Nanoparticle Coupled Antioxidants for Respiratory Illness in Veterans

纳米颗粒偶联抗氧化剂治疗退伍军人呼吸道疾病

• 批准号: 8255322
• 负责人: RODNEY JON SCHLOSSER
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8255322
• 关键词: Affect; Afghanistan; Age; Allergic; Animals; Antibodies; Antigen-Presenting Cells; Antioxidants; Binding; Cell Communication; Cell Culture Techniques; Cells; Characteristics; Coupled; Diesel Exhaust; Disease; Effectiveness; Ensure; Environmental Exposure; Enzymes; Epithelial; Epithelial Cells; Equipment; Excision; Exposure to; Free Radicals; Freedom; Frequencies; Gender; Goals; Health; Hour; Human; Human Resources; Hypersensitivity; Immune response; In Vitro; Incidence; Inflammation; Inflammatory; Inflammatory Response; Iraq; Lead; Measures; Medical; Military Personnel; Minor; Modeling; Mucin 1 protein; Mucociliary Clearance; Mus; Oxygen; Particulate Matter; Peroxides; Pharmaceutical Preparations; Play; Reactive Oxygen Species; Respiratory Mucosa; Respiratory System; Respiratory Tract Infections; Respiratory tract structure; Role; Secondary to; Smoke; Smoking; Stimulus; Structure of respiratory epithelium; Superoxide Dismutase; Superoxides; Surface; T cell response; Testing; Therapeutic; Therapeutic Agents; Therapeutic Uses; Tobacco smoke; Toxic effect; Toxin; Upper Respiratory Infections; Veterans; Water; catalase; experience; in vivo; nanoparticle; operation; particle; particle exposure; poly(lactic acid); pre-clinical; prevent; prophylactic; public health relevance; respiratory; rhinosinusitis; targeted delivery

DESCRIPTION (provided by applicant): Respiratory illnesses affect over two-thirds of Veterans deployed to Iraq or Afghanistan. The fact that respiratory tract disorders are among the most common medical conditions in Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) Veterans has been a consistent finding that affects military personnel regardless of age, rank, gender or active duty/National Guard status. Nearly 23% of OEF/OIF Veterans felt unit effectiveness was negatively affected by respiratory illnesses1. Even minor upper respiratory tract infections are known to have a significant impact on military operations2 and concern has been raised about a possible increase in frequency of respiratory tract infections and allergy among personnel deployed to Iraq1. Our Veterans experience an increased number of environmental exposures that likely contribute to these inflammatory respiratory conditions, to include tobacco smoke and diesel exhaust. Nearly half of OEF/OIF Veterans started or re-started smoking during deployment. Additionally, exposure to diesel exhaust particles (DEP) occurs from the extensive use of diesel engines in military vehicles and equipment. Both tobacco smoke and DEP are known airborne toxins that cause extensive oxidative inflammation due to free radicals and can lead to exacerbation of allergic rhinitis3. Quick degradation of free radicals results in reactive oxygen species (ROS)4-6. Antioxidant enzymes that metabolize ROS, thus serve as potential therapeutic agents. These antioxidants include superoxide dismutase (SOD), which converts superoxide, one of the most toxic ROS, to much less reactive peroxide, and catalase (CAT), which converts peroxide into water and oxygen. One problem with therapeutic use of antioxidants is ensuring that topically administered agents remain in contact with the respiratory mucosa long enough to be effective. Normal mucociliary clearance removes topical medications from the respiratory tract within 15-20 minutes when it would be more desirable to maintain mucosal contact for hours to days. We propose to achieve targeted delivery to and retention of SOD and CAT (antioxidants) on respiratory epithelium using biodegradable polylactic acid (PLA) nanoparticles (NPs). We will simultaneously coat NPs with SOD and/or CAT and a targeting antibody (Ab) to mucin 1 (MUC1), which binds to the luminal surface of airway epithelial cells. Our preliminary studies demonstrate that HSNECs play a critical role in modulating the inflammatory response to environmental stimuli, and that targeting HSNECs with antioxidants can favorably impact the subsequent APC and T cell responses. Our central hypothesis is that smoke and DEP exposure experienced by OEF/OIF Veterans impacts HSNEC-APC communication via ROS and that this inflammatory response can be ameliorated through the use of antioxidant nanoparticles targeted at the respiratory epithelium. This hypothesis will be tested by the following specific aims: Specific Aim 1: To determine binding characteristics and epithelial toxicity of antibody-antioxidant- NPs. SOD and CAT will be covalently attached to PLA NPs simultaneously with antiMUC1 Ab. NPs with different ratios of SOD, CAT and antiMUC1 will be prepared and effects of the SOD:CAT:antiMUC1 ratios upon binding characteristics, function and toxicity will be evaluated in vitro using HSNEC cultures. Specific Aim 2: To determine in vitro efficacy of antioxidant NPs in inhibiting smoke and DEP induced inflammation. We will use optimized antiMUC1-SOD/CAT-NPs identified in Aim 1 to determine efficacy and ability to prevent smoke and DEP induced in vitro inflammatory response in HSNECs and APCs as the initial steps in the immune response. Specific Aim 3: To determine in vivo efficacy of antioxidant NPs on smoke and DEP exacerbated rhinosinusitis. We will use a murine model of allergic fungal rhinosinusitis with exacerbation by smoke or DEP exposure to determine the efficacy of antiMUC1-SOD/CAT-NPs. PUBLIC HEALTH RELEVANCE: NARRATIVE (RELEVANCE TO VETERANS HEALTH) Respiratory illnesses affect over two-thirds of veterans deployed to Iraq or Afghanistan and are among the most common medical conditions in Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) veterans. Unique exposures to particulate matter in tobacco smoke and diesel exhaust particles from military vehicles likely contribute to this unusually high incidence and cause oxidative inflammation in the airway. Our strategic objective is to develop a topical medication, which could be used as a therapeutic measure against free radical pro-inflammatory action on respiratory epithelium that can persist even after removal of these environmental exposures. Our central hypothesis is that increased epithelial contact of nanoparticles conjugated with antibodies to the mucin 1 protein expressed on respiratory mucosa and with therapeutic antioxidants, superoxide and catalase, can prevent damage seen secondary to smoke and DEP exposures.

