Research Project III - Vesicant-Induced Lung Injury

研究项目3.发泡剂所致肺损伤 项目负责人：黛布拉·L·拉斯金博士 共同调查者：杰弗里·D·拉斯金博士 共同调查者：Vasanthi Sunil，博士 共同调查者：拉玛·马拉维亚，博士 共同调查者：Raymond Rancourt博士 项目摘要/摘要 暴露于芥末发泡剂后的肺损伤是这些疾病的大部分发病率和死亡率的原因。 高优先级化学威胁剂。因为目前还没有被批准的治疗芥子气的疗法 对于中毒来说，确定药物开发的机械性靶点是至关重要的。我们关注的是炎症性疾病 巨噬细胞及其释放的介质在急性肺损伤中起重要作用。 硫磺芥末和氮芥末引起的慢性病。1个巨噬细胞衍生 我们发现的在芥末肺毒性中起关键作用的促炎介质是肿瘤坏死因子α (肿瘤坏死因子)。根据我们的发现，Janssen制药公司现在正在努力将SimponiR，一种完全人性化的 抗肿瘤坏死因子抗体，进入晚期开发用于治疗芥子气肺中毒 巴达。在最近的研究中，我们发现法尼类X受体(FXR)是胆汁中重要的核受体。 具有抗炎活性的酸代谢在芥末肺中毒中也很重要。追随氮素 暴露芥末后，巨噬细胞FXR活性受到抑制。这与以下活动增加有关： 促炎症巨噬细胞和抗炎/促溶解巨噬细胞活性降低。研究 在下一个资助期内，旨在阐明氮芥诱导的潜在机制 抑制FXR。在初步研究中，我们发现调节促炎症反应的microRNAs 氮芥末暴露后巨噬细胞转录因子NFB表达失调。作为一名 结果：NF--B信号的长期激活导致肿瘤坏死因子和 细胞毒性反应性氮物种。我们假设这些介体抑制FXR及其靶点NR4A1， 巨噬细胞重新编程的中央调节因子，从促炎表型到抗炎表型。 为了验证这一假设，我们将(1)分析FXR活性降低对抗-FXR的发展的影响 芥末暴露后的炎症/促溶解巨噬细胞和肺损伤；以及(2)确定 NFB的长期激活是由于芥末引起调节NFB和KEY的microRNAs的改变 下游炎症基因产物，肿瘤坏死因子和诱导型一氧化氮合酶。这些研究的结果 将导致对芥子气肺中毒的新的机制认识和新的治疗方法的开发 减轻毒性。

Research Project 3. Vesicant-induced Lung Injury Project Lead: Debra L. Laskin, Ph.D. Co-Investigator: Jeffrey D. Laskin, Ph.D. Co-Investigator: Vasanthi Sunil, Ph.D. Co-Investigator: Rama Malaviya, Ph.D. Co-Investigator: Raymond Rancourt, Ph.D. Project Summary/Abstract Lung injury following exposure to mustard vesicants is responsible for most morbidity and mortality of these high priority chemical threat agents. As there are currently no approved therapeutics to treat mustard poisoning, it is essential to identify mechanistic targets for drug development. Our focus is on inflammatory macrophages and mediators they release which we have demonstrated contribute to both acute lung injury and chronic disease induced by sulfur mustard and nitrogen mustard. One macrophage derived proinflammatory mediator that we discovered is key in mustard lung toxicity is tumor necrosis factor alpha (TNF). Based on our findings, Janssen Pharmaceuticals is now working to move SimponiR, a fully humanized anti-TNF antibody, into advanced development for treatment of mustard lung poisoning with funds from BARDA. In recent studies we discovered that farnesoid-X receptor (FXR), a nuclear receptor important in bile acid metabolism with anti-inflammatory activity is also important in mustard lung toxicity. Following nitrogen mustard exposure, macrophage FXR activity is suppressed. This is associated with increased activity of proinflammatory macrophages and reduced activity of anti-inflammatory/proresolution macrophages. Studies during the next grant period are aimed at elucidating mechanisms underlying nitrogen mustard induced suppression of FXR. In preliminary studies we found that microRNAs that regulate the proinflammatory transcription factor NFB in macrophages are dysregulated after nitrogen mustard exposure. As a consequence, there is protracted activation of NFB signaling resulting in increased production of TNF and cytotoxic reactive nitrogen species. We hypothesize that these mediators suppress FXR and its target, NR4A1, a central regulator of macrophage reprogramming from a proinflammatory to an anti-inflammatory phenotype. To test this hypothesis, we will (1) Analyze the impact of reduced FXR activity on the development of anti- inflammatory/proresolution macrophages and lung injury following mustard exposure; and (2) Determine if protracted activation of NFB is due to mustard-induced alterations in microRNAs regulating NFB and key downstream inflammatory gene products, TNF and inducible nitric oxide synthase. Results of these studies will lead to new mechanistic insights into mustard lung poisoning and the development of novel therapeutics for mitigating toxicity.