Translation of novel and repurposed drugs to address the acute and late effects of mustard exposure

芥末去污中和对策方案或可保护暴露 暴露后立即给药时，皮肤、眼睛和肺部的表面。然而，这可能不会 足以解决与以下方面相关的延迟起病的骨髓抑制和造血中断 暴露在芥末中。当前提案的影响是提供一个全面的对策方案 这既解决了由急性皮肤介导的芥末暴露的急性和延迟有害影响 炎症和先天免疫系统，特别是巨噬细胞的过度激活。 NM介导的皮肤组织损伤导致表皮快速破裂和血管渗漏 由此导致的浮肿和疼痛的炎症。在最初的损伤之后，活化的炎症物质大量涌入。 单核细胞和巨噬细胞。巨噬细胞介导的可溶性信号分子的释放促进了一种促进 炎症状态，放大其他细胞毒性活动，包括释放活性氮 一氧化氮合酶、活性氧物种和蛋白水解酶的诱导。此外，这些激活的iNOS- 产生巨噬细胞在调节和加重全身毒性方面起着至关重要的作用。 我们建议使用一种多学科的翻译方法来调节皮肤炎症和 在小鼠和人类研究中使用体内技术的巨噬细胞活性。我们将研究这些措施的效果 螺内酯和双磷酸盐(BPS)与维生素D联合应用以抑制前-内酯的产生 炎症因子包括皮肤和激活的巨噬细胞中的肿瘤坏死因子α和诱导型一氧化氮合酶。这些药有 已在临床使用多年，已知的安全性和毒性特征。螺内酯是一种钾- 节约利尿剂(水丸)，已安全使用了50年，用于治疗高血压、液体 充血性心力衰竭和其他肾脏病变患者的超负荷和水肿。虽然有很多 螺内酯在盐皮质激素受体上的生理病理信息已经积累起来 (MR)和肾上腺，MR配体对皮肤等非经典靶点的作用发现了新的 以及令人兴奋的潜在应用。我们在此建议螺内酯作为一种微弱的利尿剂 能够减少水肿性皮肤损伤的水分含量，作为加速伤口愈合的一种方式。对.的使用 螺内酯在限制浮肿和疼痛的皮肤炎症方面可能有好处。BPS是一种药物 已经使用了40多年。除了骨骼外，这些药物还会沉积在皮肤、肝脏、 脾和骨髓，这与我们的研究兴趣一致，因为它们代表 可能是被激活的巨噬细胞的蓄水池和/或靶标。此外，BPS存款和具有长效性 对组织的影响。我们建议将BPS与大剂量维生素D3联合使用作为应对措施 NM暴露。最后，作为对最有毒暴露的系统治疗，我们建议使用一种新的免疫 来自临床聚合物的改性微粒(IMP)。在捆绑和吞噬小鬼时， 巨噬细胞被隔离在肝脏和脾中进行降解。IMPS的战略代表着一种 这笔赠款的新方面是针对严重的全身毒性。验证并确定翻译版本 我们设计的BPS和维生素D3在抑制芥末暴露后皮肤炎症中的意义 紫外线(太阳光谱辐射)替代人体暴露芥末的临床研究 人类受试者以加快未来的翻译研究。众所周知，晒伤会导致 皮肤中巨噬细胞的红肿、水泡和激活，包括iNOS和iNOS的上调 肿瘤坏死因子α。这项人类临床研究的信息将是信息性的，并证实我们的 提出了对策建议。 我们组建的团队包括来自大学内外不同中心的合作调查人员 和医院。联合调查组和顾问小组将监督该项目，帮助确定 利用以下专业知识的新机会和互补方法：皮肤药理学； 炎症和巨噬细胞；维生素D；皮肤和组织病理学；临床试验实施和 法规遵从性；统计和流行病学--所有这些都对将本研究转化为实用的 干预。 这是一种新的、高度翻译的方法，以开发潜在的对策来解决关键问题 接触芥末的发病率和死亡因素。螺内酯、双磷酸盐和维生素D是一种 可广泛获得且价格低廉，如果被证明是有益的，可能会在 化学武器暴露事件。

Countermeasure protocols of mustard decontamination and neutralization may protect exposed surfaces of the skin, eyes, and lungs when administered immediately after exposure. However, this may not be adequate to address the delayed onset of myelosuppression and disrupted hematopoiesis associated with mustard exposure. The impact of the current proposal is to provide a comprehensive countermeasure regimen that addresses both the acute and delayed detrimental effects of mustard exposure mediated by acute skin inflammation and the innate immune system, specifically macrophage hyper-activation. NM-mediated tissue injury of the skin results in rapid epidermal disruption and vascular leakage resulting edema and painful inflammation. Following the initial injury is an influx of activated inflammatory monocytes and macrophages. Release of macrophage-mediated soluble signaling molecules promotes a pro- inflammatory state which amplifies other cytotoxic activities including release of reactive nitrogen species iNOS, reactive oxygen species, and induction of proteolytic enzymes. Furthermore, these activated iNOS- producing macrophages are critically involved in mediating and exacerbating systemic toxicities. We propose to use a multidisciplinary translational approach to modulate skin inflammation and macrophage activity using in vivo techniques in mouse and human studies. We will study the effect of spironolactone and bisphosphonates (BPs) in combination with vitamin D to inhibit the production of pro- inflammatory factors including; TNFα, and iNOS in the skin and in activated macrophages. These drugs have been in clinical use for many years with