Therapeutics against chemical threat induced respiratory toxicity

针对化学威胁引起的呼吸道毒性的治疗

• 批准号: 7294905
• 负责人: Madhusoodana P. Nambiar
• 金额: $ 59.92万
• 依托单位: GENEVA FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-29 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7294905
• 关键词: Accounting; Adult Respiratory Distress Syndrome; Alveolus; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Antisense Oligonucleotides; Asthma; Biochemical; Biological Markers; Blood; Breathing; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Bronchodilator Agents; Bypass; Carboxylic Ester Hydrolases; Cause of Death; Cavia; Cells; Cessation of life; Chemical Agents; Chemical Exposure; Chemical Injury; Chemicals; Child; Chronology; Class; Clinical Trials; Complement; Condition; DABA; Diagnosis; Diagnostic Procedure; Dose; Drug Metabolic Detoxication; End Point; Enzymes; Evaluation; Exposure to; Goals; Growth; Histopathology; Hostage; Human; India; Inhalation Exposure; Injury; Invasive; Iran; Iraq; Life; Liquid substance; Liquivent; Lung; Medical; Modality; Modeling; Moscow; Mucous body substance; Numbers; Play; Poison; Population; Procedures; Purinergic P1 Receptors; Reporting; Research Personnel; Respiration; Respiratory Mucosa; Respiratory physiology; Rodent; Role; Route; SYK gene; Sarin; Severities; Subway; Survival Rate; Techniques; Technology; Therapeutic; Tokyo; Toxic effect; Toxicology; Treatment Efficacy; Treatment Protocols; Vulnerable Populations; War; Weight; carboxylesterase; chemical reaction; efficacy evaluation; keratinocyte growth factor; lung injury; methyl isocyanate; nerve agent; novel therapeutics; programs; research study; respiratory; sphingosine 1-phosphate; surfactant; therapy development; tosiben; vapor; wet lung

DESCRIPTION (provided by applicant): Direct lung injury, with pulmonary complications, accounted for most of the deaths following toxic chemical exposure in the Iran-Iraq- war, the accidental release of methyl isocyanate in Bhopal, India, the Tokyo subway sarin attack, and the hostage crisis in Moscow. These tragedies exemplify how susceptible human airways are to the effects of airborne chemicals and imply that respiratory management is most important and critical for saving life. Previous reports indicate that chemical injury is associated with direct chemical reaction followed by acute respiratory distress syndrome and late complications. A large number of civilians and an increasing number of children with pre-existing medical conditions such as asthma are more vulnerable to chemical threat agents. We propose to investigate the respiratory toxicity and lung injury following inhalation exposure to the deadly chemical threat agent sarin in animal models. Our recently developed micro-instillation technology of inhalation exposure will be used for sarin vapor exposure. Micro-instillation technology bypasses the detoxification of chemical threat agents in the airway of rodents, which have high levels of carboxylesterase and mucus. Thus, the chemical agents reach alveoli and mimics an exposure similar to human. The respiratory toxicity will be assessed by toxicological, biochemical, histopathological and respiratory functional analysis. The chronology of lung injury will be also assessed. We ill identify bronchoalveolar lavage, blood biomarkers or non-invasive respiratory parameters to diagnose the severity of exposure. A number of FDA-approved or in clinical trial as well as new therapeutic regimens will be evaluated to develop an effective medical countermeasure against pulmonary injury and its long-term consequences. We will also assess the respiratory toxicity of sarin in animals models of pre-existing medical conditions such as asthma. Potential therapeutics will be evaluated for protection against sarin exposure in asthma model. The proposed studies will define the biochemical mechanisms of respiratory toxicity and lung injury that play a central role in chemical threat agent induced toxicity and a major cause of death following exposure in normal and vulnerable populations with pre-existing medical conditions. Effective therapeutics to protect against pulmonary toxicity and its long-term consequences that can complement the existing modalities will be rapidly developed for a mass scenario.

描述（由申请人提供）：在两伊战争中暴露于有毒化学品、印度博帕尔意外释放异氰酸甲酯、东京地铁沙林袭击和莫斯科人质危机之后，直接肺损伤和肺部并发症占死亡人数的大部分。这些悲剧说明了人类呼吸道对空气中化学物质的影响是多么的敏感，并暗示了呼吸管理对于拯救生命是最重要和最关键的。以往的报道表明，化学损伤与直接化学反应相关，随后出现急性呼吸窘迫综合征和晚期并发症。大量平民和越来越多已有哮喘等疾病的儿童更容易受到化学威胁剂的伤害。我们建议在动物模型上研究吸入致命化学威胁剂沙林后的呼吸毒性和肺损伤。我们最近开发的吸入暴露微注入技术将用于沙林蒸气暴露。微滴技术绕过了啮齿类动物气道中具有高水平羧酸酯酶和粘液的化学威胁剂的解毒作用。因此，化学物质到达肺泡并模拟类似于人类的暴露。呼吸毒性将通过毒理学、生化、组织病理学和呼吸功能分析进行评估。肺损伤的时间顺序也将被评估。我们将确定支气管肺泡灌洗，血液生物标志物或非侵入性呼吸参数来诊断暴露的严重程度。将对一些fda批准的或正在进行临床试验的治疗方案以及新的治疗方案进行评估，以制定有效的医疗对策来对抗肺损伤及其长期后果。我们还将评估沙林对患有哮喘等疾病的动物模型的呼吸毒性。将评估潜在的治疗方法对哮喘模型中沙林暴露的保护作用。拟议的研究将确定呼吸毒性和肺损伤的生化机制，这些机制在化学威胁剂引起的毒性中起核心作用，也是在正常和有既往疾病的脆弱人群接触化学威胁剂后死亡的主要原因。针对大规模病例，将迅速开发出有效的治疗方法，以防止肺毒性及其长期后果，补充现有的治疗方式。