Anticoagulant and fibrinolytic therapies for toxic inhaled chemical

有毒吸入化学品的抗凝和纤溶疗法

• 批准号: 8380135
• 负责人: Carl W White
• 金额: $ 55.27万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8380135
• 关键词: Active Sites; Acute; Adrenergic Agents; Alteplase; Animals; Anticoagulant therapy; Anticoagulants; Antioxidants; Antithrombins; Biochemical; Biological Availability; Breathing; Bronchoalveolar Lavage; Bronchodilator Agents; Cessation of life; Chemicals; Chest; Chlorine; Coagulation Process; Cytolysis; Data; Disasters; Dose; Experimental Designs; Fibrin; Fibrinolytic Agents; Freezing; Frequencies; Gases; Heparin; Hour; Hypoxemia; Immunoglobulin M; In Vitro; Individual; Inflammation; Injury; Intervention; Laboratories; Lead; Lesion; Link; Lung; Lung diseases; Maps; Measures; Methods; Microdissection; Modeling; Monitor; Mustard; Mustard Gas; Obstruction; Oxidative Stress; Oxygen; Pathogenesis; Patients; Pharmaceutical Preparations; Physiology; Protease Inhibitor; Proteins; Pulse Oximetry; Rattus; Regimen; Research Design; Resolution; Respiratory physiology; Role; Signs and Symptoms; TFPI; Techniques; Terrorism; Testing; Therapeutic; Thrombin; Thrombolytic Therapy; Thromboplastin; Time; Toxic effect; Treatment Protocols; Vesicants; Work; X-Ray Computed Tomography; adrenergic; airway inflammation; analog; base; cytokine; dosage; efficacy testing; formoterol; in vivo; inhibitor/antagonist; injured airway; lung injury; novel therapeutics; prevent; research study; theories; therapy duration

Inhalation of toxic gases such as sulfur mustard (SM) and chlorine can cause exudative ainway damage and obstruction, inflammation and oxidative injury. Although antioxidant and antiprotease therapies may limit lung injury, most required administration concomitant with or almost immediately (<30 min) after toxic inhalation. Real worid scenarios for acts of terrorism and civilian disasters show that responders may not reach victims for some time. Thus, rescue countermeasures that are effective when started hours after exposure also are needed. Recent data in our laboratory indicates that catalytic antioxidants can limit or prevent airways damage, reactivity, and oxidative stress after SM analog CEES, SM, or chlorine when started at an hour after inhalation. Despite this, progressive ainways injury can still occur with massive toxic inhalation. Using sulfur mustard analog CEES, we identified critical roles for tissue factor (TF) and the coagulation cascade in causing obstructive airway fibrin-containing casts. These were identified by airway microdissection. By this technique, fibrin-containing casts were found in central and conducting ainways after inhalation of CEES, SM and chlorine. Our colleague, Dana Anderson, working at USAMRICD, has identified identical lesions in ainways of rats exposed to SM at that center, and these appear responsible for the firequent death of animals within the first 72 h after exposure. In vitro and in vivo studies indicate that two strategies, one pre-emptively inhibiting TF using specific antagonists, and one to lyse casts using tissue plasminogen activator (tPA), could be effective in limiting or reversing ainway occlusion, respectively. In fact, preliminary data indicate that tPA started 4 hours after toxic inhalation of CEES can still dramatically relieve ainway obstruction and normalize arterial oxygen saturation. We propose to inhibit airway coagulation both eariy and after ainway obstruction is well developed. Because coagulation and inflammation are integrally linked, both inflammation and secondary oxidative stress also could be decreased. We will examine acute exposure scenarios in rats, using CEES, SM and chlorine, with rescue therapies initiated 1-16 h after exposure. Arterial oxygen saturation is monitored noninvasively in each individual animal by pulse oximetry. At termination lungs are lavaged to measure cytokines, fibrin, and infiammation. Perfused snap-frozen lungs are used to measure oxidative stress markers. Fixed lung are used for microdissection and mapping, with morphometric assessment of ainway occlusion in central and dependent ainways. High resolution chest CT scans will be used to track progression and resolution of large ainway lesions and lung disease. Lung physiology will be measured in selected experiments. The most effective 'coagulation based' strategy(s) will be combined with catalytic antioxidant AEOL 10150 to determine if synergistic benefit can be obtained. These approaches should provide specific therapies for rescue of patients with ainway injury due to toxic gas inhalation.

吸入有毒气体（例如硫芥末（SM）和氯）会导致渗出性的Ainway损伤和阻塞，炎症和氧化损伤。尽管抗氧化剂和抗蛋白酶疗法可能会限制肺损伤，但在毒性吸入后，大多数必需的给药伴随或几乎立即（<30分钟）。 恐怖主义和平民灾难行为的真正恐怖情况表明，响应者可能会在一段时间内无法到达受害者。因此，还需要在接触后数小时开始时有效的救援对策。我们实验室中的最新数据表明，催化抗氧化剂可以限制或防止气道损坏， 吸入后一个小时启动时，反应性和SM类似物，SM或氯之后的氧化应激。 尽管如此，在大量的有毒吸入中，进行性AINWOWN损伤仍然会发生。使用硫芥末类似物，我们确定了组织因子（TF）的关键作用，以及凝结级联在引起阻塞性气道纤维蛋白铸件中的关键作用。这些是通过气道显微解剖来识别的。通过这项技术，在CEES，SM和氯吸入后，在中央和进行Ainways中发现了含纤维蛋白的铸件。 我们的同事达娜·安德森（Dana Anderson）在USAMRICD工作，在暴露于该中心的SM的大鼠的Ainways中已经确定了相同的病变，这些病变似乎是导致动物在暴露后的最初72小时内发生的。体外和体内研究表明，两种策略，一种先发的策略，使用特定的拮抗剂抑制TF，一种使用组织纤溶酶原激活剂（TPA）裂解铸造，可以分别有效地限制或逆转AINWay闭塞。实际上，初步数据表明，在CEES毒性吸入CEES后4小时始于TPA，仍然可以极大地缓解Ainway障碍物并使动脉氧归一化 饱和。我们建议抑制气道凝血，并在Ainway障碍物得到很好的发展之后。 由于凝结和炎症是整合的，因此炎症和继发氧化应激也可以减少。我们将使用CEES，SM和氯在大鼠中检查急性暴露情况，并在暴露后1-16小时开始进行救援疗法。动脉氧饱和度在每种动物中通过脉搏血氧饱和度来无创监测。在终止时，肺部被灌输以测量细胞因子，纤维蛋白和感染。灌注的快速肺肺用于测量氧化应激标志物。固定的肺用于显微解剖和映射，并对中央和依赖的AINWay中的AINWay闭塞进行形态计量学评估。高分辨率的胸部CT扫描将用于跟踪大型AINWay病变和肺部病的进展和分辨率。将在选定的实验中测量肺部生理学。最有效的基于“凝结”策略将与催化抗氧化剂的AEOL 10150相结合，以确定是否可以获得协同益处。这些方法应为由于有毒气体吸入而提供特定的疗法，以挽救AINWay损伤患者。