Airway Delivery of Fibrinolytic Therapy for ISALI

描述（由申请人提供）：吸入性烟雾（IS）引起的急性肺损伤（ISALI）是主要烧伤受害者的常见临床问题，导致美国每年的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，纤维性气道铸型和碎屑以及肺泡纤维蛋白沉积。气道铸型是导致肺功能障碍、发病率和预后不良的重要原因。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，雾化组织纤溶酶原激活剂；tPA可改善ISALI羊模型的肺功能障碍。我们还发表了全氟化碳（pfc）为ISALI提供独特的治疗优势，因为它们具有机械保护和细胞保护作用，支持气体交换，并且在肺部均匀分布。这些药物在受伤的肺中也有良好的耐受性。我们将检验适当给予气道的纤溶治疗在ISALI患者肺损伤的预防和逆转中有效的假设。我们的目标是选择治疗ISALI的最有效的纤溶给药方案。我们将确定是否一种生物利用度更高的纤溶素产生相对较低水平的纤溶活性；单链尿激酶PA （scuPA）或tPA，通过雾化或作为PFC混悬液最有效地逆转ISALI患者的肺功能障碍。tPA对气道液体中的主要PA抑制剂非常敏感；纤溶酶原激活物抑制剂-1 (PAI-1)，在ISALI患者气道液体中显著升高。我们最近发表的初步数据表明，scuPA通过与a2macroglubulin在气道液体中形成PAI-1抗性复合物保持生物可利用性。其他新的初步配方数据表明，我们可以在pfc中创建稳定的纤维蛋白溶酶悬浮液，并可以优化纤维蛋白溶酶的雾化。我们的具体目标是：1)优化tPA或scupa为基础的气道输送纤溶治疗的配方。2)确定雾化tPA或scuPA或tPA或scuPA的pfc悬浮液是否最有效地保护ISALI相关的肺损伤。3)确定优化气道输送纤维蛋白溶素是否能逆转ISALI患者的肺功能障碍。我们的团队由PFC给药、ISALI、羊模型、纤溶、药物配方和给药方面的专家领导

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.