C-Reactive Protein in Extremely Low Birth Weight Neonates

描述（由申请人提供）：支气管肺发育不良（BPD）是极低出生体重（ELBW）婴儿的常见疾病和死亡原因，是美国新生儿护理成本的主要来源。C-反应蛋白（CRP）是一种主要由肝细胞产生的环状五聚体，是一种急性期反应物，在炎症期间血液中显著增加，已被用作新生儿败血症的生物标志物。CRP不仅是炎症的标志，而且还调节炎症和免疫反应。CRP的产生并不局限于肝脏，由气道上皮细胞和肺泡巨噬细胞产生，并存在于正常的呼吸道分泌物中。CRP以剂量依赖的方式损害肺表面活性物质的表面张力降低功能。我们已经进行了初步研究，证明了新的发现：(a)即使排除了患有败血症的婴儿，28日龄时的血清CRP也能强烈预测ELBW婴儿36周经后年龄（PMA）时的死亡/ BPD [ROC的AUC为0.85]。没有BPD存活的婴儿的CRP低于死亡/BPD的婴儿[中位数（25 -75分）；(b)出生后第1天气管吸入物中CRP是死亡/BPD的预后标志物，并与其他炎症和肺损伤介质（IL-1p、IL-6、FGF-2和凋亡标志物）相关。这些发现支持了我们的总体假设，即CRP是ELBW婴儿不良结局（死亡或BPD）的早期标志物和中介。该项目的具体目的是：(1)确定死亡或发展为BPD的ELBW婴儿在出生后第一周是否有较高的血清CRP浓度，(2)确定死亡或发展为BPD的ELBW婴儿在出生后第一周是否有较高的气管吸入CRP浓度，以及(3)确定死亡或发展为BPD的ELBW婴儿是否具有与较高的血清CRP浓度相关的遗传多态性。方法：前瞻性研究在美国伯明翰地区新生儿重症监护病房（一个地区围产期中心）住院的120名存活于bb0 - 12小时以上15个月的ELBW婴儿。据估计，将有40名婴儿死亡或发展为BPD。残血样本（0.05 ml）将在第1、3和7天收集，用敏感的ELISA检测CRP。在第1、3和7天对机械通气婴儿收集气管吸入物。出生时的脐带血或脐带样本将被用于获得遗传多态性研究的DNA。将收集所有婴儿从出生到出院/36周PMA的临床数据。确认CRP水平是ELBW婴儿死亡/BPD的早期标志，以及CRP基因多态性使ELBW婴儿易患死亡/BPD（表明CRP是一种介质，而不仅仅是BPD的标志）将具有重要的临床意义，并可能允许有针对性地使用抗炎或抗CRP治疗治疗ELBW婴儿。

DESCRIPTION (provided by applicant): Bronchopulmonary dysplasia (BPD) is a common morbidity and cause of mortality in extremely low birth weight (ELBW) infants, and is a major contributor to the cost of neonatal care in the United States. C- reactive protein (CRP), a cyclic pentamer produced mainly by hepatocytes, is an acute phase reactant that markedly increases in blood during inflammation and has been used as a biomarker for neonatal sepsis. CRP is not just a marker of inflammation but also modulates inflammatory and immune responses. CRP production is not restricted to the liver, being produced by airway epithelial cells and alveolar macrophages, and is present in normal respiratory secretions. CRP impairs the surface-tension lowering function of lung surfactant in a dose-dependent manner. We have performed preliminary studies demonstrating the novel findings that: (a) serum CRP at 28 days of age strongly predicts death/ BPD at 36 weeks' postmenstrual age (PMA) in ELBW infants [AUC of ROC 0.85], even after excluding infants with sepsis. Infants surviving without BPD had lower CRP than infants with death/BPD [Median (25th-75thiles); 0 (0-3) vs. 11 (4-21) mg/L, p<0.001] (b) CRP in tracheal aspirates on the 1st postnatal day was a prognostic marker for death/BPD and correlated with other mediators of inflammation and lung injury (IL-1p, IL-6, FGF-2, and apoptosis markers). These findings support our overall hypothesis that CRP is an early marker and a mediator of poor outcome (death or BPD) in ELBW infants. The Specific Aims of this proposed project are (1) to determine if ELBW infants who die or develop BPD have higher serum CRP concentrations in the first postnatal week, (2) to determine if ELBW infants who die or develop BPD have higher tracheal aspirate CRP concentrations in the first postnatal week, and (3) to determine if ELBW infants who die or develop BPD have genetic polymorphisms associated with higher serum CRP concentrations. Methods: 120 ELBW infants surviving > 12 h of age admitted to the Regional Neonatal Intensive Care Unit in Birmingham, AL (a Regional Perinatal center) over 15 months will be prospectively studied. It is estimated that 40 infants will either die or develop BPD. Remnant blood samples (0.05 ml) will be collected on days 1, 3, and 7 for CRP estimation by a sensitive ELISA. Tracheal aspirates will be collected from mechanically ventilated infants on days 1, 3, and 7. Cord blood at birth or a sample of the umbilical cord will be used to obtain DNA for the genetic polymorphism study. Clinical data will be collected on all infants from birth to discharge/36 weeks PMA. Confirming that CRP level is an early marker of death/BPD in ELBW infants, and that CRP genetic polymorphism predisposes ELBW infants to death/BPD (indicating that CRP is a mediator and not just a marker of BPD) will be of major clinical significance and may permit targeted use of anti-inflammatory or anti-CRP therapies for treatment of ELBW infants.