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：
10282411
负责人：
Kurt Lu
金额：
$ 39.81万
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/10282411
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 Structure 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

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.

概括硫芥末（SM）是一种反应性双功能烷基化剂，与多种小分子反应大分子，例如DNA。 SM在第一次世界大战期间被用作化学战代理此后。 SM和氮芥末（NM）引起严重的上皮和深层组织损伤，其特征是急性接触时炎症，沉淀，肿胀和起泡。首先由中性粒细胞流入免疫细胞其次是单核细胞和巨噬细胞为受损的上皮提供防御。但是，随着时间的流逝，持续的炎症导致免疫风暴造成其他组织损害，导致长期恢复过程。由于芥末引起的损伤的复杂性，对SM损伤的治疗变得复杂结合暴露浓度和治疗时间的变量。因此，新的疗法以防止 SM暴露的有害影响是主要的未满足需求。我们的目标是使用局部和全身干预措施。具体而言，我们将专注于关闭上游关键的蜂窝事件在损伤级联中，以限制组织基质因子的免疫风暴和诱导。实现这一目标目标，我们将采用一种基于纳米颗粒的综合方法，以阻止单核细胞和巨噬细胞通过进入受伤的皮肤和2）稳定SM受伤的皮肤以阻止化学吸引力的进一步释放免疫细胞。我们已经表明，高剂量的全身性维生素D3抑制了先天免疫细胞活性并改善SM和NM暴露后皮肤的损害和循环血细胞。因此，新型纳米颗粒材料与维生素D3的组合可能会产生阳性治疗结果。我们要测试的新型颗粒是（i）i.v.给予聚（乳酸 - 乙醇酸）免疫修改微粒（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从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 NP）固有增强的重新上皮化受伤后，可以充当抗炎药；（iii）合成模拟的局部应用黑色素使用多巴胺形成的多巴胺形成球形多胺纳米颗粒（PDA NPS）。这些颗粒减少 NM引起的炎症和水肿。我们的策略是使用PLGA-IMP的系统性输注来阻断单核细胞以及巨噬细胞减轻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的功效。最终，这些调查将对SM诱导的损伤产生独特的治疗方法，这些损伤将具有抗炎，促进性的损伤，容量，副作用最小。这些新型药物还将具有多个市场可持续性因素适应症；不仅用于治疗SM损伤，而且在皮肤灼伤患者中。