Prevention of Inflammatory Lung Injury After Chlorine Exposure

预防氯暴露后肺部炎症损伤

• 批准号: 7679531
• 负责人: MICHAEL D GUNN
• 金额: $ 39.65万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7679531
• 关键词: Bacterial Infections; Cells; Chemical Warfare Agents; Chlorine; Clinical Trials; Dendritic Cells; Dose; Endotoxins; Epithelial; Event; Exudate; Human; Immune; Inflammation; Inflammation Mediators; Inflammatory; Influenza; Injury; Laboratories; Lead; Leukocytes; Lung; Mediating; Mediator of activation protein; Morbidity - disease rate; Mucous Membrane; Mus; Pathology; Pattern; Permeability; Pharmaceutical Preparations; Phase I Clinical Trials; Physiological; Pneumonia; Prevention; Reaction; Relative (related person); Research Personnel; Series; Source; Structure of parenchyma of lung; T-Lymphocyte; Testing; Toxic effect; Viral; Work; base; cell motility; cell type; chemokine receptor; chlorine gas; lung injury; macrophage; migration; monocyte; mortality; neutrophil; oxidative damage; prevent; programs; response; small molecule

DESCRIPTION (provided by applicant): Chlorine gas (CI2) is a readily available chemical warfare agent that causes a dose-dependent toxicity to pulmonary and other mucosal tissues. The major toxicity of CI2 exposure is oxidative damage of lung tissues that is thought to be due to the direct effects of CI2 reaction products combined with inflammatory mediators released by lung-infiltrating leukocytes. This proposed mechanism has not been clearly demonstrated but raises the possibility that inhibition of pulmonary inflammation following CI2 exposure will reduce subsequent morbidity and mortality. Our laboratory has identified the cells and the cell migration events that lead to immune-mediated lung damage, morbidity, and mortality during viral and bacterial infections. Our preliminary studies demonstrate that a similar pattern of inflammation occurs after chlorine exposure. These findings suggest that chlorine-induced lung injury could be substantially lessened using a specific chemokine receptor antagonist. Importantly, a pharmacologic antagonist for the chemokine receptor we have identified has already been developed and proven to be safe and effective in early clinical trials for other indications. This raises the possibility that a drug already exists that would reduce the morbidity and mortality of chlorine exposure in humans. In a series of murine studies, we will determine the extent to which specific pulmonary inflammatory cell types contribute to chlorine-induced lung injury and the consequent epithelial damage, bronchial reactivity, morbidity, and mortality. We will then examine the ability of the chemokine receptor antagonist to reduce these toxicities. These studies will provide a basis for determining if trials of chemokine receptor antagonists should be considered in humans.

描述（由申请人提供）： 氯气 (CI2) 是一种容易获得的化学战剂，会对肺部和其他粘膜组织产生剂量依赖性毒性。 CI2 暴露的主要毒性是肺组织的氧化损伤，这被认为是由于 CI2 反应产物与肺浸润白细胞释放的炎症介质结合的直接作用所致。这一拟议的机制尚未得到明确证明，但增加了 CI2 暴露后抑制肺部炎症将降低随后的发病率和死亡率的可能性。我们的实验室已经确定了病毒和细菌感染期间导致免疫介导的肺损伤、发病率和死亡率的细胞和细胞迁移事件。我们的初步研究表明，接触氯后会发生类似的炎症模式。这些发现表明，使用特定的趋化因子受体拮抗剂可以大大减轻氯引起的肺损伤。重要的是，我们已经开发出一种趋化因子受体的药理学拮抗剂，并在其他适应症的早期临床试验中证明是安全有效的。这就提出了一种可能性，即已经存在一种药物可以降低人类接触氯的发病率和死亡率。在一系列小鼠研究中，我们将确定特定肺部炎症细胞类型对氯诱导的肺损伤以及随之而来的上皮损伤、支气管反应性、发病率和死亡率的影响程度。然后我们将检查趋化因子受体拮抗剂减少这些毒性的能力。这些研究将为确定是否应考虑在人体中进行趋化因子受体拮抗剂试验提供基础。