"Preterm lung and brain responses to mechanical ventilation and corticosteroids"

“早产肺和大脑对机械通气和皮质类固醇的反应”

• 批准号: 10210416
• 负责人: NOAH H HILLMAN
• 金额: $ 11.36万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-06 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10210416
• 关键词: Acute; Adolescence; Adrenal Cortex Hormones; Affect; Affinity; Betamethasone; Birth; Brain; Brain Injuries; Brain region; Bronchopulmonary Dysplasia; Budesonide; Caring; Cerebral Palsy; Chronic; Clinical; Continuous Positive Airway Pressure; Data; Development; Dexamethasone; Dose; Encephalitis; Equilibrium; Exploratory/Developmental Grant; Exposure to; Fetal Sheep; Future; Glucocorticoid Receptor; Goals; Hour; Human; Hydrocortisone; Incidence; Individual; Infant; Inflammatory Response; Inhalation; Injury; Intervention; Life; Limbic System; Link; Liver; Lung; Lung Inflammation; Magnetic Resonance Imaging; Mechanical ventilation; Mineralocorticoid Receptor; Modeling; Molecular; Morbidity - disease rate; Neurodevelopmental Disability; Neurologic; Neurologic Effect; Neurological outcome; Neurons; Newborn Infant; Organ; Pathology; Pathway interactions; Physicians; Physiology; Premature Infant; Prevention; Regimen; Risk; Role; Savings; Severities; Sheep; Steroids; Techniques; Tidal Volume; Toxic effect; Very Low Birth Weight Infant; antenatal; clinically relevant; cost; disability; endotracheal; gray matter; innovation; insight; lamb model; lung injury; lung maturation; mRNA sequencing; mortality; neuroimaging; postnatal; preterm newborn; pulmonary function; relative effectiveness; respiratory; response; sheep model; surfactant; systemic toxicity; translational model; ventilation; white matter; white matter injury

Almost all very low birth weight preterm infants require respiratory support (mechanical ventilation or CPAP) at birth, and up to 40% of these infants will develop bronchopulmonary dysplasia (BPD). Since BPD affects the smallest and most preterm infants, many of the infants surviving with BPD have neurodevelopmental disabilities and injuries to other organs. Lung inflammation and injury resulting from mechanical ventilation are central to the development of BPD. Prolonged mechanical ventilation has been linked to MRI changes and poor neurologic outcomes, and mechanical ventilation causes systemic changes in liver, brain inflammation and MRI changes in sheep. Recent trials of inhaled budesonide, budesonide mixed with surfactant, postnatal dexamethasone, and early postnatal low-dose hydrocortisone have all decreased the risk of BPD. However, concerns exist for systemic effects of steroids. Different postnatal steroids regimens have been associated with worse neurologic outcomes. The balance between a lung benefit and neurologic harm for these regimens needs to be determined before widespread use. Our preliminary data demonstrate systemic changes in the liver and brain with mechanical ventilation that can be altered by postnatal steroids. Using a preterm lamb models, we will evaluate lung and brain responses to mechanical ventilation and postnatal steroids, and identify possible toxic effects on the newborn. By combining antenatal exposures to corticosteroid and mechanical ventilation, we can determine interactions that could alter lung maturation and postnatal lung function. Results will be assessed using physiology, pathology, and advanced molecular techniques for the lung and brain. We will use mRNA sequencing to evaluate a wide range of potential injury pathways. We propose two specific aims to 1) define the role of clinically relevant steroids (dexamethasone, budesonide in surfactant, hydrocortisone) in mechanical ventilation and 2) interactions with antenatal corticosteroids and mechanical ventilation on brain injury. Our proposal is innovative because it uses unique preterm sheep models to evaluate the lung and brain effects of postnatal steroids in clinically relevant settings of lung injury and antenatal steroids. These exploratory studies fit well with the R21 mechanism and will provide important information for assisting clinical decisions in the NICU.

几乎所有极低出生体重的早产儿都需要呼吸支持(机械通气或CPAP)。 出生，这些婴儿中高达40%将发展为支气管肺发育不良(BPD)。由于BPD会影响 最小的早产儿，许多患有bpd的婴儿都有神经发育障碍。 以及其他器官的损伤。机械通气引起的肺部炎症和损伤是 BPD的发展。长时间的机械通气与核磁共振改变和神经功能不良有关。 结果，机械通气引起全身性肝、脑炎症改变和MRI改变 羊。布地奈德吸入剂、布地奈德与表面活性物质、出生后地塞米松和 出生后早期小剂量氢化可的松都降低了BPD的风险。然而，对以下方面存在担忧 类固醇的全身效应。不同的出生后类固醇疗法与更糟糕的神经学有关 结果。需要确定这些方案对肺的益处和对神经的损害之间的平衡。 在广泛使用之前。我们的初步数据显示了肝脏和大脑的系统性变化 可以通过出生后的类固醇改变的机械通风。使用早产羔羊模型，我们将评估 肺和脑对机械通气和出生后类固醇的反应，并确定可能的毒性影响 新生儿。通过将产前接触皮质类固醇和机械通气相结合，我们可以确定 可以改变肺成熟和出生后肺功能的相互作用。结果将通过以下方式进行评估 肺和脑的生理学、病理学和先进的分子技术。我们将使用mRNAs 测序以评估广泛的潜在损伤途径。我们提出了两个具体目标来1)定义 临床相关类固醇(地塞米松、表面活性物质布地奈德、氢化可的松)在机械加工中的作用 2)产前糖皮质激素联合机械通气治疗颅脑损伤。我们的 该方案具有创新性，因为它使用了独特的早产绵羊模型来评估 肺损伤的临床相关环境中的出生后类固醇和产前类固醇。这些探索性研究 与R21机制非常吻合，将为辅助NICU的临床决策提供重要信息。