Novel therapeutics for vesicants and toxic inhaled chemicals (U54)

针对出疱剂和有毒吸入化学品的新型疗法 (U54)

• 批准号: 8737370
• 负责人: Carl W White
• 金额: $ 14.35万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 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 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8737370
• 关键词: 4 hydroxynonenal; Acute Lung Injury; Airway Resistance; Alteplase; Anti-Inflammatory Agents; Anti-inflammatory; Anticoagulants; Antioxidants; Apoptotic; Attenuated; Biological Models; Blood Vessels; Breathing; Bronchoalveolar Lavage Fluid; Cell Culture Techniques; Cell Death; Cell Proliferation; Cell Survival; Cell surface; Cells; Chemical Exposure; Chemicals; Chlorine; Chronic; Coagulation Process; Comet Assay; Culture Media; DNA Damage; Data; Disasters; Dose; Edema; Epithelial Cells; Event; Exposure to; Eye; FDA approved; Fibrin; Fibrinolytic Agents; Flavonoids; Gases; Guanosine; Hour; Human; Hydrogen Peroxide; Hypoxemia; Inbred HRS Mice; Inflammation; Inflammatory Response; Inhalation Exposure; Injury; Instruction; Lesion; Lipid Peroxidation; Lipid Peroxides; Lung; Mechlorethamine; Mediating; Medical; Microdissection; Military Personnel; Modeling; Monkeys; Mus; Mustard; Mustard Gas; Neutrophil Infiltration; Nose; Organ; Oxidative Stress; Oxidative Stress Induction; Oxygen; Pathogenesis; Permeability; Peroxonitrite; Phase; Phosphorylation; Process; Property; Proteins; Radiation; Rattus; Recombinants; Role; Safety; Signal Transduction; Skin; Sulfur; Superoxides; TFPI; Terrorism; Testing; Therapeutic; Thick; Thromboplastin; Tissues; Toxic effect; Vesicants; airway hyperresponsiveness; airway obstruction; analog; dietary supplements; injured airway; lung injury; macrophage; methacholine; nerve agent; neutrophil; novel; novel therapeutics; programs; silibinin; treatment duration

PROJECT SUMMARY (See instructions): Denver's CounterACT program was formed to develop models of sulfur mustard (SM) toxicity to lung and skin, understand injury pathogenesis, and evaluate novel antioxidants to rescue SM-mediated injuries. SM analog CEES (2-chloroethyl ethylsulfide) caused inflammation, DNA damage (8-hydroxydeoxy-guanosine accumulation; comet assay; ATM/ATR activation and downstream signaling) and lipid peroxidation (4- hydroxynonenal) in tissues, as well as inflammation. In lung, CEES caused bronchial vascular injury/leak. Airway obstructive fibrin-containing casts formed after inhalation exposures to CEES or SM, and similar lesions were apparent after chlorine (400 ppm). Catalytic antioxidant AEOL10150, which scavenges superoxide, hydrogen peroxide, lipid peroxides, and peroxynitrite, rescued: a) upper (nasal) and lower airway injuries by CEES; b) lower airway injury by SM; c) oxidative stress, inflammation and methacholine reactivity due to chlorine; and d) skin injuries by CEES such as inflammation and neutrophil infiltration. A natural dietary supplement silibinin also rescued skin injuries by CEES. New data showed: a) AEOL10150 efficacy to limit injury by escalated CEES and SM exposures, as well as acute lung injury by higher (250 ppm) chlorine concentrations, b) coagulation activation in the CEES inhalation and chlorine models, and c) efficacy of tPA (tissue-type plasminogen activator) in late rescue, starting 4h after CEES inhalation. Next cycle, Denver CounterACT will: a) establish early anticoagulant and/or late fibrinolytic agent efficacies in airways obstruction by CEES, SM and chlorine, b) evaluate AEOL10150 in profound airway injuries by these agents (both alone and combined with anticoagulant and/or fibrinolytic approaches), and c) evaluate AEOL10150 and flavonoid silibinin to rescue skin injuries by CEES, nitrogen mustard (NM), and SM. Effective anticoagulant and/or fibrinolytic agents will be cross-checked to verify lack of exacerbation of skin injuries. Endpoints of oxidative stress, inflammation, increased permeability, and, for lungs, airway obstruction, will be evaluated. Agent(s) found effective for CEES/NM would be evaluated in skin injury by SM. These approaches will identify promising rescue agents for skin and lung injury by toxic gases.

项目摘要（请参阅说明）：成立了丹佛的抵抗计划，以发展对肺和皮肤毒性的模型（SM）毒性，了解损伤发病机理，并评估新型的抗氧化剂以挽救SM介导的损伤。 SM类似物CEES（2-氯乙基硫化物）引起炎症，DNA损伤（8-羟基氧基 - 瓜氨酸积累；彗星测定； ATM/ATR激活和下游信号传导）和脂质过氧化（4-羟基诺纳纳尔）在组织中以及炎症。在肺中，CEES引起支气管血管损伤/泄漏。气道阻塞性纤维蛋白的铸造在吸入CEES或SM后形成，并且在氯（400 ppm）后明显出现类似的病变。催化抗氧化剂的AEOL10150，它清除超氧化物，过氧化氢，脂质过氧化物和过氧亚硝酸盐，被救出：a）上部（鼻腔）和下气道受伤。 b）SM降低气道伤害； c）由于氯引起的氧化应激，炎症和甲基酚反应性； d）CEES（例如炎症和中性粒细胞浸润）的皮肤损伤。天然饮食补充剂也通过CEES挽救了皮肤损伤。 New data showed: a) AEOL10150 efficacy to limit injury by escalated CEES and SM exposures, as well as acute lung injury by higher (250 ppm) chlorine concentrations, b) coagulation activation in the CEES inhalation and chlorine models, and c) efficacy of tPA (tissue-type plasminogen activator) in late rescue, starting 4h after CEES inhalation.下一个周期，丹佛的抵消将：a）建立在CEES，SM和氯的气道阻塞中的早期抗凝剂和/或晚期纤维蛋白溶解剂功效，b）评估这些试剂严重的气道损伤中的AEOL10150（单独使用，并与抗凝剂和/或纤维纤维固定型相结合），并与抗凝蛋白和/或纤维纤维固定型相结合），并将其固定在SIRIBER中。 CEES，氮芥末（NM）和SM造成的伤害。将对有效的抗凝剂和/或纤维蛋白水解剂进行交叉检查，以验证缺乏皮肤损伤的加重。将评估氧化应激，炎症，渗透率增加的终点，对于肺部的气道阻塞，将评估。发现对CEES/NM有效的药物将通过SM评估皮肤损伤。这些方法将确定有望通过有毒气体造成皮肤和肺损伤的有希望的救援剂。