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

转化新型药物和重新用途药物以解决芥末暴露的急性和迟发影响

• 批准号: 10007605
• 负责人: Kurt Lu
• 金额: $ 77.54万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10007605
• 关键词: Acute; Address; Adrenal Glands; Aftercare; Apoptosis; Attenuated; Binding; Bioavailable; Biological Markers; Blood; Blood Vessels; Bone Marrow; Bone Marrow Cells; Bone Marrow Suppression; Bulla; Cell Death; Cessation of life; Chemical Weapons; Chemicals; Cholecalciferol; Clinical; Clinical Medicine; Clinical Research; Clinical Trials; Collaborations; Congestive Heart Failure; Cutaneous; Data; Decontamination; Deposition; Devices; Diuretics; Dose; Edema; Effectiveness; Effector Cell; Epidemiology; Erythema; Essential Hypertension; Event; Exposure to; Extravasation; Eye; Fluid overload; Functional disorder; Future; Glycolates; Goals; Grant; Half-Life; Health; Hematopoiesis; Hemorrhage; Human; ITGAM gene; Immune; Induration; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Injury; Innate Immune Response; Innate Immune System; Interleukin-1 beta; Interleukin-6; Intervention; Kidney; Late Effects; Lesion; Ligands; Liver; Lung; Macrophage Activation; Marrow; Mechlorethamine; Mediating; Mineralocorticoid Receptor; Modeling; Modernization; Monitor; Morbidity - disease rate; Mus; Mustard; Mustard Gas; Myeloid Cells; Myelosuppression; Necrosis; Oral; Organ; Osteoclasts; Pain; Pathology; Patient Outcomes Assessments; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Physiological; Plasma; Polymers; Potassium; Production; Protocols documentation; Public Health; Radiation; Reaction; Reactive Nitrogen Species; Reactive Oxygen Species; Redness; Regimen; Research; Research Personnel; Safety; Sampling; Signaling Molecule; Site; Skeletal bone; Skin; Skin Tissue; Skin injury; Sodium Chloride; Spironolactone; Spleen; Sunburn; Surface; Swelling; TNF gene; Techniques; Testing; Thick; Time; Tissues; Toxic effect; Toxicant exposure; Translating; Translations; United States; Universities; University Hospitals; Up-Regulation; Vesicants; Vitamin D; Water; Work; World War I; Wound models; bisphosphonate; carboxylate; cytokine release syndrome; cytopenia; cytotoxic; delta opioid receptor; design; experience; experimental study; human subject; in vivo; interest; macrophage; monocyte; mortality; mouse model; multidisciplinary; novel; novel therapeutics; pamidronate; pill; prevent; protective effect; recruit; response; skin lesion; skin wound; statistics; systemic toxicity; tissue injury; translational approach; translational study; weapons; wound healing

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.

芥子去污和中和的对策方案可以保护暴露的 接触后立即给药时，皮肤、眼睛和肺部的表面。然而，这可能不会 足以解决与骨髓抑制相关的延迟发作和造血功能紊乱 芥末暴露。当前提案的影响是提供全面的对策方案 解决急性皮肤介导的芥末暴露的急性和迟发有害影响 炎症和先天免疫系统，特别是巨噬细胞过度激活。 NM 介导的皮肤组织损伤导致表皮快速破裂和血管渗漏 由此产生的水肿和疼痛的炎症。最初的损伤之后是激活的炎症的涌入 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亲 炎症状态会放大其他细胞毒性活性，包括活性氮的释放 iNOS、活性氧和蛋白水解酶的诱导。此外，这些激活的 iNOS- 产生巨噬细胞在介导和加剧全身毒性中发挥着重要作用。 我们建议使用多学科转化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。我们将研究效果 螺内酯和双膦酸盐 (BP) 与维生素 D 联合使用，可抑制前体的产生 炎症因素包括；皮肤和活化巨噬细胞中的 TNFα 和 iNOS。这些药物有 已在临床使用多年，具有已知的安全性和毒性特征。螺内酯是一种钾 节省利尿剂（水丸）已被安全使用了五十年，用于治疗原发性高血压、液体 充血性心力衰竭和其他肾脏疾病患者的超负荷和水肿。虽然很多 关于螺内酯对盐皮质激素受体的病理生理学信息已经积累 (MR) 和肾上腺，MR 配体对皮肤等非经典靶标的作用发现了新的 和令人兴奋的潜在应用。我们在此建议螺内酯作为弱利尿剂，具有足够的作用 能够减少水肿性皮肤病变的含水量，从而加速伤口愈合。使用 螺内酯可能有助于限制水肿和疼痛性皮肤炎症。 BP 是一种药物 已经使用了 40 多年。除骨骼外，这些药物还沉积在皮肤、肝脏、 脾脏和骨髓符合我们的研究兴趣，因为它们代表了器官和组织 可能是活化巨噬细胞的储存库和/或靶标。此外，BP 会沉积并具有持久的 在组织中的作用。我们建议将 BP 与高剂量维生素 D3 结合使用作为应对措施 近乎曝光。最后，作为对毒性最强的暴露的全身治疗，我们建议使用一种新型免疫疗法 源自临床聚合物的改性微粒（IMP）。在结合和吞噬 IMP 后， 巨噬细胞被隔离在肝脏和脾脏中降解。 IMP 策略代表了 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 BP 和维生素 D3 在抑制芥末暴露后皮肤炎症方面的重要性，我们设计 一项人体临床研究，使用紫外线（太阳光谱辐射）作为健康人暴露于芥末的替代品 人类受试者加速未来的转化研究。众所周知，晒伤会导致 皮肤发红、肿胀、起泡和巨噬细胞活化，包括 iNOS 和 肿瘤坏死因子α。这项人体临床研究的信息将为我们的使用提供信息并证实 提出的对策。 我们组建的团队包括来自大学内外不同中心的共同研究人员 和医院。联合研究人员和顾问团队将监督该项目，帮助确定 来自皮肤药理学专业知识的新机遇和补充方法； 炎症和巨噬细胞；维生素D；皮肤和组织病理学；临床试验的实施和 监管合规性；统计学和流行病学——对于将本研究转化为实际应用至关重要 干涉。 这是一种新颖且高度转化的方法，可开发潜在的对策来解决关键问题 芥末暴露导致的发病和死亡因素。螺内酯、双膦酸盐和维生素 D 是 广泛可用且价格低廉，如果被证明是有益的，可能会对整个公共卫生领域产生广泛的影响 化学武器暴露事件。