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: 9060755
• 负责人: ALAN H JOBE
• 金额: $ 28.28万
• 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 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9060755
• 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; Newborn resuscitation; Outcome; Oxygen; Pathology; Pathway interactions; Phase; Physiological; Placental Circulation; Premature Infant; Procedures; 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; gene product; injured; innovation; insight; knowledge base; lung development; lung injury; pressure; preterm lung injury; preterm newborn; response; response to injury; surfactant; targeted biomarker; 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.

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）确定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扩张的最佳策略。出生时开始通气是独特的，因为胎儿肺必须从充满液体的空气空间迅速过渡到气体交换，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。虽然肺损伤是由出生时的通气引起的，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过渡到空气呼吸期间肺损伤的复苏策略。这些操作难以在临床环境中进行评估，因为复苏的必要性，而不关注手术的单一组成部分，婴儿临床状态的巨大变化，以及需要在特定的情况下继续支持。 干预临床医生通常会在不了解其益处或潜在伤害的情况下，将新的治疗方法（如持续性通货膨胀）引入新生儿护理。这项资助的目的是确定早产和近足月羔羊新生儿复苏的安全和有用的招募策略，这些评估不能轻易地进行临床评估。我们将测量激活炎症通路的早期反应基因表达以及早产和足月羔羊肺内炎症表达的位置。我们还将测试肺损伤的严重程度是否取决于胎龄（GA），以及在极早产儿、中度早产儿和足月儿肺通气启动期间是否激活了不同的急性期损伤途径。我们还将验证早产新生羔羊通气4小时和24小时的保护策略和潜在的治疗途径。通过将可再现的复苏羔羊模型与先进的分子技术相结合，我们将确定：1）哪些肺气体体积补充操作将使损伤最小化，2）复苏操作的肺损伤如何根据肺的发育阶段而不同，以及3）最佳的通气启动是否会导致持续通气肺损伤的放大减少。这些创新研究将定义早产和近足月羔羊对募集策略的分子和生理反应，从而对损伤途径如何进展为急性和慢性肺病产生新的见解。研究结果还将使我们能够确定该领域的潜在治疗靶点和生物标志物。这些研究将为ILCOR对临床实践的建议提供科学依据，这些建议非常难以验证 通过临床试验。

项目成果

Dose of budesonide with surfactant affects lung and systemic inflammation after normal and injurious ventilation in preterm lambs.

• DOI: 10.1038/s41390-020-0809-6
• 发表时间: 2020-11
• 期刊: Pediatric research
• 影响因子: 3.6
• 作者: Hillman NH;Abugisisa L;Royse E;Fee E;Kemp MW;Kramer BW;Schmidt AF;Salomone F;Clarke MW;Musk GC;Jobe AH
• 通讯作者: Jobe AH

Animal Models, Learning Lessons to Prevent and Treat Neonatal Chronic Lung Disease.

• DOI: 10.3389/fmed.2015.00049
• 发表时间: 2015
• 期刊: Frontiers in medicine
• 影响因子: 3.9
• 作者: Jobe AH

Pressure-limited sustained inflation vs. gradual tidal inflations for resuscitation in preterm lambs.

压力限制的持续通货膨胀与渐进的潮汐通货膨胀对早产羔羊的复苏。

• DOI: 10.1152/japplphysiol.00985.2014
• 发表时间: 2015
• 期刊: Journal of applied physiology (Bethesda, Md. : 1985)
• 作者: Tingay,DavidG;Polglase,GraemeR;Bhatia,Risha;Berry,ClareA;Kopotic,RobertJ;Kopotic,ClintonP;Song,Yong;Szyld,Edgardo;Jobe,AlanH;Pillow,JJane
• 通讯作者: Pillow,JJane