Mechanical Ventilation of Newborn Mice:Impact on Alveolarization and Lung Elastin

新生小鼠机械通气：对肺泡化和肺弹性蛋白的影响

• 批准号: 7637845
• 负责人: RICHARD David BLAND
• 金额: $ 47.05万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7637845
• 关键词: Adult; Adverse effects; Affect; Air; Alveolar; Alveolus; Apoptosis; Attenuated; Biochemical; Birth; Blood capillaries; Bronchopulmonary Dysplasia; Cells; Chronic; Chronic Obstructive Airway Disease; Chronic lung disease; Defect; Deposition; Development; Disease; Distal; Dysplasia; EMILIN1 gene; Elastases; Elastic Fiber; Elastin; Exhibits; Exposure to; FBN1; Gases; Gene Proteins; Genes; Goals; Growth; Growth and Development function; Histologic; Hyperoxia; Hypertension; Image Analysis; Infant; Lead; Life; Lung; Lung diseases; Mechanical ventilation; Mechanics; Methods; Modeling; Molecular; Mus; Mutant Strains Mice; Neonatal; Newborn Infant; PI3 gene; Pharmaceutical Preparations; Phenotype; Platelet-Derived Growth Factor; Play; Pneumonectomy; Pregnancy; Premature Infant; Production; Protein-Lysine 6-Oxidase; Proteins; Pulmonary Emphysema; Radial; Research; Research Design; Research Proposals; Respiration Disorders; Respiratory Failure; Role; Serine; Stretching; Structure; Tenascin; Term Birth; Testing; Transgenic Mice; Transgenic Organisms; Tropoelastin; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Vascular remodeling; angiogenesis; capillary; cigarette smoking; citrate carrier; design; effective therapy; elastase inhibitor; fibrillin-2; fibulin; improved; indexing; insight; lung development; lung volume; mRNA Expression; mutant; novel; novel strategies; postnatal; prevent; pup; response; smoke inhalation; treatment strategy

DESCRIPTION (provided by applicant): Mechanical ventilation (MV) with O2-rich gas offers life-saving treatment for premature infants with respiratory failure, but often leads to chronic lung disease (CLD), characterized by impaired alveolarization and excess, disordered lung elastin. The goal of this research is to improve understanding of mechanisms that cause these abnormalities, and to formulate effective treatment strategies. In recent studies of newborn mice, in which lung septation and matrix organization occur mainly after term birth, we found that MV with 40% O2 for 24h led to dysregulated alveolar formation and elastin assembly, yielding lung structural defects similar to those seen in CLD. This proposal applies to mutant neonatal mice a novel experimental approach to help define mechanisms by which prolonged cyclic stretch of the developing lung, with or without modest hyperoxia, can impair alveolarization and elastin assembly, and to test a novel strategy for inhibiting these structural defects. Specific Aim 1 will determine (a) if neonatal mutant mice that over-express the specific elastase inhibitor elafin show greater alveolar and lung capillary formation and less deposition of disordered elastin than non-transgenic pups show after 24h of MV with 40% O2; and (b) if early postnatal treatment with elafin given directly into the lungs will preserve normal alveolar and lung capillary formation, and prevent or reduce excess lung elastin during prolonged MV of newborn mice. If elafin treatment preserves lung structure in MV, we will test its benefit during MV of mutant mice described in Specific Aims 2 and 3. Specific Aim 2 will determine if neonatal mice with elastin haploinsufficiency (Eln), which show abnormal lung growth after pneumonectomy or smoke inhalation, are more susceptible than non-mutant newborns to defective alveolar formation and lung elastin assembly after MV with either air or 40% O2 for 24h. Specific Aim 3 will determine if neonatal mice deficient in fibulin-5 (Fbln5, Fbln5-/-), a matrix protein that plays a critical role in elastin assembly, exhibit an exaggerated lung phenotype, compared to non-mutant newborns, in terms of defective alveolar and elastic fiber formation after lengthy MV with either air or 40% O2. Molecular, biochemical and histological methods will be used to clarify how MV can disrupt alveolar septation and elastin assembly during lung growth, and also provide insight on how these adverse effects might be prevented in infants who require prolonged MV for respiratory failure. PROJECT NARRATIVE: This research proposal, which uses normal and genetically modified newborn mice, is designed to improve our understanding of how mechanical ventilation, as applied to premature infants with respiratory failure, often inhibits lung growth and causes disorganized assembly of elastic fibers in the lung, leading to a chronic form of neonatal lung disease called bronchopulmonary dysplasia (BPD). An important aim of the project is to test the potential benefit of delivering, directly into the lungs during mechanical ventilation, a drug called elafin that prevents the breakdown of elastic fibers, which we hope will preserve lung growth and provide effective treatment for newborn infants who are susceptible to BPD. Because BPD is similar to emphysema, this research also may lead to better understanding and treatment of chronic obstructive pulmonary disease (COPD) in adults.

