Eicosanoid Balance in Lung Transplant Injury and Repair

描述（由申请人提供）：肺移植（LTX）降低了呼吸衰竭的发病率和死亡率，但急性和长期预后仍然很差。多达20%的受者发生原发性肺移植衰竭，到5年，超过一半的患者发生闭塞性细支气管炎（BO），这是除感染外死亡的主要原因。本项目重点研究肺细胞损伤和修复的两种相互抵消的类二十烷途径，前列腺素（pg）和白三烯（lt）在移植相关的急性和慢性肺损伤中的平衡。初步数据显示，PGE^添加到肺冲洗/保存溶液中，通过刺激camp依赖性蛋白激酶，可减少缺血/再灌注（I/R）损伤（已知的BO诱因）。利用我们开发的允许气流的气道移植模型，缺乏5-脂氧合酶（5- lo）基因的小鼠（负责LT合成的初始步骤）似乎可以免受BO的侵害。体外支持数据表明，在肺源性肌成纤维细胞中，LTs促进炎症介质合成和纤维化，而pg抑制炎症介质合成和纤维化。我们假设类二十烷醇调节宿主对LTX损伤的急性和慢性反应，其中pg保持血管稳态并限制气道闭塞，而lt具有相反的作用。具体目的是确定(1)内源性pg和(2)LTs及其合成酶和信号受体在肺缺血/移植损伤反应中的作用，采用肺I/R， LTX和气道移植的啮齿动物模型。Aim(3)将利用遗传（COX、前列腺素受体[EP2]和5-LO缺乏）和药理学（COX和5-LO抑制剂、LT受体拮抗剂）策略，确定类20蛋白平衡在二次打击（缺血性、病毒）损伤后BO发展中的作用。吸入PGs将作为一种潜在的新的治疗策略来减少原发性移植物衰竭和BO。综上所述，这些实验将阐明当前的类二十烷酸平衡在宿主对LTX反应中的关键作用。公共卫生影响：肺细胞产生的某些天然物质可损伤移植肺的血管和气道，导致其阻塞，而其他相关物质则具有保护作用。这项拨款旨在了解这些有害物质和保护性物质之间的平衡，以制定有利于保护移植肺免受致命伤害的策略。

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.