Prevention of Inflammatory Lung Injury After Chlorine Exposure

描述(由申请人提供)： 氯气(Cl2)是一种容易获得的化学战剂，对肺和其他粘膜组织造成剂量依赖的毒性。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反应产物与肺浸润性白细胞释放的炎症介质的直接作用所致。这一拟议的机制尚未得到明确的证明，但增加了抑制CI2暴露后的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在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，接触氯后也会出现类似的炎症模式。这些发现表明，使用一种特定的趋化因子受体拮抗剂可以显著减轻氯引起的肺损伤。重要的是，我们已经确定的趋化因子受体的药理拮抗剂已经被开发出来，并在其他适应症的早期临床试验中被证明是安全有效的。这增加了一种可能性，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。在一系列的小鼠研究中，我们将确定特定的肺炎性细胞类型在多大程度上促进了氯气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。然后我们将检查趋化因子受体拮抗剂降低这些毒性的能力。这些研究将为确定是否应该考虑在人类身上试验趋化因子受体拮抗剂提供基础。

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.