In Vivo Lung Perfusion for the Surgical Treatment of Acute Respiratory Distress Syndrome

摘要 急性呼吸窘迫综合征(ARDS)具有很高的死亡率和对患者质量的长期影响 生活。继发于脓毒症的循环性休克是ARDS的主要原因。体外膜 氧合(ECMO)和保护性通风策略是当前的护理标准；但提供 仅支持天生的治疗机制。虽然这些支持性疗法有帮助，但它们收效甚微。 严重急性呼吸窘迫综合征总死亡率的改善。目前，还没有靶向治疗的方法。 受急性呼吸窘迫综合征影响的肺部快速康复。为了解决这个问题，我们的实验室设计了一种新颖的活体 肺灌流(IVLP)技术在临床前猪体内Steen液肺灌流中的应用 ARDS的模型，允许有针对性的肺康复。这项技术包括插管 损伤肺的肺动脉(流入)和肺静脉(流出)，以实现闭路灌流 和直接治疗。该技术结合了ECMO和体外肺灌注(EVLP)的优点 评估用于移植的边缘供体肺)，以提供一个平台，在此平台上可以治疗受伤的肺 以隔离的方式进行靶向治疗，而不存在全身治疗的潜在风险。在临床上， IVLP将以经皮方式进行，可以作为ECMO治疗的辅助手段 缩短支持持续时间，从而降低发病率和死亡率。IVLP代表了一种新的方法 减少创伤或感染性休克继发ARDS的严重程度的治疗。 我们先前的EVLP和ILVP的经验有力地表明，受伤的肺可以成功地 使用IVLP靶向治疗康复。这项提议将检验使用Steen解决方案的IVLP的假设 将通过内毒素诱导的ARDS在临床前猪模型中恢复肺功能，并随后发展为 这种疗法的经皮技术。具体目标1将优化IVLP的康复能力 脂多糖诱导猪肺损伤模型的建立。这将通过实验来实现，该实验将优化 计时，确认耐用性，并改进灌流策略。特定目标2将使用体外模型，使用 肺微血管内皮细胞和肺泡上皮细胞保护机制的研究 Steen液对体外循环肺泡毛细血管屏障的影响《特定目标3》将演示 经皮IVLP治疗重症急性呼吸窘迫综合征的可行性 翻译。我们最近对IVLP进行的研究证明了IVLP治疗慢性前列腺癌的可行性和有效性。 急性呼吸窘迫综合征，代表着急性呼吸窘迫综合征管理的重大范式转变。如果成功，我们建议的研究 将EVLP定义为ARDS靶向治疗的新的、可行的平台，并将引领翻译之路 进入人体研究领域。

Summary Acute respiratory distress syndrome (ARDS) imposes high mortality and long-term effects on patient quality-of- life. Circulatory shock secondary to sepsis is the leading cause of ARDS. Extracorporeal membrane oxygenation (ECMO) and protective ventilation strategies are the current standards of care; yet provide support only for innate mechanisms of healing. While these supportive therapies are helpful, they offer little improvement in overall mortality for severe ARDS. Currently, no methods exist for targeted treatment for the rapid rehabilitation of lungs affected by ARDS. To address this, our laboratory has designed a novel in vivo lung perfusion (IVLP) technique for the perfusion of lungs in vivo with Steen solution in a preclinical porcine model of ARDS, which allows for targeted lung rehabilitation. This technique involves cannulation of the pulmonary artery (inflow) and pulmonary veins (outflow) of the injured lung to enable closed-circuit perfusion and direct treatment. This technique combines the benefits of ECMO and ex vivo lung perfusion (EVLP, used to assess marginal donor lungs for transplant) to provide a platform upon which injured lungs can be treated in vivo with targeted therapies in an isolated fashion without the potential risks of systemic treatment. Clinically, IVLP would be performed in a percutaneous fashion that could function as an adjuvant to ECMO therapy to shorten duration of support resulting in reduced morbidity and mortality. IVLP represents a novel method of therapy to reduce the severity of ARDS secondary to trauma or septic shock. Our prior experience with both EVLP and ILVP strongly suggest that injured lungs can be successfully rehabilitated utilizing IVLP targeted therapy. This proposal will test the hypothesis that IVLP with Steen solution will rehabilitate lungs with LPS-induced ARDS in a preclinical porcine model with subsequent development of percutaneous techniques for this therapy. Specific Aim 1 will optimize the rehabilitative capacity of IVLP using a porcine model of LPS-induced lung injury. This will be accomplished through experiments that will optimize timing, confirm durability, and improve perfusion strategies. Specific Aim 2 will use in vitro models using pulmonary microvascular endothelial cells and alveolar epithelial cells to define mechanisms for the protective effects of Steen solution on the alveolar-capillary barrier during IVLP. Specific Aim 3 will demonstrate the feasibility of percutaneous IVLP for the treatment of severe ARDS, which will be necessary for clinical translation. Our recent studies with IVLP demonstrate the feasibility and efficacy of IVLP for the treatment of ARDS, representing a major paradigm shift in the management of ARDS. If successful, our proposed studies will define EVLP as a novel, viable platform for targeted therapy of ARDS and will lead a path for translation into human studies.