived cyclooxygenase products in ANIT hepatotoxicity, rats were treated with aspirin or ibuprofen. Neither pretreatment ameliorated ANIT-induced hepatic insult. These results suggest that platelets contribute to the expression of ANIT-induced liver injury, but they do not appear to act through the production of cyclooxygenase metabolites.
给大鼠施用α-萘基异硫氰酸酯（ANIT）会导致门静脉周围胆管溶解性肝病。炎症是肝损伤的一个标志，毒性的表达依赖于血液中的中性粒细胞。其他炎症细胞介质在ANIT诱导的肝损伤中的作用尚不清楚。我们假设血小板参与了ANIT肝毒性的表达。为了验证这一点，在给大鼠用ANIT治疗之前，通过施用抗大鼠血小板血清（PAb）来减少循环血小板。在整个实验过程中，PAb治疗方案有效地减少了循环血小板。口服ANIT 24小时后，对大鼠实施安乐死，并通过血清丙氨酸转氨酶（ALT）和γ-谷氨酰转移酶（GGT）活性的升高来评估肝损伤。通过测量血清总胆红素浓度和胆汁流量来评估胆汁淤积。血小板数量的减少与ANIT给药后血浆ALT活性和胆红素浓度升高的减弱有关。然而，PAb治疗并没有减弱血浆GGT（胆管上皮细胞损伤的标志物）的升高。通过评估体内用ANIT治疗的大鼠富含血小板血浆中的血小板聚集反应，来评估ANIT诱导的血小板功能变化。ANIT治疗适度降低了体外血小板对ADP和胶原刺激的聚集反应。为了进一步探讨血小板衍生的环氧化酶产物在ANIT肝毒性中的作用，给大鼠用阿司匹林或布洛芬进行治疗。两种预处理均未改善ANIT诱导的肝损伤。这些结果表明血小板有助于ANIT诱导的肝损伤的表达，但它们似乎不是通过环氧化酶代谢产物的产生起作用的。
