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

氯气所致肺系统损伤的防治

• 批准号: 7635750
• 负责人: Sadis Matalon
• 金额: $ 60.62万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-29 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7635750
• 关键词: 3-nitrotyrosine; Acetylcysteine; Acids; Adult Respiratory Distress Syndrome; Agonist; Air; Albumins; Albuterol; Alveolar; Amiloride; Amino Acids; Animal Model; Anterior nares; Antioxidants; Apical; Apoproteins; Biochemical; Blood; Blood gas; Breathing; Bronchoalveolar Lavage; CCL2 gene; Carrier Proteins; Chemical Weapons; Chemicals; Chemistry; Chlorine; Deferoxamine; Disinfectants; Edema; Electrical Resistance; Epithelial; Epithelial Cells; Event; Exposure to; Flare; Gases; Glutathione; Guidelines; Health; Hour; Human; Hydrolysis; Hypoxemia; In Vitro; Infasurf; Inflammation; Inflammatory; Injury; Interleukin-6; Ion Transport; Ions; Lectin; Length; Lipids; Liquid substance; Lung; Measurement; Measures; Modality; Modeling; Modification; Morbidity - disease rate; Na(+)-K(+)-Exchanging ATPase; Nitrates; Nitric Oxide; Nitrites; Oxidants; Oxygen; Paramedical Personnel; Peptides; Permeability; Peroxidases; Persons; Pharmacologic Substance; Physiological; Plasma; Population; Prevention; Process; Production; Proteins; Pulmonary Edema; Pulmonary Surfactants; Rattus; Reaction; Reduced Glutathione; Research; Research Personnel; Resistance; Respiratory Failure; Respiratory distress; Respiratory physiology; Risk; Series; Sodium; Structure of parenchyma of lung; Surface Tension; Symptoms; System; TNF gene; Terbutaline; Testing; Therapeutic; Time; United States; War; Water; Water Purification; adduct; aerosolized; alveolar epithelium; alveolar type II cell; ascorbate; base; chlorine gas; cytokine; epithelial Na+ channel; experience; improved; in vivo; indexing; interstitial; intravenous injection; lung injury; monolayer; mortality; nitration; nitrogen chloride; oxidation; peripheral blood; prevent; programs; reactive oxygen intermediate; research study; surfactant

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.

描述（由申请人提供）：氯（C12）是一种适度可溶的高反应性氧化剂气体，广泛用于水纯化，制造药物和化学物质以及有效的消毒剂。暴露于氯气的人可能会在最初的6-24小时（H）中出现轻度症状。然而，在此潜伏期之后，可能发展为富含蛋白质的水肿的严重肺损伤，低氧血症的发作。目前，尚未阐明导致这种损伤的细胞和生化事件。 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.因此，全身服用反应性物种清除剂（例如抗坏血酸酯，N-乙酰基体-甲基（NAC）和脱发氧胺，以及增强表面活性剂水平，离子传输和副细胞耐药性的药物（例如，基于lectin to ext to expopuity to tn to tn to tnffa） C12将减少肺损伤，发病率和死亡率。功能（包括表面活性剂功能和组成），肺在体内运输离子的能力以及体内的体外和清晰的肺水肿，大鼠肺泡空间中的炎症细胞因子水平以及血浆，血浆，动脉血液气体和pH值的水平，以及低反应性探测器的水平，以及profective svengers sevengers sevengers and Sporment，nac和4 act in nac和6.5 syporsh and nac和4 s 12，6.5 syporsh and anf ins and and nac和4 s 12，nak and 4 syk and and anf in。在接触48小时后，每6小时一次暴露后每6小时一次静脉注射NAC，抗坏血酸和脱氧胺和尖端肽，将重复这些测量值。在特定的目标＃3中，我们将评估气管内灌输的抗坏血酸，NAC，脱铁酰胺，Inpasurf（表面活性剂替代剂混合物），白化酚和尖端肽的功效，以及在C12曝光后呼吸衰竭的大鼠生存中，以及呼吸道衰竭的雾化性沙丁醇。这项研究的主题既及时又重要：每年在美国制造超过2500万吨氯，大部分天然气都是通过铁路运输的，可以用作化学武器。