SPLENIC TOXICITY OF ANILINE

我们的长期目标是阐明脾毒性暴露于芳香胺的机制，并制定预防/治疗策略。 我们使用工业化学品苯胺作为原型胺。 苯胺暴露除引起高铁血红蛋白血症、溶血和溶血性贫血外，还导致选择性脾毒性。 这种选择性脾损伤的机制还不清楚。 在我们以前的资助期间的研究表明，苯胺暴露增加铁含量，脂质过氧化，蛋白质氧化和脂质衍生的过氧化物-蛋白质加合物（氧化应激的标志物）在大鼠脾脏。 这些事件伴随着诸如血管充血、血窦和成纤维细胞增加、吞噬红细胞、囊增厚和纤维化的形态学变化。 我们假设苯胺毒性是由氧化应激引起的，并假设以下事件导致脾毒性的顺序：苯胺（和/或其代谢产物）损伤红细胞，红细胞沉积在脾脏中，从而增加总铁和活性铁（游离铁）。 这种铁超负荷产生氧化剂（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[纤维化细胞因子介导的胶原蛋白合成增加和转录因子活化]。 这一假设的事件序列将通过追求三个具体目标进行测试：目标1确定介导苯胺毒性的氧化物种和铁物种。 目的2将表征苯胺暴露大鼠脾脏中的氧化生物分子，特别是脂质过氧化产物及其蛋白质和DNA加合物;氧化蛋白质也将被表征。 目的3将研究如何诱导纤维化细胞因子，激活应激诱导的转录因子（S），胶原蛋白的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，并将确定氧化应激，脂质过氧化的醛类产物，纤维化细胞因子和转录因子在这一过程中的作用。 了解苯胺毒性的机制将是非常重要的，在开发新的预防和治疗策略的芳香胺，一般。

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.