SPLENIC TOXICITY OF ANILINE

我们的长期目标是阐明暴露于芳香胺导致脾毒性的机制，并制定预防/治疗策略。我们使用工业化学品苯胺作为一种原型胺。除了引起高铁血红蛋白血症、溶血和溶血性贫血外，苯胺暴露还会导致选择性脾毒性。这种选择性脾损伤的机制尚不清楚。我们之前的研究表明，苯胺暴露增加了大鼠脾脏中的铁含量、脂质过氧化、蛋白质氧化和脂质衍生的醛蛋白加合物（氧化应激标志物）。这些事件伴随着血管充血、窦状窦和成纤维细胞增多、红细胞吞噬、包膜增厚和纤维化等形态学改变。我们假设苯胺毒性是由氧化应激引起的，并假设导致脾毒性的事件顺序如下：苯胺（和/或其代谢物）损害红细胞，红细胞沉积在脾脏中，因此增加总铁和活性铁（游离铁）。这种铁超载产生氧化剂（可能是羟基自由基），引起氧化应激，导致细胞功能障碍和纤维化[由纤维化细胞因子和转录因子激活介导的胶原合成增加]。这一假设的事件序列将通过追求三个特定目标进行测试：目标1确定介导苯胺毒性的氧化物种和铁物种。目的2描述苯胺暴露大鼠脾脏中氧化的生物分子，特别是脂质过氧化产物及其蛋白质和DNA加合物；氧化蛋白也将被表征。目的3将研究如何诱导纤维化细胞因子；应激诱导的转录因子(s)的激活和胶原合成有助于苯胺毒性。我们的项目将阐明苯胺诱导脾毒性的机制，并将明确氧化应激、脂质过氧化醛产物、纤维化细胞因子和转录因子在这一过程中的作用。总的来说，了解苯胺毒性的机制对于开发新的预防和治疗芳香胺的策略非常重要。

Our long-term goal is to elucidate the mechanisms of splenic toxicity resulting from exposure to aromatic amines, and to develop preventive/therapeutic strategies. We use the industrial chemical aniline as a prototypic amine. Besides causing methemoglobinemia, hemolysis and hemolytic anemia, aniline exposure also results in selective splenic toxicity. The mechanism(s) for this selective splenic damage are not well understood. Studies in our previous funding period demonstrated that aniline exposure increased iron content, lipid peroxidation, protein oxidation and lipid-derived aldehyde-protein adducts (markers of oxidative stress) in rat spleens. These events are accompanied by such morphological changes as vascular congestion, increased sinusoids and fibroblasts, erythrophagocytocysis, capsular thickening and fibrosis. We hypothesize that aniline toxicity is caused by oxidative stress, and postulate the following sequence of events leading to splenic toxicity: Aniline (and/or its metabolites) damage erythrocytes, which are deposited in the spleen, and so increase total and reactive iron (free iron). This iron overload generates oxidants (probably hydroxyl radicals), causing oxidative stress leading to cellular dysfunction and fibrosis [increased collagen synthesis mediated by fibrogenic cytokines and activation of transcription factors)]. This hypothesized sequence of events will be tested by pursuing three specific aims: Aim 1 identify the oxidizing species and iron species that mediate aniline toxicity. Aim 2 will characterize the oxidized biomolecules in the spleens of aniline-exposed rats, especially the lipid peroxidation products and their protein and DNA adducts; the oxidized proteins will also be characterized. Aim 3 will examine how the induction of fibrogenic cytokines; activation of stress-induced transcription factor(s), and collagen synthesis contribute to aniline toxicity. Our project will elucidate the mechanism(s) of aniline-induced splenic toxicity, and will define the roles of oxidative stress, aldehyde products of lipid peroxidation, fibrogenic cytokines and transcription factor(s) in this process. Understanding the mechanism(s) of aniline toxicity will be very important in developing novel preventive and therapeutic strategies for aromatic amines, in general.