Initiation and Progression of Preterm Lung Injury with Ventilation

通气引起早产肺损伤的发生和进展

基本信息

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
项目类别：
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

项目摘要

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，国际联络复苏委员会（ILCOR）确定了自早产和学期婴儿的知识差距。这些间隙是出生时膨胀和通风肺的最佳操作。出生时通风的启动是独一无二的，因为胎儿肺必须迅速从充满液体的空体转换为气体交换，并且出生时带有正压的通风会导致气道上皮损伤，从而发展为弥漫性肺部炎症。尽管肺部损伤是通过出生时通风开始的，但要开发损伤的标记需要时间。要克服持续通风的混杂作用，我们开发了一种新生儿复苏的胎儿绵羊模型，该模型可以保持胎盘循环，从而使我们能够隔离和评估旨在减少肺部受伤的肺部损伤，以减少肺部损伤在生育过程中过渡期间的肺部受伤。这些操作很难在临床环境中进行评估干涉。临床医生通常将新的治疗方法（例如持续的通货膨胀）引入新生儿护理，而无需了解受伤或受伤的潜力。这笔赠款的目的是确定在早产和近期羔羊中的新生儿复苏的安全招聘操作，这是无法轻易在临床上评估的评估。我们将测量激活炎症途径的早期反应基因表达以及在早产和术语羔羊肺中炎症表达的位置。我们还将测试肺损伤的严重程度是否取决于胎龄（GA），以及在非常早产，中度早产和肺部肺部通风期间是否激活了不同的急性相损伤途径。我们还将验证预通4和24小时的早产新生羔羊中的保护策略和潜在的治疗途径。通过将复制的复苏羔羊模型与先进的分子技术相结合，我们将确定：1）哪种肺气体积募集操作将最小化损伤，2）肺部因肺部发育阶段的发展而导致肺部的肺部受伤造成的肺部损伤如何差异，而如果肺的发育阶段的发展，以及3）如果肺部不断损害，则导致通气效率降低。这些创新的研究将定义对早产和近期羔羊招募动作的分子和生理反应，从而有了新的见解，对有害途径如何发展为急性和慢性肺部疾病。结果还将使我们能够确定该领域的潜在治疗目标和生物标志物。这些研究将为ILCOR的临床实践提供科学依据，这些建议很难验证通过临床试验。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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)
影响因子：
0
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

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