Optimization of a Rabbit Retained Hemothorax Model for Evidence-Based Pharmacologic Interventions

摘要 滞留血胸是胸膜腔出血的并发症，与胸部创伤有关， 恶性肿瘤、抗凝或止血障碍，每年影响数以千计的美国患者，促进 呼吸受损，很难处理，现在主要通过手术治疗。很多病人都很穷 外科候选人和去皮质手术是一项主要的胸部手术，会带来很大的并发症。文学作品 提示胸腔内纤溶治疗(IPFT)是有益的，但目前还没有被批准用于RH的药物， 也没有既定的剂量计划。RH的药物干预是可取的，但在临床前 由于缺乏合适的临床前模型来测试新的战略方法，测试受到了阻碍。这 该项目通过开发和验证符合以下条件的兔RH模型来解决这一差距 测试。文献中报道的少数几种先前的模型不适合于这种测试，并且具有止血和 纤溶系统与人类有很大不同。我们在成功的创作方面有丰富的经验 并使用与RH相似的以胸膜组织为特征的兔模型，如四环素诱导的胸膜 受伤或脓胸。我们已经使用这些模型来推进脓胸的新疗法，与NHLBI合作 Smartt和已经将一种这样的药物：单链尿激酶型纤溶酶原激活剂(ScuPA)带入I期 临床试验测试。我们还成立了一家公司；肺治疗公司(LTI)，它吸引了足够的 为独立将scuPA带入国际第二阶段测试提供资金，该阶段计划于第一阶段开始 2020年第四季度。我们的初步数据表明，我们可以生成模型并使用经过验证的 完成我们设想的工作的绩效指标最终将用于指导scuPA的剂量 或使用其他有希望的药物进行近期临床试验测试。该项目对LTI和FITS感兴趣 NHLBI的任务是。我们的唯一目标是建立兔RH模型，该模型将被表征并 使用针对每个子目标的经过充分审查的绩效衡量标准进行验证。在次级目标中，我们将建立 根据我们的经验和初步发现，生成模型的最佳条件。我们将使用国家- 最先进的小动物胸部CT和超声成像、肺功能测试和形态测量分析 将组织损伤作为性能指标，以验证模型的开发并测试年龄和 性别对RH结局的影响。该模型还将促进对胸膜组织发病机制的理解 与RH相关，可能与其他形式的胸膜损伤不同。我们的团队处于独特的地位，可以 完成我们的目标并生成兔子模型。通过与NHLBI通过催化再次合作，我们 未来将使用该模型生成临床前数据，以实现对RH的scuPA的临床试验测试，这可能 涉及LTI的支持。可以预见的是，该模型将推动该领域的发展，从而能够测试其他几个 有希望的战略，可以转化为临床试验测试，最终可能使患者受益，通过提供 新的、耐受性良好的、更有效的药物治疗，用于遭受RH后果的患者。

Abstract Retained hemothorax is a complication of bleeding into the pleural space that is associated with chest trauma, malignancy, anticoagulation or hemostatic disorders, affects thousands of US patients annually, promotes respiratory compromise, is difficult to manage and is now mainly treated surgically. Many patients are poor surgical candidates and decortication is a major chest surgery that entails significant morbidities. The literature suggests that intrapleural fibrinolytic therapy (IPFT) can be salutary, but there are no agents approved for RH, nor are there established dosing schedules. Pharmacologic interventions for RH are desirable but preclinical testing has been hampered by the lack of suitable preclinical models to test new strategic approaches. This project addresses that gap through the development and validation of a rabbit RH model amenable to such testing. The few prior models reported in the literature are not suitable for this testing and have hemostatic and fibrinolytic systems that differ importantly from humans. We have extensive experience in the successful creation and use of rabbit models that like RH are characterized by pleural organization, as in tetracycline-induced pleural injury or empyema. We have used the models to advance new therapeutics for empyema, partnered with NHLBI SMARTT and have brought one such agent; single chain urokinase plasminogen activator (scuPA) to phase I clinical trial testing. We also founded a company; Lung Therapeutics, Inc. (LTI) that has attracted sufficient funding to independently bring scuPA to international phase II testing, which is scheduled to begin in the first quarter of 2020. Our preliminary data demonstrate that we can generate the model and use validated performance measures to accomplish the work that we envision will ultimately be used to guide dosing of scuPA or the use of other promising agents for near-term clinical trial testing. This project is of interest to LTI and fits the mission of the NHLBI. Our sole aim is to generate the rabbit RH model which will be characterized and validated using the well-vetted performance measures for each subaim. In the subaims, we will establish the optimal conditions to generate the model based on our experience and preliminary findings. We will use state- of-the-art small animal chest CT and ultrasound imaging, pulmonary function testing and morphometric analyses of tissue injury as performance measures to validate development of the model and test the effects of age and gender on RH outcomes. The model will also advance understanding of the pathogenesis of pleural organization associated with RH, which likely differs from other forms of pleural injury. Our team is uniquely positioned to accomplish our objective and generate the rabbit model. By again partnering with NHLBI through Catalyze, we will in future use the model to generate preclinical data to enable clinical trial testing of scuPA of RH, which may involve the support of LTI. The model will predictably advance the field, enabling the testing of several other promising strategies that can be translated to clinical trial testing that may ultimately benefit patients by providing new, well-tolerated and more effective pharmacotherapy for patients suffering from the consequences of RH.