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

基本信息

批准号：
10682629
负责人：
Kurt Lu
金额：
$ 56.59万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
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/10682629
关键词：
Acceleration Acute Adsorption 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 Combined Modality Therapy Complement DNA DNA Damage Data Development Dopamine Dose Drops Edema Epidermis Epithelium 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 Macrophage Marketing Mechlorethamine Melanins Modeling Mustard Mustard Gas NF-kappa B Nanotechnology Organ Patients Pharmaceutical Preparations Pigments Porosity 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 biomaterial compatibility carboxylate carboxylation cytokine cytokine release syndrome cytopenia efficacy study efficacy testing immune activation immunoreaction immunoregulation in vivo individualized medicine innovation intravenous administration macromolecule monocyte mortality nanolipoprotein particles nanoparticle neutralizing antibody neutrophil novel novel therapeutics particle prevent repaired scavenger receptor side effect skin barrier skin burn skin damage skin wound small molecule synergism systemic intervention tissue injury translational approach wound

项目摘要

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.

概括硫芥（SM）是一种反应性双功能烷基化剂，可与多种小分子和 DNA等大分子。 SM在第一次世界大战期间多次被用作化学战剂此后。 SM 和氮芥 (NM) 会导致严重的上皮和深层组织损伤，其特征是急性接触时发炎、硬结、肿胀和起泡。免疫细胞首先由中性粒细胞涌入其次是单核细胞和巨噬细胞为受损的上皮细胞提供防御；然而，随着时间的推移，持续的炎症会导致免疫风暴，从而导致额外的组织损伤，从而导致长期恢复过程。由于芥子气损伤的复杂性，SM损伤的治疗也很复杂结合暴露浓度和治疗时间的变量。因此，新的疗法可以预防 SM 暴露的有害影响是一个未满足的主要需求。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诱导组织基质因子。为了实现这一目标为了实现这一目标，我们将采用基于纳米颗粒的综合方法来 1) 阻断单核细胞和巨噬细胞防止进入受伤的皮肤，2) 稳定 SM 受伤的皮肤，阻止化学引诱剂的进一步释放免疫细胞。我们已经证明，高剂量全身施用维生素 D3 会抑制先天免疫细胞活性并改善接触 SM 和 NM 后对皮肤和循环血细胞的损伤。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-乙醇酸）免疫给药修饰微粒（PLGA-IMP）。这些颗粒具有抗炎特性，因为它们会阻止单核细胞和中性粒细胞离开血管并进入组织损伤部位； (二) 局部应用合成的功能性高密度脂蛋白纳米颗粒 (HDL NP) 本质上增强了上皮再形成受伤后可作为抗炎剂； (iii) 局部应用合成模拟物使用多巴胺形成球形聚多巴胺纳米粒子（PDA NPs）的黑色素。这些颗粒减少 NM 引起的炎症和水肿。我们的策略是全身输注 PLGA-IMP 来阻断单核细胞和巨噬细胞，以减轻 NM 和 SM 暴露引起的皮肤和全身症状。我们将使用HDL NP 以皮肤和免疫细胞 NF-kB 活性为目标，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 结合的功效。最终，这些研究将为 SM 引起的损伤提供独特的治疗方法，具有抗炎、促消退、容量与最小的副作用。这些新药还将具有市场可持续性因素，因为它具有多种适应症；不仅用于治疗 SM 损伤，还用于治疗皮肤烧伤患者。