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: 8392968
• 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/8392968
• 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.

描述（由申请人提供）： 呼吸道疾病会影响部署到伊拉克或阿富汗的退伍军人中三分之二。呼吸道疾病是持久自由（OEF）和伊拉克自由行动（OIF）的最常见医疗状况之一，无论年龄，职位，性别或现役/国民警卫队身份如何，都会影响军事人员。近23％的OEF/OIF退伍军人认为单位有效性受呼吸道疾病的负面影响1。即使是轻微的上呼吸道感染也对军事行动产生重大影响，并且人们对部署到伊拉克1的人员之间的呼吸道感染频率可能增加和过敏引起了人们的关注。我们的退伍军人经历了更多可能导致这些炎症呼吸系统疾病的环境暴露数量，包括烟草烟雾和柴油排气。在部署期间，将近一半的OEF/OIF退伍军人开始或重新开始吸烟。此外，暴露于柴油排气颗粒（DEP）是由于在军用车辆和设备中广泛使用柴油发动机而发生的。烟草烟雾和DEP都是已知的空中毒素，由于自由基的自由基引起广泛的氧化炎症，并可能导致过敏性鼻炎3。自由基的快速降解会导致活性氧（ROS）4-6。代谢ROS的抗氧化剂酶，因此用作潜在的治疗剂。这些抗氧化剂包括超氧化物歧化酶（SOD），将超氧化物（最有毒的ROS之一转化为反应性过氧化剂之一）和过氧化氢酶（Cat）（CAT），将过氧化物转化为水和氧气。治疗使用抗氧化剂的一个问题是确保局部给药的药物与呼吸粘膜保持接触足够长以有效。正常的粘膜纤毛间隙在15-20分钟内从呼吸道中去除局部药物，因为它更需要保持粘膜接触数小时至几天。我们建议使用可生物降解的聚乳酸（PLA）纳米颗粒（NPS）实现呼吸性上皮上的SOD和CAT（抗氧化剂）的目标递送。我们将用SOD和/或CAT以及粘液1（MUC1）的靶向抗体（AB）同时涂覆NP，该抗体（MUC1）与气道上皮细胞的腔表面结合。我们的初步研究表明，HSNEC在调节对环境刺激的炎症反应中起关键作用，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的通信，并且可以通过使用针对呼吸性上皮的抗氧化剂纳米颗粒来改善这种炎症反应。该假设将通过以下特定目的进行检验：特定目的1：确定抗体 - 抗氧化剂NP的结合特征和上皮毒性。 SOD和CAT将与Antimuc1 AB同时共价附加到PLA NPS。将准备具有不同比率的SOD，CAT和ANTIMUC1的NP，并且将使用HSNEC培养物在体外评估SOD：CAT：ANTIMUC1比对结合特征，功能和毒性的影响。具体目标2：确定抗氧化剂NP在抑制烟雾和DEP诱导炎症中的体外功效。我们将使用在AIM 1中鉴定的优化的抗MUC1-SOD/CAT-NPS来确定HSNEC和APC中烟雾和DEP诱导的烟雾和DEP诱导的能力作为免疫反应的初始步骤。特定目的3：确定抗氧化剂NP对烟雾和Dep恶化的鼻鼻涕的体内功效。我们将使用一种因烟雾或DEP暴露而加重的过敏真菌鼻鼻涕的鼠模型，以确定抗MUC1-SOD/CAT-NPS的功效。