Duke University, Division of Infectious Diseases & International Health, Department of Medicine, Durham, North Carolina, USA
Duke University, Duke Global Health Institute, Durham, North Carolina, USA.
Infect Immun. 2019 Mar 25;87(4). doi: 10.1128/IAI.00655-18. Print 2019 Apr.
The low bioavailability of nitric oxide (NO) and its precursor, arginine, contributes to the microvascular pathophysiology of severe falciparum malaria. To better characterize the mechanisms underlying hypoargininemia in severe malaria, we measured the plasma concentrations of amino acids involved in arginine synthesis in children with uncomplicated falciparum malaria (UM; = 61), children with cerebral falciparum malaria (CM; = 45), and healthy children (HC; = 109). We also administered primed infusions of l-arginine uniformly labeled with C and N to 8 children with severe falciparum malaria (SM; age range, 4 to 9 years) and 7 healthy children (HC; age range, 4 to 8 years) to measure the metabolic flux of arginine, hypothesizing that arginine flux is increased in SM. Using two different tandem mass spectrometric methods, we measured the isotopic enrichment of arginine in plasma obtained at 0, 60, 90, 120, 150, and 180 min during the infusion. The plasma concentrations of glutamine, glutamate, proline, ornithine, citrulline, and arginine were significantly lower in UM and CM than in HC ( ≤ 0.04 for all pairwise comparisons). Of these, glutamine concentrations were the most markedly decreased: median, 457 μM (interquartile range [IQR], 400 to 508 μM) in HC, 300 μM (IQR, 256 to 365 μM) in UM, and 257 μM (IQR, 195 to 320 μM) in CM. Arginine flux during steady state was not significantly different in SM than in HC by the respective mass spectrometric methods: 93.2 μmol/h/kg of body weight (IQR, 84.4 to 129.3 μmol/h/kg) versus 88.0 μmol/h/kg (IQR, 73.0 to 102.2 μmol/h/kg) ( = 0.247) by the two mass spectrometric methods in SM and 93.7 μmol/h/kg (IQR, 79.1 to 117.8 μmol/h/kg) versus 81.0 μmol/h/kg (IQR, 75.9 to 88.6 μmol/h/kg) ( = 0.165) by the two mass spectrometric methods in HC. A limited supply of amino acid precursors for arginine synthesis likely contributes to the hypoargininemia and NO insufficiency in falciparum malaria in children.
一氧化氮 (NO) 及其前体精氨酸的生物利用度低，导致严重恶性疟原虫病的微血管病理生理学改变。为了更好地描述严重疟疾低精氨酸血症的发病机制，我们测定了无并发症恶性疟原虫病患儿（UM； = 61）、伴发脑型疟疾的恶性疟原虫病患儿（CM； = 45）和健康儿童（HC； = 109）的血浆中参与精氨酸合成的氨基酸浓度。我们还对 8 名严重恶性疟原虫病患儿（SM；年龄 4 至 9 岁）和 7 名健康儿童（HC；年龄 4 至 8 岁）进行了 l-精氨酸预输注，并用 C 和 N 均匀标记，以测量精氨酸的代谢通量，假设 SM 中精氨酸通量增加。使用两种不同的串联质谱方法，我们在输注 0、60、90、120、150 和 180 分钟时测量了输注过程中获得的血浆中精氨酸的同位素丰度。UM 和 CM 患儿的血浆谷氨酸、谷氨酸、脯氨酸、鸟氨酸、瓜氨酸和精氨酸浓度明显低于 HC（所有两两比较均为 ≤ 0.04）。其中，谷氨酸浓度下降最明显：HC 中为 457 μM（四分位距 [IQR]，400 至 508 μM），UM 中为 300 μM（IQR，256 至 365 μM），CM 中为 257 μM（IQR，195 至 320 μM）。两种质谱方法测定的 SM 患儿和 HC 患儿的稳态精氨酸通量均无显著差异：分别为 93.2 μmol/h/kg 体重（IQR，84.4 至 129.3 μmol/h/kg）和 88.0 μmol/h/kg（IQR，73.0 至 102.2 μmol/h/kg）（ = 0.247），SM 中两种质谱方法和 93.7 μmol/h/kg（IQR，79.1 至 117.8 μmol/h/kg）和 81.0 μmol/h/kg（IQR，75.9 至 88.6 μmol/h/kg）（ = 0.165），HC 中两种质谱方法。精氨酸合成的氨基酸前体供应有限可能导致儿童恶性疟原虫病中低精氨酸血症和一氧化氮不足。
