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: 8270062
• 负责人: Sadis Matalon
• 金额: $ 12.45万
• 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 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8270062
• 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; Interferons; Interleukin-6; Ion Transport; Ions; Lectin; Length; Lipids; Liquid substance; Lung; Lung Inflammation; 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; oxidant gases; oxidation; peripheral blood; prevent; programs; 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) 是一种中等溶解度、高反应性的氧化剂气体，广泛用于水净化、药品和化学品的制造以及作为有效的消毒剂。接触氯气的人可能会在最初 6-24 小时 (h) 内出现轻微症状。然而，在此潜伏期之后，可能会出现严重的肺损伤，其特征是富含蛋白质的水肿和低氧血症的发生。目前，导致这种损伤的细胞和生化事件尚未阐明。我们认为，C12 及其水解产物与一氧化氮 (NO) 相互作用形成活性氯化氧和氮中间体 (RONS)，引发自传播链式反应，其产物会损害肺泡上皮细胞，降低其吸收能力。产生和分泌表面活性剂，主动转运钠 (Na+) 离子并维持紧密的半渗透屏障。因此，全身施用活性物质清除剂（例如抗坏血酸、N-乙酰半胱氨酸（NAC）和去铁胺），以及增加表面活性剂水平、离子转运和旁细胞抵抗力的药物（例如沙丁胺醇（一种长效b-激动剂） ）和最近描述的基于 TNFa 凝集素区域的肽（尖端肽），在接触 C12 后不久就会减少肺损伤、发病率和死亡率。这一假设将通过以下方法进行检验。将大鼠 II 型肺泡 (ATII) 上皮细胞（SPECIFIC AIM #1）或大鼠（SPECIFIC AIMS #2）的汇合单层暴露于 C12（50-200 ppm，持续 30 分钟），并在 0.5、6、12 处测量以下指数暴露后24小时：肺功能的生理生化指标（包括表面活性剂功能和成分）、肺在体内转运离子的能力和体外和体内清除肺水肿、大鼠肺泡腔和血浆中炎症细胞因子的水平、动脉血气和 pH 值，以及 0.5、6、12 时的低活性物质清除剂（抗坏血酸、NAC）水平，暴露后 24 小时和 48 小时。在静脉注射 NAC、抗坏血酸和去铁胺以及沙丁胺醇和尖端肽后，暴露后每 6 小时重复一次这些测量，持续 48 小时。在具体目标#3中，我们将评估气管内滴注抗坏血酸、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 后呼吸衰竭大鼠的生存方面的功效接触。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。

项目成果

Post-exposure antioxidant treatment in rats decreases airway hyperplasia and hyperreactivity due to chlorine inhalation.

大鼠暴露后抗氧化治疗可减少吸入氯引起的气道增生和高反应性。

• 发表时间: 2012-05
• 影响因子: 6.4
• 作者: Fanucchi, Michelle V;Bracher, Andreas;Doran, Stephen F;Squadrito, Giuseppe L;Fernandez, Solana;Postlethwait, Edward M;Bowen, Larry;Matalon, Sadis
• 通讯作者: Matalon, Sadis

Hyaluronan mediates airway hyperresponsiveness in oxidative lung injury.

透明质酸介导氧化性肺损伤中的气道高反应性。

• 发表时间: 2015-05-01
• 作者: Lazrak, Ahmed;Creighton, Judy;Yu, Zhihong;Komarova, Svetlana;Doran, Stephen F;Aggarwal, Saurabh;Emala Sr, Charles W;Stober, Vandy P;Trempus, Carol S;Garantziotis, Stavros;Matalon, Sadis
• 通讯作者: Matalon, Sadis

Ascorbate and deferoxamine administration after chlorine exposure decrease mortality and lung injury in mice.

接触氯后给予抗坏血酸和去铁胺可降低小鼠的死亡率和肺损伤。

• DOI: 10.1165/rcmb.2010-0432oc
• 发表时间: 2011-08-01
• 期刊: American journal of respiratory cell and molecular biology
• 影响因子: 6.4
• 作者: S. Zarogiannis;Asta Jurkuvenaite;S. Fern;ez;ez;Stephen F. Doran;A. Yadav;G. Squadrito;E. Postlethwait
• 通讯作者: E. Postlethwait

Chlorine gas exposure disrupts nitric oxide homeostasis in the pulmonary vasculature.

氯气暴露会破坏肺血管系统中的一氧化氮稳态。

• 发表时间: 2014-07-03
• 影响因子: 4.5
• 作者: Honavar, Jaideep;Bradley, Eddie;Bradley, Kelley;Oh, Joo Yeun;Vallejo, Matthew O;Kelley, Eric E;Cantu;Doran, Stephen;Dell'italia, Louis J;Matalon, Sadis;Patel, Rakesh P
• 通讯作者: Patel, Rakesh P

Respiratory syncytial virus infection increases chlorine-induced airway hyperresponsiveness.

呼吸道合胞病毒感染会增加氯引起的气道高反应性。

• 发表时间: 2015-08-01
• 作者: Song, Weifeng;Yu, Zhihong;Doran, Stephen F;Ambalavanan, Namasivayam;Steele, Chad;Garantziotis, Stavros;Matalon, Sadis
• 通讯作者: Matalon, Sadis