Prevention and Treatment of Chlorine Gas Induced Injury to the Pulmonary System

描述（由申请人提供）：氯（C12）是一种中等溶解度、高活性氧化剂气体，广泛用于水净化、药品和化学品生产以及强效消毒剂。暴露于氯气的人员可能会在最初的6-24小时（h）内出现轻微症状。然而，在此潜伏期之后，可能会发生以富含蛋白质的水肿和低氧血症发作为特征的严重肺损伤。目前，导致这种损伤的细胞和生化事件尚未阐明。我们建议，活性氧-氯和氮中间体（RONS），由C12及其水解产物与一氧化氮（NO）的相互作用形成，启动自蔓延的连锁反应，其产物损害肺泡上皮细胞降低其产生和分泌表面活性剂的能力，积极运输钠（Na+）离子，并保持紧密的，半渗透性屏障。因此，在暴露于C12后不久，全身施用反应性物质清除剂（例如抗坏血酸盐、N-乙酰半胱氨酸（NAC）和去铁胺，以及增加表面活性剂水平、离子转运和细胞旁抗性的试剂（例如沙丁胺醇（一种长效β-激动剂）和最近描述的基于TNF α的凝集素区域的肽（tip肽））将降低肺损伤、发病率和死亡率。将通过暴露大鼠肺泡II型（ATII）上皮细胞的融合单层来检验该假设（特定目的#1）或大鼠（具体目标#2）至C12（50-200 ppm，30 min），并在暴露后0.5、6、12和24 h测量以下指数：肺功能生理生化指标（包括表面活性剂功能和组成），肺在体内和体外转运离子的能力以及体内清除肺水肿的能力，在暴露后0.5、6、12、24和48 h，大鼠肺泡腔和血浆中的炎性细胞因子水平、动脉血气和pH值，以及低活性物质清除剂（抗坏血酸盐，NAC）水平。在暴露后48小时，静脉注射NAC、抗坏血酸盐和去铁胺以及沙丁胺醇和tip肽后，每6小时重复这些测量。在具体目标#3中，我们将评估气管内滴注抗坏血酸盐、NAC、去铁胺、Infasurf（表面活性剂替代混合物）、沙丁胺醇和尖端肽以及雾化沙丁胺醇在延长C12暴露后呼吸衰竭大鼠存活率方面的功效。这项研究的主题既及时又重要：美国每年生产超过2500万吨氯，其中大部分气体通过铁路运输，可用作化学武器。

DESCRIPTION (provided by applicant): Chlorine (C12) is a moderately soluble, highly reactive oxidant gas, used extensively for water purification, manufacturing of Pharmaceuticals and chemicals and as a potent disinfectant. Persons exposed to chlorine gas, may experience mild symptoms for the first 6-24 hours (h). However, following this latency period, severe lung injury, characterized by protein-rich edema and the onset of hypoxemia may develop. Presently, the cellular and biochemical events leading to this injury have not been elucidated. We propose that reactive oxygen-chloride and nitrogen intermediates (RONS), formed by the interaction of C12 and its hydrolysis products with nitric oxide (NO), initiate self-propagating chain reactions, the products of which damage alveolar epithelial cells decreasing their ability to produce and secrete surfactant, actively transport sodium (Na+) ions and maintain a tight, semi-permeable barrier. Thus, systemic administration of reactive species scavengers (such as ascorbate, N-acetyl-cysteine (NAC), and deferoxamine, as well as agents that augment surfactant levels, ion transport and paracellular resistance (such as albuterol (a long acting b-agonist) and a recently described peptide based on the lectin region of TNFa (tip peptide), shortly after exposure to C12 will decrease lung injury, morbidity and mortality. This hypothesis will be tested by exposing either confluent monolayers of rat alveolar type II (ATII) epithelial cells (SPECIFIC AIM # 1) or rats (SPECIFIC AIMS #2) to C12 (50-200 ppm for 30 min) and measure the following indices at 0.5, 6, 12 and 24 h post exposure: physiological and biochemical indices of lung function (including surfactant function and composition), ability of the lungs to transport ions in vivo and in vitro and clear pulmonary edema in vivo, levels of inflammatory cytokines in the rat alveolar space and in the plasma, arterial blood gases and pH, as well as levels of low reactive species scavengers (ascorbate, NAC) at 0.5, 6, 12, 24 and 48 h post exposure. These measurements will be repeated following intravenous injections of NAC, ascorbate and deferoxamine as well as albuterol and the tip peptide, every 6 h post exposure for 48 h. In SPECIFIC AIM #3 , we will assess the efficacy of intratracheally instilled ascorbate, NAC, deferoxamine, Infasurf (a surfactant replacement mixture), albuterol and the tip peptide, as well as aerosolized albuterol, in prolonging survival of rats with respiratory failure post C12 exposure. The subject matter of this research is both timely and important: more than 25 million tons of chlorine is manufactured annually in the United States and the majority of this gas is transported by rail and can be used as a chemical weapon.