不对称二甲基精氨酸与新生儿持续性肺动脉高压病理进程的相关性研究

Association of asymmetric dimethylarginine with the pathological process of persistent pulmonary hypertension of the newborn

摘要:

目的 探讨不对称二甲基精氨酸（asymmetric dimethylarginine，ADMA）在新生儿持续性肺动脉高压（persistent pulmonary hypertension of the newborn，PPHN）足月儿循环系统中的变化规律及其与治疗响应的关系，探索其成为治疗靶标和治疗响应标志物的可能性。 方法 前瞻性选取出生3 d内、被诊断患有PPHN的足月新生儿30例为PPHN组，同时选取胎龄和日龄与PPHN患儿匹配的在新生儿科接受治疗或观察的非PPHN新生儿20例为对照，收集两组患儿治疗第1、7、14天的血清样本，用高效液相色谱串联质谱法检测血清中的L-精氨酸、ADMA及其同分异构体对称二甲基精氨酸（symmetric dimethylarginine，SDMA）的含量。 结果 对照组新生儿血清中ADMA和L-精氨酸的含量在前14 d内持续上升，而SDMA出现持续下降（P<0.05）。在第1天和第14天，对照组和PPHN组新生儿血清中的ADMA含量没有明显差别（P>0.05）；在第7天，PPHN组患儿血清中ADMA含量显著高于对照组（P<0.05），而SDMA和L-精氨酸含量没有出现变化（P>0.05）。此外，PPHN患儿经过为期7 d的治疗，肺动脉收缩压仍高于35 mm Hg者的血清ADMA浓度显著高于肺动脉收缩压≤35 mm Hg者（P<0.05）。 结论 出生后前2周，足月儿循环系统中ADMA含量和ADMA/SDMA比值呈现持续增加的过程，PPHN病理进程加速这一过程，提示ADMA可能参与PPHN病理进程；高ADMA水平与PPHN治疗抵抗有关，提示抑制ADMA可能是提高PPHN治疗响应率的潜在药物干预靶标。

Abstract:

Objective To study the change in asymmetric dimethylarginine (ADMA) in the circulation system of full-term infants with persistent pulmonary hypertension of the newborn (PPHN) and its association with treatment response, as well as the possibility of ADMA as a therapeutic target and a marker for treatment response. Methods A prospective study was performed. A total of 30 full-term neonates who were diagnosed with PPHN within 3 days after birth were enrolled as the PPHN group, and the neonates without PPHN, matched for gestational age and age, who were treated or observed in the department of neonatology were enrolled as the control group. Serum samples were collected on days 1, 7, and 14 of treatment. The high-performance liquid chromatography-tandem mass spectrometry was used to measure the serum concentrations of L-arginine, ADMA, and its isomer symmetric dimethylarginine (SDMA). Results For the neonates in the control group, the serum concentrations of ADMA and L-arginine continuously increased and the serum concentration of SDMA continuously decreased within the first 14 days of treatment. On days 1 and 14, there was no significant difference in the serum concentration of ADMA between the control and PPHN groups (P>0.05). On day 7, the PPHN group had a significantly higher serum concentration of ADMA than the control group (P<0.05), while there were no significant differences in serum concentrations of SDMA or L-arginine (P>0.05). Moreover, after 7 days of treatment, the PPHN neonates with a systolic pulmonary arterial pressure (sPAP) of >35 mmHg had a significantly higher serum concentration of ADMA than those with an sPAP of ≤35 mm Hg. Conclusions There are continuous increases in the ADMA concentration and the ADMA/SDMA ratio in the circulation system of full-term infants within the first 2 weeks after birth, and this process is accelerated by the pathological process of PPHN, suggesting that ADMA may be involved in the pathologic process of PPHN. A high level of ADMA is associated with the resistance to PPHN treatment, suggesting that inhibition of ADMA might be a potential target of drug intervention to improve the treatment response of PPHN.