Initiation and Progression of Preterm Lung Injury with Ventilation

说明(由申请人提供)：在2010年新生儿复苏指南中，复苏问题国际联络委员会确定了早产儿和足月儿在知识方面的差距。缝隙是使出生时肺部充气和通风的最佳方法。出生时开始呼吸是独一无二的，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，而出生时正压呼吸会导致呼吸道上皮损伤，进而发展为弥漫性肺部炎症。虽然肺损伤是通过出生时的呼吸开始的，但损伤的标志需要时间来发展。为了克服持续呼吸的混杂效应，我们开发了一个维持胎盘循环的新生儿复苏模型，从而使我们能够分离和评估复苏操作，旨在减少出生时空气呼吸过渡期间的肺损伤。这些手法很难在临床环境中评估，因为复苏的必要性不集中于程序的单一部分，婴儿的临床状况差异很大，以及需要在特定的支持之外继续支持 干预。临床医生经常在新生儿护理中引入新的治疗方法，如持续充气，而不知道好处或潜在的伤害。这笔赠款的目标是确定安全和有用的早产和近期羔羊新生儿复苏招募策略，这一评估不容易在临床上进行评估。我们将测量激活炎症途径的早期反应基因的表达，以及早产和足月羔羊肺部炎症的表达位置。我们还将测试肺损伤的严重程度是否依赖于胎龄(GA)，以及在极早产、中早产和足月肺开始机械通气时，是否激活了不同的急性时相损伤途径。我们还将验证4小时和24小时的早产新生羔羊的保护策略和潜在的治疗途径。通过将可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)哪种肺气量补充操作可以将损伤降至最低；2)复苏操作对肺损伤的影响因肺发育阶段的不同而有何不同；3)最佳的呼吸机启动是否会在持续通风的情况下减少肺损伤的扩大。这些创新的研究将定义早产和近期羔羊对招募动作的分子和生理反应，从而对损伤途径如何进展为急性和慢性肺部疾病提供新的见解。结果还将使我们能够确定潜在的治疗目标和该领域的生物标记物。这些研究将为ILCOR关于临床实践的建议提供科学基础，这些建议很难验证 通过临床试验。 公共卫生相关性：虽然大约10%的新生儿和大多数极低出生体重的早产儿在出生时需要一些帮助来呼吸，但还没有确定充气和通风的最佳动作。早产儿出生时很容易损伤早产儿肺，机械通气导致早产儿长期残疾。这些研究将确定对足月儿和早产儿有益的肺复张策略，并促进我们对出生时通风激活的炎症途径的了解。

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.