Mechanism of sulfur mustard induced lung injury

芥子气致肺损伤的机制

基本信息

批准号：
7727021
负责人：
Neerad Mishra
金额：
$ 31.18万
依托单位：
LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7727021
关键词：
Abscess Acetylcholine Acetylcholinesterase Acute Address Airway Resistance Alkylating Agents Allergens Ambrosia Animal Experiments Animals Anti-Cholinergics Anti-Inflammatory Agents Anti-inflammatory Antibodies Antidotes Antigens Antioxidants Apoptosis Apoptotic Asthma Atropine Attenuated Autoantigens Autoimmune Process Autoimmune Responses Autoimmunity B-Lymphocytes Basal Cell Binding Biological Biological Assay Body Temperature Breathing Bronchial Spasm Bronchiectasis Bronchoalveolar Lavage Bronchoalveolar Lavage Fluid Bronchoconstriction Bulla CCL2 gene CD8B1 gene Categories Cell Death Cell membrane Cell surface Cells Cessation of life Chemical Agents Chemical Weapons Cholinergic Agents Chronic Chronic Bronchitis Collaborations Combined Modality Therapy Condition Corrosives Coughing Cytotoxic T-Lymphocytes Data Depth Dermal Development Diagnostic Dinitrochlorobenzene Disease Dose EMSA Early Intervention End Point Enzyme-Linked Immunosorbent Assay Epinephrine Epithelial Exhibits Experimental Designs Exposure to Extrinsic asthma Eye FK506 Fever Future Health Personnel Health Services Research Histopathology Hour Human Hydralazine Immigration Immune response Immunity Immunohistochemistry Immunosuppression Immunosuppressive Agents Implant In Vitro Infiltration Inflammation Inflammatory Injury Interleukin-13 Intervention Iran Iraq Kinetics Lactate Dehydrogenase Lactate Dehydrogenases Leukocytes Leukopenia Leukotrienes Liquid substance Lung Lung Inflammation Lupus Lymphocyte Major Histocompatibility Complex Measures Membrane Proteins Methods Mitogen-Activated Protein Kinase Inhibitor Mitogen-Activated Protein Kinases Modeling Modification Muscarinic Acetylcholine Receptor Muscarinic Antagonists Mustard Gas Natural Immunity Necrosis Neurotransmitters Nuclear Pain Pathology Pathway interactions Patients Penicillin G Pharmaceutical Preparations Pharyngeal structure Physical condensation Plethysmography Pneumonia Population Post-Translational Protein Processing Probability Procainamide Process Production Property Proteins Publishing Pulmonary Fibrosis Rattus Rattus norvegicus Reaction Recurrence Reporting Reverse Transcriptase Polymerase Chain Reaction Risk Role Signal Transduction Site Skin Small Inducible Cytokine A3 Smooth Muscle Soldier Spectrophotometry Spleen Steroids Stress Structure of parenchyma of lung Sulfamethoxazole Sulfides Symptoms Synapses Syndrome T-Lymphocyte Terrorism Testing Therapeutic Agents Therapeutic Intervention Therapeutic immunosuppression Time Tissues Toxic Epidermal Necrolysis Toxic effect Treatment Protocols Turpentine Veterans War Week Western Blotting Work World War I airway hyperresponsiveness airway inflammation atopy base chemokine cholinergic cytokine design direct application human MAPK14 protein improved in vivo indexing inhibitor/antagonist lung injury macrophage migration neutrophil outcome forecast research study respiratory response stem transcription factor

