Mechanism of sulfur mustard induced lung injury

硫芥致肺损伤的机制 硫芥（SM）是一种强大的烷基化剂，在第一次世界大战期间和1999年被广泛使用。 20世纪80年代的两伊战争，以及中情局、国防部和国会研究服务局（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物质。而暴露于 高剂量的SM可能是致命的，亚致死暴露导致严重的急性和慢性损伤，主要是对 肺、皮肤和眼睛，并且迄今为止没有针对SM的有效治疗。呼吸系统的后果 急性SM暴露包括咽喉疼痛、咳嗽和哮喘样症状，如呼吸急促， 支气管痉挛，气道高反应性，以及可能在数月后出现的延迟效应， SM暴露后10年，包括慢性支气管炎、哮喘、支气管扩张和肺纤维化。 由于SM致肺损伤的机制尚不清楚，因此SM肺损伤的研究一直是阻碍SM肺损伤治疗发展的主要障碍。 合理的治疗干预。根据已发表的数据，我们认为与肺损伤相关的 SM暴露的原因在于它的两种性质：（a）SM是一种非常强大的烷基化剂， 快速改变细胞蛋白质，我们假设主要的生物学效应源于 这些修饰的免疫学后果。早期效应来自于 先天免疫（炎症）和相关的细胞死亡，以及 激活针对修饰的（烷基化的）自身抗原的适应性免疫应答， 对于慢性自身免疫状态，（B）SM抑制乙酰胆碱酯酶，该乙酰胆碱酯酶升高突触水平， 乙酰胆碱引起急性支气管收缩、支气管痉挛和哮喘恶化。 因此，抗炎、免疫抑制、抗凋亡和抗胆碱能药物的组合 SM暴露后立即给药可能会改善早期和晚期的呼吸影响， SM毒性。为了解决工作假设，我们建议：（1）评估炎症在SMinduced 肺损伤;（2）观察SM急性吸入对气道阻力的影响;（3）确定SM吸入对气道阻力的影响。 SM暴露对适应性免疫发展的影响，以及（4）检查潜在的 治疗剂（特别是联合治疗）对SM暴露的急性和慢性毒性的影响。 我们相信，这些研究将阐明SM的急性和慢性呼吸影响的机制 暴露和提供一个合理的方法来设计和测试治疗干预的疗效。

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.