Airway Delivery of Fibrinolytic Therapy for ISALI

ISALI 气道纤溶治疗

• 批准号: 8760552
• 负责人: Perenlei Enkhbaatar
• 金额: $ 78.07万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8760552
• 关键词: Acute Lung Injury; Address; Adult Respiratory Distress Syndrome; Affect; Alteplase; Alveolar; Alveolus; Bioavailable; Biological Availability; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Burn injury; Cessation of life; Characteristics; Clinical; Clinical Management; Clinical Trials; Complex; Cyclic GMP; Data; Death Rate; Defect; Deposition; Dose; Drug Delivery Systems; Drug Formulations; Fibrin; Fibrinolysis; Fire - disasters; Fluorocarbons; Functional disorder; Gases; Human; Impairment; Intervention; Intratracheal Intubation; Liquid substance; Lung; Mechanical ventilation; Methods; Military Personnel; Modeling; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Outcome; Patients; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Plasmin; Plasminogen Activator Inhibitor 1; Population; Prevention; Publishing; Recruitment Activity; Resistance; Sheep; Smoke; Suspension substance; Suspensions; System; Techniques; Testing; Therapeutic; Thrombolytic Therapy; Time; Toxicology; Treatment Efficacy; Treatment Protocols; Urokinase; airway obstruction; base; clinical practice; improved; inhibitor/antagonist; injured; innovation; long term hospitalization; lung injury; mortality; novel; novel strategies; programs; public health relevance; respiratory

DESCRIPTION (provided by applicant): Inhalational smoke (IS)-induced acute lung injury (ISALI) is a common clinical problem in major burn victims, contributing to the US annual burn-related death rate of 2-3 per 100,000 population, one of the highest in the developed world. ISALI is characterized by severe airway obstruction, fibrinous airway casts and debris and alveolar fibrin deposition. Airway casts are an important cause of lung dysfunction, morbidity and poor outcomes. There is no effective pharmacotherapy for this problem at this time. We have published preliminary data that shows that nebulization of tissue plasminogen activator; tPA improves lung dysfunction in our ovine model of ISALI. We have also published that perfluorocarbons (PFCs) offer unique therapeutic advantages for ISALI as they are mechanoprotective and cytoprotective, support gas exchange, and are uniformly distributed in the lung. These agents are also well-tolerated in the injured lung. We will test the hypothesis that fibrinolytic therapy appropriately delivered to airways is effective in both prevention and reversal of lung damage in ISALI. Our objective is to select the most effective fibrinolytic delivey regimen for treatment of ISALI. We will determine if a more bioavailable fibrinolysin that generates relatively lower levels of fibrinolytic activity; single chain uroknase PA (scuPA), or tPA, delivered either by nebulization or as a PFC suspension most effectively reverses lung dysfunction in ISALI in sheep. tPA is exquisitely sensitive to the major PA inhibitor in airway fluids; plasminogen activator inhibitor-1 (PAI-1), which is markedly increased in airway fluids in ISALI. Our new recently published preliminary data show that scuPA remains bioavailable via formation of PAI-1 resistant complexes with a2macroglubulin in airway fluids. Additional new preliminary formulation data show that we can create stable suspensions of fibrinolysins in PFCs and can optimize nebulization of the fibrinolysins. Our Specific Aims are: 1) To optimize formulations of tPA or scuPA-based fibrinolytic therapy for airway delivery. 2) Determine whether nebulization of tPA or scuPA or PFC-suspensions of tPA or scuPA most effectively protects against lung injury associated with ISALI and 3) To determine whether optimized airway delivery of fibrinolysins reverses lung dysfunction in established ISALI. Our team, led by experts in PFC drug delivery, ISALI, ovine modeling, fibrinolysis, drug formulation and delivery if drugs to the airway will apply a range of state of the art techniques to complete the aims. This project will likely yield novel, clinically tractable, potentially paradigm shifting approaches to safely improve outcomes in ISALI.

描述（由申请人提供）：吸入性烟雾（IS）诱导的急性肺损伤（ISALI）是严重烧伤患者的常见临床问题，导致美国每年烧伤相关死亡率为每10万人2-3人，是发达国家中最高的死亡率之一。ISALI的特征是严重的气道阻塞，气道铸型和碎片以及肺泡纤维蛋白沉积。气道管型是肺功能障碍、发病率和不良结局的重要原因。目前还没有有效的药物治疗这个问题。我们已经发表的初步数据表明，雾化吸入组织纤溶酶原激活剂; tPA改善我们的ISALI绵羊模型的肺功能障碍。我们还发表了全氟化碳（PFC）为ISALI提供了独特的治疗优势，因为它们具有机械保护和细胞保护作用，支持气体交换，并且均匀分布在肺部。这些药物在受伤的肺中也耐受良好。我们将检验一个假设，即纤溶治疗适当地提供给气道是有效的预防和逆转肺损伤ISALI。本研究的目的是选择治疗ISALI最有效的溶栓治疗方案。我们将确定是否有一种生物利用度更高的纤溶酶，产生相对较低水平的纤溶活性;单链尿激酶PA（scuPA），或tPA，通过雾化或PFC混悬液递送，最有效地逆转ISALI绵羊的肺功能障碍。tPA对气道液中的主要PA抑制剂纤溶酶原激活物抑制剂-1（PAI-1）非常敏感，PAI-1在ISALI的气道液中显著增加。我们最近发表的新的初步数据表明，scuPA通过在气道液中与α 2巨球蛋白形成派-1抗性复合物而保持生物可利用性。额外的新的初步配方数据表明，我们可以在PFC中产生纤维蛋白溶解酶的稳定悬浮液，并且可以优化纤维蛋白溶解酶的雾化。我们的具体目标是：1）优化用于气道递送的基于tPA或scuPA的纤溶治疗的制剂。2)确定雾化tPA或scuPA或tPA或scuPA的PFC-悬浮液是否最有效地防止与ISALI相关的肺损伤，和3）确定纤维蛋白溶解酶的优化气道递送是否逆转已建立的ISALI中的肺功能障碍。我们的团队由PFC药物递送、ISALI、绵羊建模、纤维蛋白溶解、药物制剂和递送方面的专家领导， 将药物输送到气道将应用一系列最先进的技术来完成目标。该项目可能会产生新的，临床上易于处理的，潜在的范式转移方法，以安全地改善ISALI的结果。