Mechanism of sulfur mustard induced lung injury

芥子气致肺损伤的机制

• 批准号: 8120833
• 负责人: Neerad Mishra
• 金额: $ 33.56万
• 依托单位: LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 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/8120833
• 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 Proteins; Cell surface; Cells; Cessation of life; Chemical Agents; Chemical Weapons; Cholinergic Agents; Chronic; Chronic Bronchitis; Collaborations; Combined Modality Therapy; Corrosives; Coughing; Cytotoxic T-Lymphocytes; Data; Dermal; Development; Diagnostic; Dinitrochlorobenzene; Disease; Dose; EMSA; Early treatment; Enzyme-Linked Immunosorbent Assay; Epinephrine; Epithelial; Exhibits; Experimental Designs; Exposure to; Extrinsic asthma; Eye; FK506; Fever; Future; Health Personnel; Histopathology; Hour; Human; Hydralazine; Immigration; Immune response; Immunohistochemistry; Immunosuppression; Immunosuppressive Agents; Implant; In Vitro; Infiltration; Inflammation; Inflammatory; Injury; Interleukin-13; Intervention; Iran; Iraq; Kinetics; Lactate Dehydrogenase; Leukocytes; Leukopenia; Leukotrienes; Liquid substance; Lung; Lung Inflammation; Lymphocyte; Major Histocompatibility Complex; Measures; 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; Research; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Services; 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; Time; Tissues; Toxic Epidermal Necrolysis; Toxic effect; Treatment Protocols; Turpentine; Veterans; War; Western Blotting; Work; World War I; adaptive immunity; airway hyperresponsiveness; airway inflammation; atopy; base; chemokine; cholinergic; cytokine; design; direct application; effective therapy; efficacy testing; human MAPK14 protein; improved; in vivo; indexing; inhibitor/antagonist; lung injury; lupus-like; macrophage; migration; neutrophil; outcome forecast; research study; respiratory; response; stem; transcription factor; weapons

Mechanism of Sulfur Mustard Induced Lung Injury 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.

硫磺芥末致肺损伤的机制 硫磺芥末(SM)是一种强大的烷化剂，在第一次世界大战期间和在 20世纪80年代的两伊战争，以及中央情报局、国防部和国会研究服务处(CRS)的分析师 将SM列为最有可能被用作恐怖主义化学武器的毒剂。当接触到 高剂量的SM可能是致命的，亚致命暴露会导致严重的急性和慢性伤害，主要是对 肺部、皮肤和眼睛，到目前为止，还没有有效的治疗SM的方法。呼吸系统疾病的后果 急性接触SM包括喉咙痛、咳嗽和类似哮喘的症状，如呼吸急促， 支气管痉挛，呼吸道高反应性，以及延迟效应，可能在几个月后出现 SM暴露数年后，包括慢性支气管炎、哮喘、支气管扩张和肺纤维化。 由于丹参所致肺损伤的机制尚不清楚，一直是阻碍其发展的主要障碍。 治疗干预的基本原理。根据已发表的数据，我们认为肺损伤与 与SM接触的结果来自于它的两个性质：(A)SM是一种非常强大的烷基化试剂， 快速修饰细胞蛋白质，我们假设主要的生物效应源于 这些修饰的免疫学后果。早期的影响来自于激活 先天免疫(炎症)和相关的细胞死亡，以及 针对修饰的(烷基化的)自身抗原的适应性免疫反应的激活，导致 对于慢性自身免疫状态，(B)SM抑制乙酰胆碱酯酶，该酶提高突触水平 乙酰胆碱可引起急性支气管收缩、支气管痉挛和加重哮喘。 因此，抗炎、免疫抑制、抗细胞凋亡和抗胆碱能药物的组合 在接触SM后立即给药可能会改善Sm对呼吸的早期和晚期影响 SM毒性。为了解决这一工作假说，我们建议：(1)评估炎症在疾病中的作用 肺损伤，(2)，检查急性吸入SM对呼吸道阻力的影响，(3)确定 SM暴露对适应性免疫发育的影响，以及(4)检验潜在的影响 治疗药物(特别是联合疗法)对SM暴露的急性和慢性毒性。 我们相信，这些研究将描绘出SM急性和慢性呼吸效应的机制(S) 并为设计和测试治疗干预措施的效果提供了一种基本的方法。