Increased asymmetric dimethylarginine in severe falciparum malaria: association with impaired nitric oxide bioavailability and fatal outcome.
Increased asymmetric dimethylarginine in severe falciparum malaria: association with impaired nitric oxide bioavailability and fatal outcome.
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DOI：
10.1371/journal.ppat.1000868
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发表时间：
2010-04-22
期刊：
影响因子：
6.7
通讯作者：
Anstey NM
中科院分区：
文献类型：
--
作者：
Yeo TW;Lampah DA;Tjitra E;Gitawati R;Darcy CJ;Jones C;Kenangalem E;McNeil YR;Granger DL;Lopansri BK;Weinberg JB;Price RN;Duffull SB;Celermajer DS;Anstey NM
不对称二甲基精氨酸(ADMA)是一氧化氮合酶(NOS)的内源性抑制物，是危重疾病死亡率的预测指标。严重疟疾(SM)与NO生物利用度降低有关，但ADMA在疟疾NO生物利用度受损和不良后果的发病机制中的作用尚不清楚。在患有和不患有恶性疟疾的成年人中，我们测试了如下假设：1)血浆ADMA与疾病严重程度成比例增加，2)与血管和肺功能受损有关，没有生物利用度，3)与死亡率增加独立相关。我们测定了49例SM患者、78例中重度疟疾(MSM)患者和19例健康对照(HC)的血浆二甲基精氨酸、呼出的NO浓度和内皮功能。对SM患者进行重复的ADMA和内皮功能检测。多变量回归用于评估ADMA对死亡率和无生物利用度的影响。SM患者血浆ADMA水平(0.85µM；95%CI为0.74~0.96)高于MSM(0.54µM；95%CI为0.5~0.56)和肥胖组(0.64µM；95%CI为0.58~0.70；p<；0.001)。ADMA是SM患者死亡率的独立预测因子，每升高一个微摩尔数，死亡几率增加18倍(95%CI2.0-181；p = 0.01)。在所有疟疾患者中，ADMA与呼出NO减少(rS = −0.31)和内皮功能降低(rS = −0.32)独立相关，在SM患者中与呼出NO减少(rS = −0.72)独立相关。ADMA在SM中增加，并与血管和肺内NO生物利用度降低相关。ADMA对一氧化氮合酶的抑制可能导致重症疟疾死亡率的增加。严重恶性疟疾与微血管灌注受损、肺损伤和一氧化氮(NO)生物利用度降低有关，但这些过程的原因尚不完全清楚。不对称二甲基精氨酸(ADMA)是一氧化氮合酶(NOS)的竞争性内源性抑制物，是其他危重疾病死亡率的独立预测因子，并可损害慢性病的血管功能。宿主和疟疾寄生虫都能产生ADMA。这项疟疾研究的主要新发现是，ADMA是恶性疟疾死亡的独立预测因子，并与受疟疾寄生虫影响的至少两个器官系统--血管衬里和肺部--一氧化氮的可用性降低有关。这项研究有助于了解危重疾病中肺和内皮一氧化氮的调节和可用性，并确定可能导致重症疟疾死亡的致病过程。增加NO可获得性或降低ADMA水平的治疗方法可能有可能成为严重疟疾的辅助治疗。
Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is a predictor of mortality in critical illness. Severe malaria (SM) is associated with decreased NO bioavailability, but the contribution of ADMA to the pathogenesis of impaired NO bioavailability and adverse outcomes in malaria is unknown. In adults with and without falciparum malaria, we tested the hypotheses that plasma ADMA would be: 1) increased in proportion to disease severity, 2) associated with impaired vascular and pulmonary NO bioavailability and 3) independently associated with increased mortality. We assessed plasma dimethylarginines, exhaled NO concentrations and endothelial function in 49 patients with SM, 78 with moderately severe malaria (MSM) and 19 healthy controls (HC). Repeat ADMA and endothelial function measurements were performed in patients with SM. Multivariable regression was used to assess the effect of ADMA on mortality and NO bioavailability. Plasma ADMA was increased in SM patients (0.85 µM; 95% CI 0.74–0.96) compared to those with MSM (0.54 µM; 95%CI 0.5–0.56) and HCs (0.64 µM; 95%CI 0.58–0.70; p<0.001). ADMA was an independent predictor of mortality in SM patients with each micromolar elevation increasing the odds of death 18 fold (95% CI 2.0–181; p = 0.01). ADMA was independently associated with decreased exhaled NO (rs = −0.31) and endothelial function (rs = −0.32) in all malaria patients, and with reduced exhaled NO (rs = −0.72) in those with SM. ADMA is increased in SM and associated with decreased vascular and pulmonary NO bioavailability. Inhibition of NOS by ADMA may contribute to increased mortality in severe malaria. Severe falciparum malaria is associated with impaired microvascular perfusion, lung injury and decreased bioavailability of nitric oxide (NO), but the causes of these processes are not fully understood. Asymmetrical dimethylarginine (ADMA), a competitive endogenous inhibitor of nitric oxide synthase (NOS), is an independent predictor of mortality in other critical illnesses, and can impair vascular function in chronic disease. ADMA can be produced by both the host and malaria parasites. The major novel findings of this study in malaria are that ADMA is an independent predictor of death in falciparum malaria, and is associated with decreased availability of nitric oxide in at least two organ systems affected by malaria parasites, the lining of blood vessels and the lungs. This study contributes to knowledge of regulation and availability of pulmonary and endothelial NO in critical illness and identifies pathogenic processes which may contribute to death in severe malaria. Therapies which increase the availability of NO or which reduce ADMA levels may have potential for adjunctive therapy of severe malaria.
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DOI：
10.1016/j.jchromb.2009.10.035
发表时间：
2010-01-01
影响因子：
3
作者：
Jones, Catherine E.;Darcy, Christabelle J.;McNeil, Yvette R.
通讯作者：
McNeil, Yvette R.
DOI：
10.1164/ajrccm.157.3.9705060
发表时间：
1998-03-01
影响因子：
24.7
作者：
Brett, SJ;Evans, TW
通讯作者：
Evans, TW
DOI：
10.1161/01.atv.0000168414.06853.f0
发表时间：
2005-07-01
影响因子：
8.7
作者：
Kielstein, JT;Bode-Böger, SM;Hoeper, MM
通讯作者：
Hoeper, MM
影响因子：
6.3
作者：
Nijveldt, RJ;Teerlink, T;Van Leeuwen, PAM
通讯作者：
Van Leeuwen, PAM
影响因子：
15.1
作者：
O'Dwyer, Michael J.;Dempsey, Felicity;Ryan, Thomas
通讯作者：
Ryan, Thomas