Eicosanoid Balance in Lung Transplant Injury and Repair

肺移植损伤和修复中的类二十烷酸平衡

• 批准号: 7841120
• 负责人: David J. Pinsky
• 金额: $ 23.76万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7841120
• 关键词: Acute; Acute Lung Injury; Acute respiratory failure; Agonist; Air; Animal Model; Arachidonate 5-Lipoxygenase; Biological Preservation; Bleomycin; Blood Vessels; Blood flow; Breathing; Bronchiolitis Obliterans; Bronchitis; Cause of Death; Cells; Chronic; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Development; Dinoprostone; Edema; Eicosanoid Production; Eicosanoids; Enzymes; Epithelial; Epoprostenol; Equilibrium; Family; Fibrosis; Flushing; G-Protein-Coupled Receptors; Genes; Genetic; Grant; Homeostasis; Iloprost; Immune response; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory; Injury; Ischemia; Knockout Mice; Laboratories; Leukocyte Trafficking; Leukotriene B4; Leukotrienes; Lipoxygenase Inhibitors; Liquid substance; Lung; Lung Transplantation; Lymphocyte; Measures; Mediating; Modeling; Morbidity - disease rate; Mus; Myofibroblast; Obstruction; Organ; Outcome; Pathway interactions; Patients; Physiological; Procedures; Production; Prostaglandin Production; Prostaglandin Receptor; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Prostaglandins I; Protein Kinase; Public Health; Pulmonary Gas Exchange; Rattus; Receptor Signaling; Reperfusion Injury; Reperfusion Therapy; Research Personnel; Respiratory physiology; Rodent Model; Role; Series; Signal Pathway; Signal Transduction; Solutions; Testing; Therapeutic; Thrombosis; Time; Translating; Transplantation; Viral; analog; cell injury; cyclooxygenase 1; cysteinyl-leukotriene; cytokine; enzyme biosynthesis; graft failure; improved; inhibitor/antagonist; injured; injured airway; injury and repair; lipid mediator; lung injury; lung ischemia; lung preservation; mortality; mouse model; novel therapeutics; programs; prostaglandin EP2 receptor; receptor; research study; response; response to injury; synthetic enzyme; tool; vasoconstriction

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.

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，但急性和长期结局仍然很差。原发性肺移植物衰竭发生在多达20％的受体中，到5年，超过一半的患者发生了细支气管炎闭塞剂（BO），这是感染以外的主要死亡原因。该项目的重点是与急性和慢性肺损伤相关的两种反窃听的类花生酸酯途径与肺，前列腺素（PGS）（PGS）（PGS）（PGS）（PGS）（PGS）（PGS）（LTS）之间的平衡。初步数据表明，通过刺激依赖CAMP依赖性蛋白激酶的肺部/保存溶液中添加了PGE^，减少了缺血/再灌注（I/R）损伤（I/R）损伤（BO的已知贡献者）。使用我们开发的空气流允许气道移植模型，在5-脂氧合酶（5-lo）基因中缺乏小鼠，负责LT合成的第一步，似乎受到了BO的保护。体外支持数据表明，在肺衍生的肌纤维细胞中，LTS促进，但PGS抑制炎症介质的合成和纤维化。我们假设类花生酸可以调节急性和慢性宿主对LTX损伤的反应，PGS保留血管稳态并限制气道闭塞，但LTS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）LTS及其合成酶和信号受体在缺血/移植损伤的反应中的作用。 AIM（3）将在第二次命中（缺血性，病毒）损伤后，使用遗传（Cox，Prostanoid受体[EP2]和5-LO缺乏症）和药理学（COX和5-LO抑制剂，LT受体拮抗剂）策略来确定eicosanoid平衡在BO发育中的作用。吸入PG将被研究为一种潜在的新治疗策略，以减少原发性移植衰竭和BO。综上所述，这些实验将阐明主要的类素平衡作为宿主对LTX响应的关键方面的作用。公共卫生的影响：肺部细胞制造的某些本地物质会伤害移植肺部的血管和气道，导致其阻塞，而其他相关物质则具有保护性。该赠款旨在了解这些有害和保护性物质之间的平衡，以制定策略，这些策略可能会使平衡以保护移植的肺免受致命损伤。