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，但急性和长期结果仍然很差。高达20%的受者发生原发肺移植失败，5年后，超过一半的患者发展为闭塞性细支气管炎(BO)，这是感染以外的主要死亡原因。该项目的重点是在移植相关的急性和慢性肺损伤中，肺内两条相互抵消的二十烷基类细胞损伤和修复途径--前列腺素(PGs)和白三烯(LTS)之间的平衡。初步数据显示，添加到肺冲洗/保存液中的PGE^通过刺激cAMP依赖的蛋白激酶来减少缺血/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的呼吸道移植模型，5-脂氧合酶(5-LO)基因缺陷的小鼠，负责LT合成的初始步骤，似乎受到BO的保护。体外支持数据表明，在肺来源的肌成纤维细胞中，LTS促进炎症介质的合成和纤维化，而PGs抑制炎症介质的合成和纤维化。我们假设二十烷类化合物调节宿主对LTX损伤的急性和慢性反应，PGs维持血管内稳态并限制呼吸道闭塞，而LTS具有相反的作用。利用大鼠肺I/R、LTX和呼吸道移植模型，研究(1)内源性PGs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。目的(3)采用遗传学(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，确定二十烷类化合物平衡在二次打击(缺血、病毒)后BO发生中的作用。吸入PGs将被作为一种潜在的新治疗策略来研究，以减少初次移植失败和BO。综上所述，这些实验将阐明盛行的二十烷类平衡作为宿主对LTX反应的关键方面所起的作用。公共卫生影响：某些由肺部细胞产生的天然物质可损伤移植肺的血管和呼吸道，导致其阻塞，而其他相关物质具有保护作用。这笔赠款旨在了解这些有害物质和保护性物质之间的平衡，开发可能扭转平衡的策略，有利于保护移植肺免受致命伤害。

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.