Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, UCD, Sacramento, California, USA.
VA Northern California Health Care System (VANCHCS), Mather, California, USA.
JCI Insight. 2020 Jul 9;5(13):137777. doi: 10.1172/jci.insight.137777.
BACKGROUNDDysregulation of l-arginine metabolism has been proposed to occur in patients with severe asthma. The effects of l-arginine supplementation on l-arginine metabolite profiles in these patients are unknown. We hypothesized that individuals with severe asthma with low fractional exhaled nitric oxide (FeNO) would have fewer exacerbations with the addition of l-arginine to their standard asthma medications compared with placebo and would demonstrate the greatest changes in metabolite profiles.METHODSParticipants were enrolled in a single-center, crossover, double-blind l-arginine intervention trial at UCD. Subjects received placebo or l-arginine, dosed orally at 0.05 mg/kg (ideal body weight) twice daily. The primary end point was moderate asthma exacerbations. Longitudinal plasma metabolite levels were measured using mass spectrometry. A linear mixed-effect model with subject-specific intercepts was used for testing treatment effects.RESULTSA cohort of 50 subjects was included in the final analysis. l-Arginine did not significantly decrease asthma exacerbations in the overall cohort. Higher citrulline levels and a lower arginine availability index (AAI) were associated with higher FeNO (P = 0.005 and P = 2.51 × 10-9, respectively). Higher AAI was associated with lower exacerbation events. The eicosanoid prostaglandin H2 (PGH2) and Nα-acetyl-l-arginine were found to be good predictors for differentiating clinical responders and nonresponders.CONCLUSIONSThere was no statistically significant decrease in asthma exacerbations in the overall cohort with l-arginine intervention. PGH2, Nα-acetyl-l-arginine, and the AAI could serve as predictive biomarkers in future clinical trials that intervene in the arginine metabolome.TRIAL REGISTRATIONClinicalTrials.gov NCT01841281.FUNDINGThis study was supported by NIH grants R01HL105573, DK097154, UL1 TR001861, and K08HL114882. Metabolomics analysis was supported in part by a grant from the University of California Tobacco-Related Disease Research Program program (TRDRP).
据报道，严重哮喘患者的 l-精氨酸代谢失调。然而，l-精氨酸补充对这些患者的 l-精氨酸代谢产物谱的影响尚不清楚。我们假设，与安慰剂相比，加入 l-精氨酸会降低低呼出气一氧化氮（FeNO）的严重哮喘患者的哮喘加重次数，并表现出代谢产物谱的最大变化。
参与者在 UCD 参加了一项单中心、交叉、双盲 l-精氨酸干预试验。受试者接受安慰剂或 l-精氨酸，以 0.05mg/kg（理想体重）的剂量口服，每日两次。主要终点是中度哮喘加重。使用质谱法测量纵向血浆代谢物水平。采用具有受试者特异性截距的线性混合效应模型进行治疗效果检验。
最终分析纳入了 50 名受试者的队列。总体队列中，l-精氨酸并未显著降低哮喘加重。较高的瓜氨酸水平和较低的精氨酸可用性指数（AAI）与较高的 FeNO 相关（P=0.005 和 P=2.51×10-9，分别）。较高的 AAI 与较低的加重事件相关。发现前列腺素 H2（PGH2）和 Nα-乙酰-l-精氨酸等二十烷酸是区分临床应答者和非应答者的良好预测因子。
总体队列中，l-精氨酸干预并未显著降低哮喘加重。PGH2、Nα-乙酰-l-精氨酸和 AAI 可作为未来干预精氨酸代谢组学的临床试验的预测生物标志物。
ClinicalTrials.gov NCT01841281。
本研究得到 NIH 拨款 R01HL105573、DK097154、UL1 TR001861 和 K08HL114882 的支持。代谢组学分析部分得到加利福尼亚大学烟草相关疾病研究计划（TRDRP）的资助。
