Eicosanoid Balance in Lung Transplant Injury and Repair

描述（申请人提供）：肺移植（LTX）降低了呼吸衰竭的发病率和死亡率，但急性和长期结局仍然较差。原发性肺移植失败发生在高达20%的受体中，并且到5年时，超过一半的患者发展为闭塞性细支气管炎（BO），这是除感染外的主要死亡原因。该项目的重点是在与移植相关的急性和慢性肺损伤中，肺中细胞损伤和修复的两种抵消类花生酸途径之间的平衡，即前列腺素（PG）和白三烯（LT）。初步数据显示，加入到肺冲洗/保存溶液中的PGE 2通过刺激cAMP依赖性蛋白激酶而减少缺血/再灌注（I/R）损伤（BO的已知贡献者）。使用我们开发的气流允许气道移植模型，负责LT合成初始步骤的5-脂氧合酶（5-LO）基因缺陷的小鼠似乎受到BO的保护。体外支持数据表明，在肺源性肌成纤维细胞中，LT促进但PG抑制炎症介质合成和纤维化。我们假设类花生酸调节急性和慢性宿主对LTX损伤的反应，PG保持血管稳态并限制气道闭塞，但LT具有相反的作用。具体目的是使用肺I/R、LTX和气道移植的啮齿动物模型，确定（1）内源性PG和（2）LT及其合成酶和信号受体在肺对缺血/移植损伤的反应中的作用。目的（3）将确定类花生酸平衡在二次打击（缺血性、病毒性）损伤后BO发展中的作用，使用遗传（考克斯、前列腺素受体[EP 2]和5-LO缺陷）和药理学（考克斯和5-LO抑制剂、LT受体拮抗剂）策略。将研究吸入PG作为一种潜在的新治疗策略，以减少原发性移植物衰竭和BO。两者合计，这些实验将阐明的作用，占主导地位的类花生酸平衡作为一个关键方面的主机响应LTX。公共卫生影响：肺细胞产生的某些天然物质会损伤移植肺的血管和气道，导致阻塞，而其他相关物质则具有保护作用。这项资助旨在了解这些有害和保护性物质之间的平衡，以制定可能有利于保护移植肺免受致命损伤的平衡策略。

DESCRIPTION (provided by applicant): Lung transplantation (LTX) reduces morbidity and mortality from respiratory failure, but acute and long-term outcomes remain poor. Primary lung graft failure occurs in up to 20% of recipients, and by 5 years, over half of all patients develop bronchiolitis obliterans (BO), the major cause of death outside of infections. This project focuses on the balance between two countervailing eicosanoid pathways of cellular injury and repair in the lungs, prostaglandins (PGs) and leukotrienes (LTs), in acute and chronic lung injury associated with transplantation. Preliminary data show PGE^ added to the lung flush/preservation solution reduces ischemia/reperfusion (I/R) injury (a known contributor to BO), by stimulating the cAMP-dependent protein kinase. Using an air-flow permissive airway transplant model that we developed, mice deficient in the 5- lipoxygenase (5-LO) gene, responsible for the initial step in LT synthesis, appear to be protected from BO. In vitro supporting data suggest that in lung-derived myofibroblasts, LTs promote but PGs suppress inflammatory mediator synthesis and fibrosis. We hypothesize that eicosanoids modulate both the acute and chronic host responses to LTX injury, with PGs preserving vascular homeostasis and limiting airway obliteration but LTs having the opposite effect. The Specific Aims are to determine the role of (1) endogenous PGs and (2) LTs and their synthetic enzymes and signaling receptors in the response of the lungs to ischemic/transplantation injury, using rodent models of lung I/R, LTX, and airway transplantation. Aim (3) will determine the role of eicosanoid balance in BO development following second hit (ischemic, viral) injury, use genetic (COX, prostanoid receptor [EP2], and 5-LO deficient) and pharmacologic (COX and 5-LO inhibitor, LT receptor antagonist) strategies. Inhalation of PGs will be studied as a potential new therapeutic strategy to reduce primary graft failure and BO. Taken together, these experiments will elucidate the role of the prevailing eicosanoid balance as a critical facet of the host response to LTX. Public Health Implications: Certain native substances made by cells in the lungs can injure blood vessels and airways in transplanted lungs, leading to their obstruction, whereas other related substances are protective. This grant seeks to understand the balance between these injurious and protective substances, to develop strategies which may tip the balance in favor of protecting transplanted lungs from lethal injury.