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

描述（由申请人提供）：氯（C12）是一种中等可溶性，高活性的氧化气体，广泛用于水净化，制药和化学品的制造，并作为有效的消毒剂。接触氯气的人在最初6-24小时内可能会出现轻微症状。然而，在这一潜伏期之后，可能会发生以富含蛋白质的水肿和低氧血症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。我们认为，由C12及其水解产物与一氧化氮（NO）相互作用形成的活性氧-氯化物和氮中间体（RONS）启动了自传播链反应，其产物损害肺泡上皮细胞，降低其产生和分泌表面活性剂、主动运输钠（Na+）离子和维持紧密、半透性屏障的能力。因此，在暴露于C12后不久，全身给予活性物质清除剂（如抗坏血酸、n -乙酰半胱氨酸（NAC）和去铁胺），以及增加表面活性剂水平、离子转运和细胞旁耐药性的药物（如沙丁胺醇（一种长效b激动剂）和最近描述的基于TNFa凝集素区域的肽（尖肽）），将减少肺损伤、发病率和死亡率。该假设将通过将大鼠肺泡II型（ATII）上皮细胞（SPECIFIC AIMS # 1）或大鼠（SPECIFIC AIMS #2）的融合单层暴露于C12 （50-200 ppm， 30分钟）并在暴露后0.5、6、12和24小时测量以下指标来验证：暴露后0.5、6、12、24和48 h肺功能的生理生化指标（包括表面活性物质的功能和组成）、肺在体内和体外转运离子和清除肺水肿的能力、大鼠肺泡间隙和血浆中的炎症因子水平、动脉血气和pH，以及低反应性物质清除剂（抗坏血酸、NAC）的水平。这些测量将在暴露48小时后每6小时静脉注射NAC、抗坏血酸、去铁胺以及沙丁胺醇和尖端肽后重复进行。在SPECIFIC AIM #3中，我们将评估气管内灌注抗坏血酸、NAC、去铁胺、Infasurf（一种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对延长C12暴露后呼吸衰竭大鼠生存的效果。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，可以用作化学武器。

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.