In Vivo Metabolism of Pulmonary Surfactant in Infants

婴儿肺表面活性剂的体内代谢

• 批准号: 6537856
• 负责人: AARON HAMVAS
• 金额: $ 25.6万
• 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/6537856
• 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）：呼吸窘迫 婴儿中最常见的综合症综合征（RDS）是由于定量缺陷而引起的 早产后的肺表面活性剂。外源表面活性剂的失败 多达50％的婴儿的替换以重建肺功能 使用RDS表明机制与定量缺陷无关 肺表面活性剂可能会破坏婴儿亚组中的表面活性剂代谢 用致命的RDS。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 合成提出了两种替代机制，这些机制取决于估计值 表面活性剂池的大小，用于致命RDS中的表面活性剂代谢的破坏：1）如果 致死RD的婴儿的表面活性剂池尺寸比 非致命的RDS，然后致死RD的婴儿降低了内源性 表面活性剂产生和/或增加表面活性剂分解代谢；或2）如果 表面活性剂池尺寸相似，然后具有致命RD的婴儿增加了 表面活性剂的生产和分解代谢。富含的外源表面活性剂 2H4-胆碱标记的磷脂酰胆碱和表面活性剂的静脉输注 磷脂前体（以U-13C6的施用）葡萄糖，7,7,8,8-2H4-甲米酸盐， 或1-13c1乙酸）和气相色谱/质谱法（GCJM）和气体 色谱 - 燃烧界面同位素比率质谱（GC-IRMS） 将用于检验以下假设：表面活性剂分解代谢增加 具有致命RD的婴儿的特征。比较表面活性池尺寸 具有致命和非致命性RD的婴儿，表面活性剂中的2H4-胆碱富集 气管内给药后，从气管抽吸样品中获得 将测量标记的表面活性剂。比较表面活性剂的生产 致死性和非致命性RD的婴儿，13c和13c的掺入率 2H4在24小时后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7,7,8-2H4-钙板的输注。到 比较致命和非致命RD的婴儿表面活性剂分解代谢， 从气管获得的表面活性剂的清除率为13C和2H4的速率 将测量抽吸样品。早产婴儿小于29周 妊娠，婴儿小于1岁，难治性呼吸衰竭 他们正在等待肺移植，婴儿不到6个月大 将研究需要机械通气的正常肺。 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有力的方法来评估破坏 表面活性剂代谢，将导致特定且在临床上有用 恢复RDS婴儿肺功能的干预措施。