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: 8535757
• 负责人: Carl W White
• 金额: $ 62万
• 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/8535757
• 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.

吸入硫芥（SM）和氯等有毒气体可引起渗出性血管损伤和阻塞、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，但大多数需要在吸入有毒物质时或几乎立即（<30 分钟）给药。 恐怖主义行为和平民灾难的真实场景表明，救援人员可能在一段时间内无法到达受害者身边。因此，还需要在暴露后数小时内开始有效的救援对策。我们实验室的最新数据表明催化抗氧化剂可以限制或预防气道损伤， 吸入后一小时开始使用 SM 类似物 CEES、SM 或氯后的反应性和氧化应激。 尽管如此，大量吸入有毒物质仍可能导致进行性损伤。使用硫芥类似物 CEES，我们确定了组织因子 (TF) 和凝血级联在引起阻塞性气道含纤维蛋白管型中的关键作用。这些是通过气道显微解剖来识别的。通过这项技术，吸入 CEES、SM 和氯后，在中枢和传导道中发现了含有纤维蛋白的管型。 我们在 USAMRICD 工作的同事达纳·安德森 (Dana Anderson) 在该中心暴露于 SM 的老鼠身上发现了相同的病变，这些病变似乎是暴露后 72 小时内动物频繁死亡的原因。体外和体内研究表明，两种策略，一种使用特定拮抗剂预先抑制 TF，另一种使用组织纤溶酶原激活剂 (tPA) 裂解管型，可分别有效限制或逆转血管闭塞。事实上，初步数据表明，在有毒吸入CEES后4小时开始tPA仍然可以显着缓解动脉阻塞并使动脉血氧正常化 饱和。我们建议在早期和气道阻塞充分发展后抑制气道凝血。 由于凝血和炎症是紧密相关的，因此炎症和继发性氧化应激也可以减少。我们将使用 CEES、SM 和氯来检查大鼠的急性暴露情况，并在暴露后 1-16 小时开始救援治疗。通过脉搏血氧测定法无创地监测每只动物的动脉氧饱和度。在终止时，灌洗肺部以测量细胞因子、纤维蛋白和炎症。灌注速冻肺用于测量氧化应激标记物。固定肺用于显微解剖和标测，并对中央和附属通道的阻塞进行形态测量评估。高分辨率胸部 CT 扫描将用于追踪大血管病变和肺部疾病的进展和解决情况。将在选定的实验中测量肺生理学。最有效的“基于凝结”的策略将与催化抗氧化剂 AEOL 10150 相结合，以确定是否可以获得协同效益。这些方法应该为因吸入有毒气体而受伤的患者提供具体的治疗方法。