Topical and systemic interventions for mustard-induced skin injury

芥末引起的皮肤损伤的局部和全身干预

• 批准号: 10490418
• 负责人: Kurt Lu
• 金额: $ 66.1万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10490418
• 关键词: Acute; Alkylating Agents; Animal Model; Anti-Inflammatory Agents; Apoptosis; Binding; Biological; Biological Markers; Biological Process; Blood Cells; Bone Marrow; Bulla; CCL2 gene; CCL3 gene; Cells; Chemical Burns; Chemical Warfare Agents; Chemicals; Chemotactic Factors; Cholecalciferol; Cholesterol; Chronic; Cicatrix; Complement; DNA; DNA Damage; Data; Development; Dopamine; Dose; Drops; Edema; Epidermis; Epithelial; Event; Fibroblasts; Free Radicals; Glycolates; Goals; High Density Lipoproteins; ITGAM gene; Immune; Immune response; Immunology; In Vitro; Induration; Inflammation; Inflammatory; Inflammatory Infiltrate; Infusion procedures; Injury; Interferons; Intervention; Intravenous; Investigation; Late Effects; Life; Liver; MMP9 gene; Mechlorethamine; Melanins; Methods; Modeling; Mustard; Mustard Gas; NF-kappa B; Nanotechnology; Organ; Patients; Pharmaceutical Preparations; Pigments; Process; Property; Reaction; Recovery; Regimen; Signal Transduction; Site; Skin; Skin injury; Spleen; Swelling; TNF gene; Testing; Therapeutic; Time; Tissues; Topical application; Toxic effect; Toxin; Transforming Growth Factor beta; UV protection; Ultraviolet Rays; Universities; Weight; World War I; base; biomaterial compatibility; carboxylate; cytokine; cytokine release syndrome; cytopenia; efficacy study; efficacy testing; immune activation; immunoreaction; immunoregulation; in vivo; individualized medicine; innovation; macromolecule; macrophage; monocyte; mortality; nanoparticle; neutralizing antibody; neutrophil; novel; novel therapeutics; particle; prevent; repaired; scavenger receptor; side effect; skin barrier; skin burn; skin color; skin damage; skin wound; small molecule; synergism; systemic intervention; tissue injury; translational approach; wound

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.

总结 硫芥（SM）是一种反应性双官能烷基化剂，其与各种小分子反应， 大分子如DNA。SM在第一次世界大战期间被用作化学战剂， 然后SM和氮芥（NM）引起严重的上皮和深部组织损伤，其特征在于急性炎症反应。 接触后出现炎症、硬结、肿胀和起泡。免疫细胞首先通过中性粒细胞流入 随后是单核细胞和巨噬细胞为受损的上皮提供防御;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，导致长期的免疫缺陷。 恢复过程。由于芥子气引起的损伤的复杂性，SM损伤的治疗是复杂的 结合暴露浓度和治疗时间的变量。因此，新的治疗方法，以防止 SM暴露的有害影响是一个主要的未满足的需求。我们的目标是制定对策 局部和系统干预。具体来说，我们将专注于关闭上游的关键细胞事件 在损伤级联中限制免疫风暴和组织基质因子的诱导。实现这一 为了达到这一目标，我们将采取一种全面的基于纳米颗粒的方法来1）阻断单核细胞和巨噬细胞 2）稳定SM损伤的皮肤以阻断化学引诱剂的进一步释放， 免疫细胞。我们已经表明，高剂量的维生素D3全身给药抑制先天性免疫， 细胞活性，并改善SM和NM暴露后对皮肤和循环血细胞的损伤。 因此，新型纳米材料与维生素D3的组合可能产生积极的治疗效果 结果我们将测试的新颗粒是（i）聚（乳酸-共-乙醇酸）免疫的静脉内施用 改性微粒（PLGA-IMP）。这些颗粒具有抗炎特性，因为它们阻止了 单核细胞和中性粒细胞离开血管并进入组织损伤部位;（ii）局部应用 合成的功能性高密度脂蛋白纳米颗粒（HDL NPs）固有地增强上皮再生 在创伤后，并可作为抗炎剂;和（iii）局部应用的合成模拟物 使用多巴胺将黑色素形成为球形聚多巴胺纳米颗粒（PDA NPs）。这些颗粒减少 NM诱导的炎症和水肿。我们的策略是采用PLGA-IMP全身灌注阻断单核细胞 和巨噬细胞以减轻NM和SM暴露的皮肤和全身表现。我们将使用HDL NP靶向皮肤和免疫细胞NF-kB活性，我们将使用PDA NP局部阻断急性炎症。 我们还将研究这些颗粒与维生素D3组合的功效。最终，这些 研究将为SM诱导的损伤产生独特的治疗， 以最小的副作用。这些新型药物也将通过具有多个 适应症;不仅用于治疗SM损伤，而且用于皮肤烧伤患者。