描述（由申请人提供）： 部署到伊拉克或阿富汗的退伍军人中超过三分之二患有呼吸道疾病。事实上，呼吸道疾病是持久自由行动 (OEF) 和伊拉克自由行动 (OIF) 退伍军人中最常见的医疗状况之一，这一事实已成为影响军事人员的一致发现，无论其年龄、军衔、性别或现役/国民警卫队身份如何。近 23% 的 OEF/OIF 退伍军人认为单位效能受到呼吸系统疾病的负面影响1。据了解，即使是轻微的上呼吸道感染也会对军事行动产生重大影响2，并且人们担心部署到伊拉克的人员呼吸道感染和过敏的频率可能会增加1。我们的退伍军人经历了越来越多的环境暴露，可能导致这些炎症性呼吸道疾病，包括烟草烟雾和柴油机尾气。近一半的 OEF/OIF 退伍军人在部署期间开始或重新开始吸烟。此外，军用车辆和设备中广泛使用柴油发动机也会导致柴油机尾气颗粒 (DEP) 暴露。烟草烟雾和 DEP 都是已知的空气传播毒素，它们会因自由基而引起广泛的氧化炎症，并可能导致过敏性鼻炎恶化3。自由基的快速降解产生活性氧 (ROS)4-6。代谢ROS的抗氧化酶因此可作为潜在的治疗剂。这些抗氧化剂包括超氧化物歧化酶 (SOD) 和过氧化氢酶 (CAT)，前者可将超氧化物（毒性最强的 ROS 之一）转化为活性低得多的过氧化物，后者可将过氧化物转化为水和氧气。使用抗氧化剂进行治疗的一个问题是确保局部施用的药物与呼吸道粘膜保持足够长的接触以发挥作用。正常的粘膜纤毛清除功能可在 15-20 分钟内将局部药物从呼吸道中清除，而此时更需要保持粘膜接触数小时至数天。我们建议使用可生物降解的聚乳酸 (PLA) 纳米颗粒 (NP) 来实现 SOD 和 CAT（抗氧化剂）在呼吸道上皮细胞上的靶向递送和保留。我们将同时用 SOD 和/或 CAT 以及粘蛋白 1 (MUC1) 的靶向抗体 (Ab) 包被纳米粒子，粘蛋白 1 (MUC1) 与气道上皮细胞的管腔表面结合。我们的初步研究表明，HSNEC 在调节对环境刺激的炎症反应中发挥着关键作用，并且用抗氧化剂靶向 HSNEC 可以有利地影响随后的 APC 和 T 细胞反应。我们的中心假设是，OEF/OIF 退伍军人经历的烟雾和 DEP 暴露会影响 HSNEC-APC 通过 ROS 的通讯，并且可以通过使用针对呼吸道上皮的抗氧化剂纳米粒子来改善这种炎症反应。该假设将通过以下具体目标进行检验： 具体目标 1：确定抗体-抗氧化剂-纳米颗粒的结合特征和上皮毒性。 SOD 和 CAT 将与抗 MUC1 Ab 同时共价连接至 PLA NP。将制备具有不同比例的 SOD、CAT 和 antiMUC1 的 NP，并使用 HSNEC 培养物在体外评估 SOD:CAT:antiMUC1 比例对结合特性、功能和毒性的影响。具体目标 2：确定抗氧化纳米粒子在抑制烟雾和 DEP 诱导的炎症方面的体外功效。我们将使用目标 1 中确定的优化抗MUC1-SOD/CAT-NP 来确定预防烟雾和 DEP 在 HSNEC 和 APC 中诱导的体外炎症反应的功效和能力，作为免疫反应的初始步骤。具体目标 3：确定抗氧化剂 NP 对烟雾和 DEP 加剧的鼻窦炎的体内功效。我们将使用因烟雾或 DEP 暴露而加剧的过敏性真菌性鼻窦炎小鼠模型来确定抗 MUC1-SOD/CAT-NP 的功效。 公共卫生相关性： 叙述（与退伍军人健康的相关性） 呼吸系统疾病影响着部署到伊拉克或阿富汗的退伍军人的三分之二以上，并且是持久自由行动 (OEF) 和伊拉克自由行动 (OIF) 退伍军人中最常见的医疗状况之一。独特的暴露于烟草烟雾中的颗粒物和军用车辆的柴油机尾气颗粒可能导致这种异常高的发病率，并导致气道氧化炎症。我们的战略目标是开发一种外用药物，可用作对抗自由基对呼吸道上皮的促炎作用的治疗措施，即使在去除这些环境暴露后，这种作用仍能持续存在。我们的中心假设是，与呼吸道粘膜上表达的粘蛋白 1 蛋白的抗体以及治疗性抗氧化剂、超氧化物和过氧化氢酶缀合的纳米颗粒增加上皮接触，可以防止继发于烟雾和 DEP 暴露的损伤。