Protection against acetaminophen-induced liver injury and lethality by interleukin 10: Role of inducible nitric oxide synthase
Protection against acetaminophen-induced liver injury and lethality by interleukin 10: Role of inducible nitric oxide synthase
复制标题
DOI：
10.1053/jhep.2002.30956
复制
发表时间：
2002-02-01
期刊：
影响因子：
13.5
通讯作者：
Pohl, LR
中科院分区：
文献类型：
--
作者：
Bourdi, M;Masubuchi, Y;Pohl, LR
由于缺乏动物模型，特异质药物性肝炎（DIH）的机制研究仍然是一个具有挑战性的问题。在动物中不能产生这种类型的肝毒性，在人类中相对罕见，可能与抗炎因子的产生有关，抗炎因子可防止药物-蛋白加合物通过免疫Z，p和非免疫机制引起肝损伤。我们通过使用对乙酰氨基酚（APAP）诱导的小鼠肝损伤模型来验证这一假设。APAP治疗后，观察到白细胞介素（IL）-4，IL-10和IL-13的血清水平显著增加，这些细胞因子调节炎症介质的产生和细胞介导的自身免疫。当用APAP治疗IL-10敲除（KO）小鼠时，这些小鼠中的大多数在24至48小时内死于肝损伤。这种对APAP诱导的肝损伤的易感性增加似乎与肝脏促炎细胞因子、肿瘤坏死因子（TNF）-α和IL-1以及诱导型一氧化氮合酶（iNOS）的表达升高相关。在这方面，与IL-10 KO小鼠相比，缺乏IL-10和iNOS基因的小鼠受到保护，免受APAP诱导的肝损伤和致死性。所有菌株，包括野生型动物，产生了相似量的肝脏APAP-蛋白加合物，表明IL-10 KO小鼠对APAP肝毒性的易感性增加不是由APAP-蛋白加合物的形成增强引起的。总之，这些研究结果表明，药物诱导的肝损伤的正常反应的一个重要特征可能是抗炎因子，如IL-10的表达增加。这些因子的某些多态性可能在决定个体对特异质DIH的易感性中起作用。
Mechanistic study of idiosyncratic drug-induced hepatitis (DIH) continues to be a challenging problem because of the lack of animal models. The inability to produce this type of hepatotoxicity in animals, and its relative rarity in humans, may be linked to the production of anti-inflammatory factors that prevent drug-protein adducts from causing liver injury by immune Z, p and nonimmune mechanisms. We tested this hypothesis by using a model of acetaminophen (APAP)-induced liver injury in mice. After APAP treatment, a significant increase was observed in serum levels of interleukin (IL)-4, IL-10, and IL-13, cytokines that regulate inflammatory mediator production and cell-mediated autoimmunity. When IL-10 knockout (KO) mice were treated with APAP, most of these mice died within 24 to 48 hours from liver injury. This increased susceptibility to APAP-induced liver injury appeared to correlate with an elevated expression of liver proinflammatory cytokines, tumor necrosis factor (TNF)-alpha, and IL-1, as well as inducible nitric oxide synthase (iNOS). In this regard, mice lacking both IL-10 and iNOS genes were protected from APAP-induced liver injury and lethality when compared with IL-10 KO mice. All strains, including wild-type animals, generated similar amounts of liver APAP-protein adducts, indicating that the increased susceptibility of IL-10 KO mice to APAP hepatotoxicity was not caused by an enhanced formation of APAP-protein adducts. In conclusion, these findings suggest that an important feature of the normal response to drug-induced liver injury may be the increased expression of anti-inflammatory factors such as IL-10. Certain polymorphisms of these factors may have a role in determining the susceptibility of individuals to idiosyncratic DIH.