known safety and toxicity profiles. Spironolactone is a potassium- sparing diuretic (water pill) that has been safely used for five decades to treat essential hypertension, fluid overload and edema in patients with congestive heart failure and other kidney pathologies. While much information has been accumulated on the physiopathology of spironolactone on the mineralocorticoid receptor (MR) and the adrenal glands, the effect of MR ligands on non-classical targets such as the skin has found new and exciting potential applications. We hereby propose that spironolactone being a weak diuretic has sufficient capacity to reduce water content of edematous skin lesions as a way to accelerate wound healing. The use of spironolactone may have benefits in limiting edema and painful skin inflammation. BPs are medications that has been used for over 40 years. In addition to the skeletal bones, these drugs deposit in the skin, liver, spleen, and bone marrow which aligns with our research interest as they represent organs and tissues that may be reservoirs and/or targets for activated macrophages. Furthermore, BPs deposit and have long-lasting effects in the tissue. We propose to use BPs in conjunction with high dose vitamin D3 as countermeasures to NM exposure. Lastly, as a systemic treatment for the most toxic exposure, we propose to use a novel immune modifying microparticle (IMPs) which are derived from clinical polymers. Upon binding and engulfment of IMPs, macrophages are sequestered for degradation in the liver and spleen. The strategy with IMPs represents a new aspect of this grant to target severe systemic toxicity. To validate and determine the translational significance of BPs and vitamin D3 in suppressing skin inflammation following mustard exposure, we designed a human clinical study using UV (solar spectrum radiation) as a surrogate for mustard exposure in healthy human subjects to expedite future translational studies. It is well known that sunburn exposure leads to redness, swelling, vesication, and activation of macrophages in the skin including upregulation of iNOS and TNFα. Information from this human clinical study will be informative and confirmatory of the use of our proposed countermeasures. Our assembled team involve co-investigators from different centers within and outside the university and hospital. The team of co-investigators and consultants will have oversight of the project, helping to identify new opportunities and complementary approaches drawing from expertise in: dermatopharmacology; inflammation and macrophages; vitamin D; skin and tissue pathology; clinical trials implementation and regulatory compliance; statistics and epidemiology - all critical to the translation of this study into a practical intervention. This is a novel and highly translational approach to develop potential countermeasure to address key morbidity and mortality factors from mustard exposure. Spironolactone, bisphosphonates, and vitamin D are a widely available and inexpensive and, if shown to be beneficial, could have a broad public health impact in the event of chemical weapon exposure.