In Vivo Metabolism of Pulmonary Surfactant in Infants

婴儿肺表面活性剂的体内代谢

• 批准号: 6331907
• 负责人: AARON HAMVAS
• 金额: $ 26.96万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6331907
• 关键词: gas chromatography; human subject; infant human (0-1 year); mass spectrometry; metabolism; patient oriented research; pediatrics; pulmonary surfactants; radiotracer; respiratory distress syndrome of newborn

DESCRIPTION: (Scanned from the applicant's description): Respiratory distress syndrome (RDS) in infants most commonJy results from a quantitative deficiency of pulmonary surfactant after premature birth. Failure of exogenous surfactant replacement to reconstitute pulmonary function in up to 50 percent of infants with RDS suggests that mechanisms unrelated to quantitative deficiencies in pulmonary surfactant may disrupt surfactant metabolism in a subgroup of infants with lethal RDS. Preliminary data from studies utilizing naturally occurring, stable, non-radioactive isotope labeled metabolic precursors of phospholipid synthesis suggest two alternative mechanisms, which depend on estimates of the surfactant pool size, for disrupted surfactant metabolism in lethal RDS: 1) if surfactant pool sizes are smaller in infants with lethal RDS than in those with non-lethal RDS, then infants with lethal RDS have decreased endogenous surfactant production and/or increased surfactant catabolism; or 2) if surfactant pool sizes are similar, then infants with lethal RDS have increased surfactant production and catabolism. Exogenous surfactant enriched with 2H4-choline labeled phosphatidylcholine and intravenous infusions of surfactant phospholipid precursors (administered as U-13C6]glucose, 7,7,8,8-2H4-palmitate, or 1-13C1acetate) and gas chromatography/mass spectrometry (GCJMS) and gas chromatography-combustion interface isotope ratio mass spectrometry (GC-IRMS) will be used to test the hypothesis that: Increased surfactant catabolism characterizes infants with Lethal RDS. To compare surfactant pool sizes in infants with lethal and non-lethal RDS, 2H4-choline enrichment in surfactant obtained from tracheal aspirate samples after intratracheal administration of labeled surfactant will be measured. To compare surfactant production in infants with lethal and non-lethal RDS, the rate of incorporation of 13C and 2H4 into surfactant obtained from tracheal aspirate samples after a 24 hour infusion of 1-13C1acetate and 7,7,8,8-2H4-palmitate will be measured. To compare surfactant catabolism in infants with lethal and non-lethal RDS, the rate of clearance of 13C and 2H4 from surfactant obtained from tracheal aspirate samples will be measured. Premature infants less than 29 weeks gestation, infants less than 1 year of age with refractory respiratory failure who are awaiting lung transplantation, and infants less than 6 months of age with normal lungs who require mechanical ventilation will be studied. Techniques using labeled metabolic precursors of surfactant phospholipid synthesis provide a unique and powerful approach to evaluate disruption of surfactant metabolism and will lead to specific and clinically useful interventions to restore pulmonary function in infants with RDS.

描述：（从申请人的描述中扫描）：呼吸困难 婴儿综合症 (RDS) 最常见的原因是数量不足 早产后肺表面活性物质的变化外源性表面活性剂失效 替代疗法可帮助高达 50% 的婴儿重建肺功能 RDS 表明与数量缺陷无关的机制 肺表面活性物质可能会破坏婴儿亚群的表面活性物质代谢 具有致命的 RDS。来自利用自然发生的研究的初步数据， 稳定的、非放射性同位素标记的磷脂代谢前体 综合提出了两种替代机制，这取决于对 表面活性剂库大小，对于致命 RDS 中表面活性剂代谢的破坏：1) 如果 患有致死性 RDS 的婴儿的表面活性剂池大小比患有致死性 RDS 的婴儿要小 非致死性 RDS，那么患有致死性 RDS 的婴儿内源性下降 表面活性剂的产生和/或表面活性剂分解代谢的增加；或 2) 如果 表面活性剂池大小相似，则患有致命 RDS 的婴儿增加 表面活性剂的产生和分解代谢。富含外源表面活性剂 2H4-胆碱标记的磷脂酰胆碱和表面活性剂静脉输注 磷脂前体（以U-13C6]葡萄糖、7,7,8,8-2H4-棕榈酸酯形式施用， 或 1-13C1 乙酸盐）和气相色谱/质谱 (GCJMS) 和气体 色谱-燃烧界面同位素比质谱法 (GC-IRMS) 将用于检验以下假设： 表面活性剂分解代谢增加 是患有致死性 RDS 婴儿的特征。比较表面活性剂池大小 患有致死性和非致死性 RDS、表面活性剂中 2H4-胆碱富集的婴儿 气管内给药后从气管吸出物样本中获得 将测量标记的表面活性剂。比较表面活性剂的产量 患有致死性和非致死性 RDS 的婴儿，13C 和 24 小时后，2H4 进入从气管抽吸样品中获得的表面活性剂 将测量 1-13C1 乙酸盐和 7,7,8,8-2H4-棕榈酸盐的输注。到 比较具有致死性和非致死性 RDS 的婴儿的表面活性剂分解代谢， 气管表面活性剂清除 13C 和 2H4 的速率 将测量吸出的样品。 29周以下的早产儿 妊娠期、患有难治性呼吸衰竭的 1 岁以下婴儿 等待肺移植的人和 6 个月以下的婴儿 将研究需要机械通气的正常肺部。 使用表面活性剂磷脂的标记代谢前体的技术 合成提供了一种独特而强大的方法来评估破坏 表面活性剂代谢，并将导致特定的和临床有用的 恢复 RDS 婴儿肺功能的干预措施。