描述（由申请人提供）：使用富含o2气体的机械通气（MV）为呼吸衰竭的早产儿提供了挽救生命的治疗，但往往导致慢性肺部疾病（CLD），其特征是肺泡受损和肺弹性蛋白过量紊乱。本研究的目的是提高对导致这些异常的机制的理解，并制定有效的治疗策略。在最近对新生小鼠的研究中，肺分离和基质组织主要发生在足月出生后，我们发现40% O2持续24小时的MV导致肺泡形成和弹性蛋白组装失调，产生与CLD相似的肺结构缺陷。该建议适用于突变新生小鼠，这是一种新的实验方法，可以帮助确定发育中的肺在有或没有适度高氧的情况下延长循环拉伸的机制，可以损害肺泡化和弹性蛋白组装，并测试抑制这些结构缺陷的新策略。特异性目的1将确定(a)与非转基因幼鼠相比，过度表达特异性弹性蛋白酶抑制剂elafin的新生突变小鼠在40% O2的24小时MV后，是否表现出更大的肺泡和肺毛细血管形成以及更少的无序弹性蛋白沉积；以及(b)是否在出生后早期将弹力素直接注入肺部，以保持新生小鼠在长时间MV期间正常肺泡和肺毛细血管的形成，并防止或减少肺弹力素过量。如果elafin治疗保留了MV中的肺结构，我们将在Specific Aims 2和3中描述的突变小鼠MV期间测试其益处。特异性目的2将确定弹性蛋白单倍功能不全（Eln）新生小鼠在肺切除术或吸入烟雾后肺生长异常，是否比非突变新生儿更容易在空气或40%氧气中MV 24小时后肺泡形成和肺弹性蛋白组装缺陷。特异性Aim 3将确定在长时间空气或40%氧气MV后，与非突变新生儿相比，缺乏纤维蛋白-5 (Fbln5, Fbln5-/-)（一种在弹性蛋白组装中起关键作用的基质蛋白）的新生小鼠，在肺泡和弹性纤维形成缺陷方面是否表现出夸张的肺表型。分子、生化和组织学方法将用于阐明MV如何在肺生长过程中破坏肺泡分隔和弹性蛋白组装，并为如何预防因呼吸衰竭而需要延长MV的婴儿的这些不良反应提供见解。项目描述：该研究计划使用正常和转基因新生小鼠，旨在提高我们对机械通气如何抑制呼吸衰竭早产儿肺生长并导致肺弹性纤维组装紊乱的理解，从而导致慢性新生儿肺部疾病，称为支气管肺发育不良（BPD）。该项目的一个重要目的是测试在机械通气过程中直接将一种名为elafin的药物输送到肺部的潜在益处，这种药物可以防止弹性纤维的破坏，我们希望这种药物能保持肺部的生长，并为易患BPD的新生儿提供有效的治疗。由于BPD与肺气肿相似，这项研究也可能有助于更好地了解和治疗成人慢性阻塞性肺疾病（COPD）。