项目摘要

Sulfur mustard (SM) is a powerful alkylating agent that was used extensively during the World War I and in 1980s' Iran-Iraq war, and analysts in the CIA, DOD, and the Congressional Research Service (CRS) have ranked SM as the highest probability agent to be used as a chemical weapon for terrorism. While exposure to high doses of SM may be lethal, sublethal exposures cause serious acute and chronic injuries primarily to the lung, skin and eyes and, to date, there is no effective treatment against SM. The respiratory consequences of acute SM exposure include throat pain, cough, and asthma-like symptoms, such as tachypnea, bronchospasms, and airway hyperresponsiveness, and the delayed effects, which might arise after months to years after SM exposure, comprise chronic bronchitis, asthma, bronchiectasis, and pulmonary fibrosis. Because the mechanism of SM-induced lung injury is not clear, it is a major hurdle in the development of rationale therapeutic interventions. Based on the published data, we propose that the lung injury associated with SM exposure results from its two properties: (a) SM is an extremely powerful alkylating agent that rapidly modifies cellular proteins, and we hypothesize that the major biological effects stem from the immunological consequences of these modifications. The early effects emerge from the activation of innate immunity (inflammation) and the associated cell death, and the delayed effects from the activation of the adaptive immune response directed to the modified (alkylated) self-antigens, leading to a chronic autoimmune status, (b) SM inhibits acetylcholinesterase that raises the synaptic level of acetylcholine causing acute bronchoconstriction, bronchospasms, and exacerbated asthma. Therefore, a combination of anti-inflammatory, immunosuppressive, anti-apoptotic, and anti-cholinergic drugs administered immediately after SM exposure might ameliorate both the early and the late respiratory effects of SM toxicity. To address the working hypothesis, we propose to: (1) evaluate the role of inflammation in SMinduced lung injury, (2), examine the effects of acute SM inhalation on airway resistance, (3) ascertain the effects of SM exposure on the development of adaptive immunity, and (4) examine the effects of potential therapeutic agents (particularly combination therapies) on the acute and chronic toxicities of SM exposure. These studies, we believe, will delineate the mechanism(s) of acute and chronic respiratory effects of SM exposure and provide a rationale approach to design and test the efficacy of therapeutic interventions.

硫芥末（SM）是一种强大的烷基化剂，在第一次世界大战期间广泛使用 1980年代的伊朗 - 伊拉克战争，以及中央情报局，国防部和国会研究服务局（CRS）的分析师将SM排名为最高的概率，被用作恐怖主义的化学武器。在暴露时高剂量的SM可能是致命的，可杀死的暴露主要导致严重的急性和慢性伤害肺，皮肤和眼睛，迄今为止，还没有有效的SM治疗方法。呼吸后果急性SM暴露包括喉咙痛，咳嗽和类似哮喘的症状，例如tachypnea，支气管播和气道高反应性以及延迟的效果，几个月后可能会出现 SM暴露几年后，包括慢性支气管炎，哮喘，支气管扩张和肺纤维化。因为SM诱导的肺损伤的机制尚不清楚，所以这是发展的主要障碍理由治疗干预措施。根据已发布的数据，我们建议肺部损伤与 SM暴露的两种特性导致：（a）SM是一种极强大的烷基化剂，快速修饰细胞蛋白，我们假设主要的生物学作用源于这些修饰的免疫学后果。早期效应来自激活先天免疫（炎症）和相关的细胞死亡，以及延迟的影响针对修饰（烷基化）自我抗原的自适应免疫反应的激活，领先至慢性自身免疫性状态，（b）SM抑制乙酰胆碱酯酶提高突触水平乙酰胆碱导致急性支气管收缩，支气管施加和恶化的哮喘。因此，抗炎，免疫抑制，抗凋亡和抗胆碱能药物的结合 SM暴露后立即给药可能会改善早期和晚期呼吸作用 SM毒性。为了解决工作假设，我们提出：（1）评估炎症在示威中的作用肺损伤（2）检查急性SM吸入对气道电阻的影响，（3）确定 SM暴露对自适应免疫发展的影响，（4）检查潜力的影响 SM暴露的急性和慢性毒性上的治疗剂（尤其是联合疗法）。我们认为，这些研究将描述SM的急性和慢性呼吸作用的机制暴露并提供一种理由方法来设计和测试治疗干预措施的功效。