Mechanisms Of Drug-induced Toxicities

我们继续研究药物性肝病（DILD）的分子基础，这是一种罕见但通常危及生命的毒性。它是急性肝衰竭的主要原因，也是药物退出临床使用的主要原因。我们推测，这种疾病的特异质性质部分是由于缺乏肝保护因子。这一想法在今年通过以下方式进行了探索： 1.去年，我们报道了内源性IL-13保护小鼠免受对乙酰氨基酚诱导的肝病（AILD），至少部分是通过下调几种促炎细胞因子和趋化因子。今年，我们发现使用几种中和抗体，IL-13敲除小鼠对AILD的易感性增加是由于几种因素的组合，包括干扰素γ，NK（T）细胞和中性粒细胞。IL-13可能不仅保护人类免于AILD，还保护人类免于由其他药物引起的肝病。 2.目前的证据表明，DILD通常是由肝脏药物-蛋白加合物诱导的过敏反应（药物诱导的过敏性肝炎，DIAH）引起的。DIAH的低发病率和不能在动物中复制它表明，致耐受性机制可能会阻止DIAH在大多数人和动物中发生。在这方面，去年我们发现肝毒性剂量的对乙酰氨基酚（APAP）与小鼠胸腺、脾脏和肝淋巴结中T细胞和/或B细胞的显著损失以及适应性免疫系统的抑制有关。今年，我们发现肾上腺切除的小鼠对这些作用有抵抗力，这表明应激和内源性皮质类固醇可能会降低动物和人类对DIAH的易感性。 3.今年，我们发现内源性IL-4也可以保护小鼠免受AILD。基于对来自野生型和IL-4敲除小鼠的血清蛋白在肝毒性剂量的APAP后的多重分析，似乎IL-4至少部分地通过下调几种促炎细胞因子来保护小鼠免受AILD。

We have continued our studies of the molecular basis of drug-induced liver disease (DILD), which is a rare but often life-threatening toxicity. It is the major cause of acute liver failure and a principal reason drugs are withdrawn from clinical use. We have hypothesized that the idiosyncratic nature of this disease is due in part to a deficiency in hepatoprotective factors. This idea has been explored in the following ways this year: 1. Last year we reported that endogenous IL-13 protected mice from acetaminophen-induced liver disease (AILD), at least in part, by down-regulating several proinflammatory cytokines and chemokines. This year we have found with the use of several neutralizing antibodies that the increased susceptibility of IL-13 knockout mice to AILD is due to a combination of several factors including interferon gamma, NK(T) cells, and neutrophils. It is possible that IL-13 also protects humans from not only AILD, but also liver diseaese caused by other drugs. 2. Current evidence indicates that DILD is often caused by an allergic response (drug-induced allergic hepatitis, DIAH) induced by hepatic drug-protein adducts. The low incidence of DIAH and inability to reproduce it in animals suggests that tolerogenic mechanisms may prevent DIAH from occurring in most people and animals. In this regard, last year we discovered that hepatotoxic doses of acetaminophen (APAP) were associated with marked losses of T cells and/or B cells cells in the thymus, spleen, and hepatic lymph nodes of mice as well as depression of the adaptive immune system. This year we have found that adrenalectomized mice are resistant to these effects, suggesting that stress and endogenous corticosteroids may decrease susceptibility to DIAH in both animals and humans. 3. This year we have discovered that endogenous IL-4 also protects mice form AILD. Based upon multiplex analysis of serum proteins from wild-type and IL-4 knockout mice following hepatotoxic doses of APAP, it appears that IL-4 protects mice from AILD, at least in part, by downreguling several proinflammatory cytokines.