Initiation and Progression of Preterm Lung Injury with Ventilation

通气引起早产肺损伤的发生和进展

• 批准号: 8333719
• 负责人: ALAN H JOBE
• 金额: $ 29.89万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8333719
• 关键词: Acute; Address; Air; Biological Markers; Birth; Breathing; Caring; Chronic lung disease; Clinical; Clinical Trials; Delivery Rooms; Development; Diffuse; ERG gene; Economic Inflation; Environmental air flow; Epithelial; Evaluation; Fetal Lung; Functional Residual Capacity; Gases; Gene Expression; Gestational Age; Goals; Grant; Guidelines; Hour; Infant; Inflammation; Inflammatory; Injury; International; Intervention; Knowledge; Liquid substance; Location; Lung; Lung Inflammation; Measures; Mechanical ventilation; Modeling; Molecular; Newborn Infant; Outcome; Oxygen; Pathology; Pathway interactions; Phase; Physiological; Placental Circulation; Premature Infant; Procedures; Proteins; Recommendation; Recruitment Activity; Resuscitation; Severities; Sheep; Staging; Stretching; Structure of parenchyma of lung; Techniques; Testing; Therapeutic; Tidal Volume; Time; Very Low Birth Weight Infant; age difference; base; clinical practice; design; disability; fetal; injured; innovation; insight; knowledge base; lung development; lung injury; pressure; preterm lung injury; response; response to injury; surfactant; therapeutic target

DESCRIPTION (provided by applicant): In the 2010 guidelines for newborn resuscitation, the International Liaison Committee on Resuscitation (ILCOR) identified gaps in knowledge, for both preterm and term infants. The gaps are the optimal maneuvers to inflate and ventilate the lungs at birth. The initiation of ventilation at birth is unique because the fetal lung must transition rapidly from fluid filled airspaces to a gas exchange, and ventilation with positive pressure at birth causes airway epithelial injury which progresses to diffuse lung inflammation. Although the lung injury is initiated with ventilation at birth, it takes time for markers of injury to develop.To overcome the confounding effects of continued ventilation, we developed a fetal sheep model of newborn resuscitation that maintains placental circulation, thus allowing us to isolate and evaluate resuscitation maneuvers designed to reduce lung injury during the transition to air breathing at birth. These maneuvers are difficult to evaluate in the clinical setting because of th necessities to resuscitate without focusing on single components of the procedure, the great variability in the clinical status of infants, and the need to continue support beyond the specific intervention. Clinicians routinely introduce new treatments, such as a sustained inflation, into newborn care without knowledge of benefits or potential for injury. The goal of this grant is to identify the safe and useful recruitment maneuvers for newborn resuscitation in preterm and near-term lambs, evaluations that cannot be easily assessed clinically. We will measure early response gene expression that activates inflammatory pathways and the location of expression of the inflammation within the lungs of preterm and term lambs. We also will test whether the severity of lung injury is dependent on gestational age (GA), and whether different acute phase injury pathways are activated during initiation of ventilation of very preterm, moderately preterm and term lungs. We will also validate protective strategies and potential therapeutic pathways in preterm newborn lambs ventilated for 4 and 24 hours. By combining a reproducible lamb model of resuscitation with advanced molecular techniques, we will determine: 1) which lung gas volume recruitment maneuvers will minimize injury, 2) how lung injury from resuscitation maneuvers differs based on the developmental stage of the lungs, and 3) if an optimum initiation of ventilation will result in decreased amplification of lung injury with continued ventilation. These innovative studies will define the molecular and physiologic responses to recruitment maneuvers in preterm and near-term lambs, resulting in new insights into how injurious pathways progress to acute and chronic lung disease. The results also will allow us to identify potential treatment targets and biomarkers for the field. These studies will provide a scientific basis for ILCOR recommendations for clinical practices that are very difficult to verify by clinical trials. PUBLIC HEALTH RELEVANCE: Although approximately 10% of all newborns and the majority of very low birth weight preterm infants need some assistance to breathe at birth, the optimal maneuvers to inflate and ventilate the lungs have not been defined. It is easy to injure the preterm lung at birth and mechanical ventilation contributes to the long term disability in very preterm infants. These studies will determine beneficial lung recruitment maneuvers for both term and preterm infants, and advance our knowledge on inflammatory pathways activated by ventilation at birth.

描述（由申请人提供）：在 2010 年新生儿复苏指南中，国际复苏联络委员会 (ILCOR) 指出了早产儿和足月儿的知识差距。这些间隙是出生时肺部充气和通气的最佳操作。出生时通气的启动是独特的，因为胎儿肺必须迅速从充满液体的空气空间过渡到气体交换，出生时正压通气会导致气道上皮损伤，进而发展为弥漫性肺部炎症。虽然肺损伤是在出生时通气引起的，但损伤标志物的形成需要时间。为了克服持续通气的混杂效应，我们开发了一种维持胎盘循环的新生儿复苏胎羊模型，从而使我们能够隔离和评估旨在减少出生时空气呼吸过渡期间肺损伤的复苏操作。这些操作很难在临床环境中进行评估，因为需要在不关注手术的单一组成部分的情况下进行复苏，婴儿临床状态的巨大差异，以及需要在特定情况之外继续提供支持。 干涉。临床医生经常在新生儿护理中引入新的治疗方法，例如持续充气，但不知道其好处或潜在的伤害。这笔赠款的目的是确定用于早产和近足月羔羊新生儿复苏的安全且有用的复苏策略，这些评估在临床上无法轻易评估。我们将测量激活炎症途径的早期反应基因表达以及早产儿和足月羔羊肺部炎症表达的位置。我们还将测试肺损伤的严重程度是否取决于胎龄（GA），以及在极早产、中度早产和足月肺通气开始期间是否激活不同的急性期损伤途径。我们还将验证 4 小时和 24 小时通气的早产新生羔羊的保护策略和潜在治疗途径。通过将可重复的羔羊复苏模型与先进的分子技术相结合，我们将确定：1）哪种肺气体容量补充操作可以最大程度地减少损伤，2）复苏操作造成的肺损伤如何根据肺部的发育阶段而有所不同，以及3）最佳的通气启动是否会导致持续通气时肺损伤的放大程度降低。这些创新研究将定义早产和近足月羔羊对肺复张操作的分子和生理反应，从而对有害途径如何发展为急性和慢性肺部疾病提供新的见解。结果还将使我们能够确定该领域潜在的治疗靶点和生物标志物。这些研究将为 ILCOR 针对很难验证的临床实践的建议提供科学依据 通过临床试验。 公众健康相关性：虽然大约 10% 的新生儿和大多数极低出生体重早产儿在出生时需要一些呼吸辅助，但肺部充气和通气的最佳操作尚未确定。早产儿出生时很容易损伤肺，机械通气会导致极早产儿的长期残疾。这些研究将确定对足月儿和早产儿有益的肺复张方法，并增进我们对出生时通气激活的炎症途径的了解。