Topical and systemic interventions for mustard-induced skin injury

摘要 硫磺芥末(SM)是一种反应性双官能团烷基化试剂，可与多种小分子和 像DNA这样的大分子。SM在第一次世界大战期间被用作化学战剂，并多次 之后。SM和氮芥末(NM)可引起严重的上皮和深层组织损伤，其特征是急性 接触时发炎、硬化、肿胀和起泡。中性粒细胞首先进入免疫细胞 其次是单核细胞和巨噬细胞对受损的上皮细胞提供防御；然而，随着时间的推移， 持续的炎症导致免疫风暴，引起额外的组织损伤，导致长时间的 恢复过程。由于芥末所致损伤的复杂性，SM损伤的治疗很复杂 结合暴露浓度和治疗时间的变量。因此，预防该病的新疗法 SM暴露的有害影响是一个主要的未得到满足的需求。我们的目标是制定对策，使用 局部和系统性干预。具体地说，我们将重点关闭上游的关键手机事件 在损伤级联中限制免疫风暴和诱导组织基质因子。要做到这一点 为了达到这个目标，我们将采用一种基于纳米颗粒的综合方法来阻断单核细胞和巨噬细胞。 防止进入受伤的皮肤和2)稳定SM受伤的皮肤，以阻止化学诱导剂的进一步释放 免疫细胞。我们已经证明，全身注射大剂量维生素D3会抑制先天免疫。 细胞活性，改善SM和NM暴露后对皮肤和循环血细胞的损害。 因此，新型纳米颗粒材料与维生素D3的组合可能会产生积极的治疗效果 结果。我们将测试的新粒子是(I)i.v。聚乳酸-羟基乙酸共聚物免疫接种的研究 改性微粒(PLGA-IMPS)。这些颗粒具有抗炎特性，因为它们能阻止 单核细胞和中性粒细胞离开血管进入组织损伤部位；(Ii)局部应用 人工合成的功能性高密度脂蛋白纳米粒(HDLNPs)固有地促进再上皮化 可作为消炎剂；及(Iii)局部应用一种合成的模拟 黑色素利用多巴胺形成球形多巴胺纳米颗粒(PDA NPs)。这些粒子减少了 NM诱导的炎症和水肿。我们的策略是通过全身输注PLGA-IMP来阻断单核细胞 和巨噬细胞，以减轻NM和SM暴露所致的皮肤和全身症状。我们将使用HDL语言 NP靶向皮肤和免疫细胞的核因子-kB活性，我们将使用PDA纳米粒局部阻断急性炎症。 我们还将研究这些颗粒与维生素D3联合使用的疗效。最终，这些 研究将为SM诱导的损伤提供独特的治疗方法，具有抗炎、促进溶解、 容量，副作用最小。这些新药还将具有市场可持续性因素，因为 适应症；不仅用于治疗SM损伤，也适用于皮肤烧伤患者。

SUMMARY Sulfur mustard (SM) is a reactive bifunctional alkylating agent that reacts with a variety of small molecules and macromolecules such as DNA. SM was used as a chemical warfare agent during World War I and many times thereafter. SM and nitrogen mustard (NM) cause severe epithelial and deep tissue injury characterized by acute inflammation, induration, swelling, and blistering upon contact. The influx of immune cells first by neutrophils followed by monocytes and macrophages provide defense to the damaged epithelium; however, with time, persistent inflammation results in an immune storm that incurs additional tissue damage resulting in a long recovery process. Treatment of SM injuries is complicated due to the complexity of the mustard-induced injury combined with variables of exposure concentration and time to therapy. Thus, novel therapies to prevent the deleterious effects of SM exposure is a major unmet need. Our goal is to develop countermeasures using topical and systemic interventions. Specifically we will focus on switching off key cellular events upstream in the injury cascade to limit the immune storm and induction of tissue matrix factors. To achieve this goal, we will undertake a comprehensive nanoparticle-based approach to 1) block monocytes and macrophages from entering injured skin and 2) stabilize SM injured skin to block further release of chemo-attractants for immune cells. We have shown that a high dose systemic administration of vitamin D3 suppresses innate immune cell activity and ameliorates damage to the skin and circulating blood cells following SM and NM exposure. Therefore, combinations of novel nanoparticle-based materials with vitamin D3 may yield positive treatment results. The novel particles that we will test are (i) i.v. administration of poly (lactic-co-glycolic acid) immune modifying microparticles (PLGA-IMPs). These particles have anti-inflammatory properties because they block monocytes and neutrophils from leaving the vessels and entering into sites of tissue injury; (ii) topical application of synthetic, functional high-density lipoprotein nanoparticles (HDL NPs) inherently enhance re-epithelialization following wounding and can act as anti-inflammatory agents; and (iii) topical application of a synthetic mimic of melanin using dopamine formed into spherical polydopamine nanoparticles (PDA NPs). These particles reduce NM-induced inflammation and edema. Our strategy is use systemic infusion of PLGA-IMP to block monocyte and macrophages to mitigate skin and systemic manifestations from NM and SM exposure. We will use HDL NP to target skin and immune cells NF-kB activity, and we will use PDA NPs to topically block acute inflammation. We will also investigate the efficacy of these particles in combination with vitamin D3. Ultimately, these investigations will yield unique treatments for SM-induced injury that will have anti-inflammatory, pro-resolving, capacity with minimal side effects. These novel drugs also will have market sustainability factor by having multiple indications; not only for treating SM injury, but in patients with skin burns.