Research Project III - Vesicant-Induced Lung Injury

研究项目3.糜烂性肺损伤 项目负责人：Debra L.拉斯金博士 共同研究者：Jeffrey D.拉斯金博士 合作研究者：Vasanthi Sunil，Ph.D. 合作研究者：拉马Malaviya博士 合作研究者：Raymond Rancourt，Ph.D. 项目总结/摘要 肺损伤后暴露于芥子水泡是负责大多数发病率和死亡率，这些 高优先级化学威胁物由于目前还没有批准的治疗芥末的疗法， 因此，确定药物开发的机制靶点至关重要。我们的重点是 巨噬细胞和介质，他们释放，我们已经证明有助于急性肺损伤 以及硫芥和氮芥引起的慢性疾病。一个巨噬细胞衍生 我们发现，在芥子气肺毒性中起关键作用的促炎介质是肿瘤坏死因子α (TNF）。根据我们的研究结果，杨森制药公司现在正在努力将一种完全人性化的 抗TNF α抗体，用于治疗芥子气肺中毒的先进开发，资金来自 巴尔达。近年来，我们发现胆汁中的一种重要的核受体--法尼醇X受体（FXR） 具有抗炎活性的酸代谢在芥子气肺毒性中也是重要的。继氮 芥子气暴露，巨噬细胞FXR活性受到抑制。这与增加的活动有关， 促炎巨噬细胞和抗炎/促消退巨噬细胞的活性降低。研究 在下一个赠款期间，旨在阐明氮芥诱导的潜在机制， 抑制FXR。在初步研究中，我们发现调节促炎性细胞因子的microRNA， 巨噬细胞中的转录因子NF κ B B在氮芥暴露后失调。作为 因此，存在NF κ B B信号传导的延长激活，导致TNF κ B的产生增加， 细胞毒性活性氮物质。我们假设这些介质抑制FXR及其靶点NR4A1， 巨噬细胞从促炎表型到抗炎表型重编程的中枢调节因子。 为了验证这一假设，我们将（1）分析FXR活性降低对抗-HCV发展的影响。 炎症/促消退巨噬细胞和芥子气暴露后的肺损伤;和（2）确定是否 NF κ B B的长期激活是由于芥子诱导的调节NF κ B B的microRNA的改变， 下游炎症基因产物、TNF α和诱导型一氧化氮合酶。这些研究结果 将导致对芥子气肺中毒的新的机制见解和新的治疗方法的发展， 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.