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：（从申请人的描述扫描）：呼吸窘迫 婴儿呼吸窘迫综合征（RDS）最常见的原因是 肺表面活性物质的浓度外源性表面活性剂失效 在高达50%的婴儿中进行替代以重建肺功能 与RDS的关系表明，机制无关的定量缺陷， 肺表面活性物质可能会破坏婴儿亚组的表面活性物质代谢 致命的呼吸窘迫综合征利用天然存在的， 稳定非放射性同位素标记的磷脂代谢前体 综合建议两种替代机制，这取决于估计的 表面活性剂池大小，用于致死RDS中表面活性剂代谢中断：1）如果 致死性RDS婴儿的表面活性物质池的大小小于 非致死性RDS，那么患有致死性RDS的婴儿内源性 表面活性剂产生和/或增加的表面活性剂催化剂;或2）如果 表面活性剂池的大小相似，那么患有致死性RDS的婴儿 表面活性剂生产和催化剂。外源性表面活性剂， 2 H4-胆碱标记的磷脂酰胆碱和静脉输注表面活性剂 磷脂前体（作为U-13 C6]葡萄糖、7，7，8，8 - 2 H4-棕榈酸酯、 或1- 13 C1乙酸酯）和气相色谱/质谱（GCJMS）以及气体 色谱-燃烧界面同位素比值质谱法 将用于检验以下假设：增加表面活性剂催化剂 描述了致死性RDS婴儿的特征。为了比较表面活性剂池的大小， 致死性和非致死性RDS婴儿，表面活性剂中2 H4-胆碱富集 从气管内给药后的气管吸出物样品中获得 将测量标记的表面活性剂。为了比较以下国家的表面活性剂产量， 致死性和非致死性RDS的婴儿，13 C掺入率， 24小时后，2 H4进入从气管抽吸物样品中获得的表面活性剂 将测量1- 13 C1乙酸酯和7，7，8，8 - 2 H4-棕榈酸酯的输注。到 比较致死性和非致死性RDS婴儿的表面活性剂catastrophin， 从气管内获得的表面活性剂中清除13 C和2 H4的速率 将测量抽吸样品。小于29周的早产儿 妊娠，1岁以下婴儿，难治性呼吸衰竭 等待肺移植的患者，以及6个月以下的婴儿 需要机械通气的正常肺部患者将进行研究。 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和有效方法来评估 表面活性剂代谢，并将导致具体的和临床上有用的 呼吸窘迫综合征婴儿的肺功能恢复干预。