Welty S E, Smith C V, Benzick A E, Montgomery C A, Hansen T N
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030.
Biochem Pharmacol. 1993 Jan 26;45(2):449-58. doi: 10.1016/0006-2952(93)90082-8.
Vascular congestion and liver swelling have long been recognized as features of the hepatotoxic effects of acetaminophen (AAP) in mice and rats and have been proposed as contributing factors to the eventual extent of necrosis produced. Neutrophil accumulation in the hepatic microcirculation has been proposed as being responsible for the blockage of hepatic blood flow and thereby the expansion of the region of damage. We therefore determined in mice the effects of hepatotoxic doses of AAP on the messenger RNA for intercellular adhesion molecule-1 (ICAM-1), which is a critical determinant of neutrophil adhesion, activation and ultimately of neutrophil-mediated tissue injury. Hepatotoxic doses of AAP did not upregulate ICAM-1 messenger RNA. However, doses of bacterial lipopolysaccharide (LPS) did cause a rapid and dramatic increase in ICAM-1 message, which was accompanied by a much greater hepatic accumulation of neutrophils, but which led to only scattered single cell necrosis. In addition, we investigated the effects of pentoxifylline (PTX) on AAP-induced vascular congestion and on hepatic necrosis as evaluated histologically and by measurement of plasma transaminase activities. Although PTX has been shown to increase blood cell deformability and improve vascular perfusion in a number of animal models of restricted blood flow, and is used in humans for the treatment of intermittent claudication, we found no decrease in AAP-induced hepatic swelling or in AAP-induced necrosis in response to PTX. With some dosing regimens, PTX-treated animals proved to be slightly more susceptible to AAP, which may be related to the reported potentiation of the cytotoxicities of a number of alkylating anti-cancer drugs by PTX and other methylxanthines. We conclude from these studies that upregulation of ICAM-1 and subsequent adhesion and vascular plugging by neutrophils are not significant determinants of AAP-induced liver swelling and necrosis and that whatever hemorheological advantages PTX might offer in AAP-induced hepatic damage appear to be overshadowed by effects that potentiate the toxic responses.
血管充血和肝脏肿大长期以来一直被认为是对乙酰氨基酚（AAP）对小鼠和大鼠产生肝毒性作用的特征，并且被认为是导致最终坏死程度的促成因素。有人提出肝微循环中的中性粒细胞积聚是肝血流受阻的原因，从而也是损伤区域扩大的原因。因此，我们在小鼠中确定了肝毒性剂量的AAP对细胞间粘附分子-1（ICAM-1）信使RNA的影响，ICAM-1是中性粒细胞粘附、激活以及最终中性粒细胞介导的组织损伤的关键决定因素。肝毒性剂量的AAP并未上调ICAM-1信使RNA。然而，细菌脂多糖（LPS）的剂量确实导致ICAM-1信使RNA迅速且显著增加，同时伴有肝脏中中性粒细胞的大量积聚，但仅导致散在的单细胞坏死。此外，我们研究了己酮可可碱（PTX）对AAP诱导的血管充血以及肝坏死的影响，通过组织学评估和血浆转氨酶活性测量来进行评估。尽管在一些血流受限的动物模型中，PTX已被证明可增加血细胞变形能力并改善血管灌注，并且在人类中用于治疗间歇性跛行，但我们发现PTX对AAP诱导的肝脏肿大或AAP诱导的坏死并无减轻作用。在某些给药方案下，经PTX处理的动物对AAP的敏感性略高，这可能与PTX和其他甲基黄嘌呤对多种烷化抗癌药物细胞毒性的增强作用有关。我们从这些研究中得出结论，ICAM-1的上调以及随后中性粒细胞的粘附和血管阻塞并非AAP诱导的肝脏肿大和坏死的重要决定因素，并且PTX在AAP诱导的肝损伤中可能提供的任何血液流变学优势似乎都被增强毒性反应的作用所掩盖。
