Catalytic antioxidants in sulfur mustard toxicity

硫芥毒性中的催化抗氧化剂

• 批准号: 7866619
• 负责人: Brian J Day
• 金额: $ 31.53万
• 依托单位: NATIONAL JEWISH HEALTH
• 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/7866619
• 关键词: 2-chloroethyl ethyl sulfide; Acute; Acute Lung Injury; Adult Respiratory Distress Syndrome; Amyotrophic Lateral Sclerosis; Animal Model; Antioxidants; Attenuated; Benzoic Acids; Bilirubin; Biliverdine; Catabolism; Cells; Cerebral Ischemia; Charge; Chemical Warfare Agents; Chronic; Clinical; DNA; Dermal; Development; Dose; Drug Kinetics; Elements; Enzymes; Epithelial Cells; Extracellular Space; Fibrosis; Goals; Heme; Human; Hydrogen Peroxide; Inflammation; Inflammatory; Inflammatory Response; Injury; Laboratories; Lead; Life; Lipid Peroxides; Lipids; Lung; Manganese; Metalloporphyrins; Metals; Mitochondria; Modeling; Molecular Weight; Monkeys; Motor Neuron Disease; Mus; Mustard; Mustard Gas; Nitrogen; Oxidation-Reduction; Oxidative Stress; Oxygen; Oxygen Therapy Care; Oxygenases; Parents; Pathway interactions; Peroxidases; Peroxonitrite; Phase; Play; Porphyrins; Proteins; Radiation; Rattus; Reactive Oxygen Species; Role; Route; Safety; Skin; Source; Structure; Superoxide Dismutase; Superoxides; Tetrapyrroles; Therapeutic; Therapeutic Index; Therapeutic Intervention; Time; Toxic effect; Transgenic Model; analog; base; catalase; cellular targeting; cigarette smoke-induced; cytotoxic; effective therapy; efficacy testing; exposed human population; in vitro Model; lung injury; macromolecule; mimetics; neutrophil; novel; oxidative damage; prevent; response; response to injury; safety study; tissue oxygenation; 2-chloroethyl ethyl sulfide; Acute; Acute Lung Injury; Adult Respiratory Distress Syndrome; Amyotrophic Lateral Sclerosis; Animal Model; Antioxidants; Attenuated; Benzoic Acids; Bilirubin; Biliverdine; Catabolism; Cells; Cerebral Ischemia; Charge; Chemical Warfare Agents; Chronic; Clinical; DNA; Dermal; Development; Dose; Drug Kinetics; Elements; Enzymes; Epithelial Cells; Extracellular Space; Fibrosis; Goals; Heme; Human; Hydrogen Peroxide; Inflammation; Inflammatory; Inflammatory Response; Injury; Laboratories; Lead; Life; Lipid Peroxides; Lipids; Lung; Manganese; Metalloporphyrins; Metals; Mitochondria; Modeling; Molecular Weight; Monkeys; Motor Neuron Disease; Mus; Mustard; Mustard Gas; Nitrogen; Oxidation-Reduction; Oxidative Stress; Oxygen; Oxygen Therapy Care; Oxygenases; Parents; Pathway interactions; Peroxidases; Peroxonitrite; Phase; Play; Porphyrins; Proteins; Radiation; Rattus; Reactive Oxygen Species; Role; Route; Safety; Skin; Source; Structure; Superoxide Dismutase; Superoxides; Tetrapyrroles; Therapeutic; Therapeutic Index; Therapeutic Intervention; Time; Toxic effect; Transgenic Model; analog; base; catalase; cellular targeting; cigarette smoke-induced; cytotoxic; effective therapy; efficacy testing; exposed human population; in vitro Model; lung injury; macromolecule; mimetics; neutrophil; novel; oxidative damage; prevent; response; response to injury; safety study; tissue oxygenation

The long-term goal of this project is to develop an effective treatment for mustard gas induced injury This project will focus on the use of small molecular weight catalytic antioxidants to help understand the role o reactive oxygen species and their formation in 2-chloroethyl ethyl sulfide (CEES)-induced lung and derma injury. CEES is a strong electrophile that readily reacts with cellular macromolecules and depletes endogenous antioxidants. In addition, CEES stimulates a strong inflammatory response that is characterized by neutrophi influx. Mustard exposure is often associated with producing adult respiratory distress syndrome (ARDS) tha requires supplemental oxygen therapy to maintain adequate tissue oxygenation. Recent studies have suggested that CEES-induced lung injury could be attenuated by exogenous instillation of catalytic antioxidants such as superoxide dismutase and catalase. My laboratory has extensively studied manganese porphyrins anc demonstrated them to be efficient scavengers of superoxide, hydrogen peroxide, lipid peroxides and peroxynitrite. Manganese porphyrins are highly effective against a variety of intracellular and extracellula oxidative stress models. We currently have developed a lead metalloporphyrin that is in phase I human clinica trials. Recently we found that the breakdown products of these metalloporphyrins to also possess poten antioxidant activity. This discovery has lead to the development of metalloporphyrin analogs (metallated lineai tetrapyrroles) that have high activity. We propose to test the efficacy of catalytic antioxidants that include AEOL 10150 and the metallated linear tetrapyrroles for the treatment of mustard gas-induced lung and derma injury. We will 1) determine the efficacy of catalytic antioxidants in rat and human models of CEES-induced lunc injury; 2) determine the efficacy of catalytic antioxidants in mouse and human models of CEES-induced derma injury; and 3) develop and characterize a new class of catalytic antioxidants, the linear tetrapyrroles. We wil correlate changes in injury responses to markers of oxidative stress. The significance of these studies are that they have the possibility to provide rapid relief and prevent life threatening injury to comba troops and/or civilians that may become exposed to a mustard gas attack.

该项目的长期目标是为芥末气体损伤开发有效的治疗方法 该项目将着重于使用小分子量催化抗氧化剂来帮助了解O的作用。 活性氧及其在2-氯乙基硫化物（CEES）诱导的肺和真皮中的形成 受伤。 CEES是一种强大的亲电器，很容易与细胞大分子和内源性耗尽的反应 抗氧化剂。此外，CEES刺激了具有中性嗜血杆菌特征的强烈炎症反应 涌入。芥末的暴露通常与产生成人呼吸窘迫综合征（ARDS）有关 需要补充氧气治疗以维持足够的组织氧合。最近的研究 建议通过外源滴注催化抗氧化剂来减轻CEES诱导的肺损伤 例如超氧化物歧化酶和过氧化氢酶。我的实验室已经广泛研究了锰卟啉ANC 证明它们是对超氧化物，过氧化氢，脂质过氧化物和 过氧亚硝酸盐。锰卟啉对各种细胞内和细胞外有效 氧化应激模型。我们目前已经开发了一种在I期临床中的铅金属磷脂 试验。最近，我们发现这些金属磷脂的分解产物也具有POTEN 抗氧化活性。这一发现导致了金属卟啉类似物的发展（金属的lineai 具有较高活性的四吡咯。我们建议测试包括 AEOL 10150和金属的线性四吡咯，用于治疗芥末气体诱导的肺和真皮 受伤。我们将1）确定催化抗氧化剂在CEES诱导的LUNC的大鼠和人类模型中的疗效 受伤; 2）确定催化抗氧化剂在小鼠和人体模型中的疗效 受伤; 3）开发和表征新的催化抗氧化剂，即线性四吡咯。我们会 对氧化应激标记的损伤反应的变化相关。这些研究的意义是 他们有可能提供快速缓解并防止对Comba生命的伤害 可能暴露于芥末气攻击的部队和/或平民。