Initiation and Progression of Preterm Lung Injury with Ventilation

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婴儿的知识差距。这些间隙是出生时肺部充气和通气的最佳方式。出生时开始通气是独特的，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过通气开始的，但损伤标志物的形成需要时间。为了克服持续通气的混淆效应，我们开发了一个维持胎盘循环的新生儿复苏胎羊模型，从而使我们能够分离和评估旨在减少出生时向空气呼吸过渡期间肺损伤的复苏动作。这些操作很难在临床环境中进行评估，因为复苏的必要性，而不是关注程序的单一组成部分，婴儿临床状态的巨大可变性，以及需要继续支持超出特定范围

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.