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

体内肺灌注手术治疗急性呼吸窘迫综合征

• 批准号: 9903430
• 负责人: Irving L. Kron
• 金额: $ 58.02万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9903430
• 关键词: Acute Lung Injury; Address; Adenosine; Adjuvant; Adult Respiratory Distress Syndrome; Affect; Agonist; Alveolar; Anatomy; Antioxidants; Blood; Blood capillaries; Calcium; Cannulas; Cannulations; Caring; Cells; Clinical; Clinical Trials; Cultured Cells; Cytoskeleton; Development; Endothelial Cells; Endothelium; Epithelial; Epithelial Cells; Epithelium; Extracorporeal Membrane Oxygenation; Family suidae; Fostering; Functional disorder; Hour; Human; Immune; Impairment; In Vitro; Institution; Intervention; Laboratories; Lead; Long-Term Effects; Lung; Lung Transplantation; Measures; Mechanical Ventilators; Methods; Modeling; Molecular; Monitor; Morbidity - disease rate; NADPH Oxidase; Operative Surgical Procedures; Pathway interactions; Patients; Perfusion; Permeability; Phase; Physiological; Play; Production; Proteins; Protocols documentation; Pulmonary artery structure; Pulmonary veins; Quality of life; Regional Perfusion; Rehabilitation therapy; Reporting; Respiratory Failure; Risk; Role; Secondary to; Sepsis; Septic Shock; Severities; Shock; Signal Pathway; Standardization; Supportive care; TLR4 gene; Techniques; Testing; Therapeutic; Tight Junctions; Translating; Translations; Transplantation; Trauma; United States National Institutes of Health; Work; alveolar epithelium; attenuation; base; clinical practice; clinical translation; cytokine; design; experience; experimental study; healing; improved; in vitro Model; in vivo; lung injury; migration; mortality; neutrophil; novel; pre-clinical; pressure; protective effect; pulmonary function; pulmonary rehabilitation; receptor; success; surfactant; targeted delivery; targeted treatment; ventilation

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.

概括 急性呼吸窘迫综合征 (ARDS) 造成高死亡率并对患者质量产生长期影响 生活。败血症继发的循环休克是 ARDS 的主要原因。体外膜 氧合（ECMO）和保护性通气策略是当前的护理标准；还提供 仅支持固有的治愈机制。虽然这些支持疗法很有帮助，但效果甚微。 严重 ARDS 的总体死亡率有所改善。目前尚无针对该病的针对性治疗方法 受 ARDS 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体内 肺灌注 (IVLP) 技术，用于在临床前猪体内用 Steen 溶液进行肺灌注 ARDS 模型，允许有针对性的肺部康复。该技术涉及插管 受伤肺部的肺动脉（流入）和肺静脉（流出）以实现闭路灌注 和直接治疗。该技术结合了 ECMO 和离体肺灌注（EVLP，用于 评估用于移植的边缘供体肺）提供一个平台，在此基础上可以治疗受伤的肺 以孤立的方式进行体内靶向治疗，没有全身治疗的潜在风险。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代表了一种新颖的方法 治疗以减轻继发于创伤或感染性休克的 ARDS 的严重程度。 我们之前在 EVLP 和 ILVP 方面的经验强烈表明，受伤的肺部可以成功修复 采用 IVLP 靶向治疗康复。该提案将测试 IVLP 与 Steen 解的假设 将在临床前猪模型中通过 LPS 诱导的 ARDS 恢复肺部功能，并随后开发 该疗法的经皮技术。具体目标 1 将使用以下方法优化 IVLP 的康复能力 LPS诱导的肺损伤的猪模型。这将通过优化实验来实现 计时、确认耐久性并改进灌注策略。具体目标 2 将使用体外模型 肺微血管内皮细胞和肺泡上皮细胞以确定保护机制 IVLP 期间 Steen 溶液对肺泡毛细血管屏障的影响。具体目标 3 将展示 经皮 IVLP 治疗严重 ARDS 的可行性，这对于临床来说是必要的 翻译。我们最近对 IVLP 的研究证明了 IVLP 治疗以下疾病的可行性和有效性： ARDS，代表了 ARDS 管理的重大范式转变。如果成功的话，我们提出的研究 将 EVLP 定义为 ARDS 靶向治疗的新颖、可行的平台，并将引领转化之路 进入人类研究。