N-acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial.
N-acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial.
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DOI：
10.1002/art.34502
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发表时间：
2012-09
影响因子：
--
通讯作者：
Perl, Andras
中科院分区：
文献类型：
--
作者：
Lai, Zhi-Wei;Hanczko, Robert;Bonilla, Eduardo;Caza, Tiffany N.;Clair, Brandon;Bartos, Adam;Miklossy, Gabriella;Jimah, John;Doherty, Edward;Tily, Hajra;Francis, Lisa;Garcia, Ricardo;Dawood, Maha;Yu, Jianghong;Ramos, Irene;Coman, Ioana;Faraone, Stephen V.;Phillips, Paul E.;Perl, Andras
系统性红斑狼疮（SLE）患者表现出t细胞功能障碍，这可以通过线粒体跨膜电位（Δψm）和谷胱甘肽调节雷帕霉素（mTOR）的哺乳动物靶点。因此，在这项随机双盲安慰剂对照研究中，研究了谷胱甘肽前体n -乙酰半胱氨酸（NAC）的安全性、耐受性和有效性。36例SLE患者每日服用安慰剂或1.2 g、2.4 g或4.8 g NAC。治疗前、治疗中、治疗后3个月分别采用BILAG、SLEDAI和疲劳评定量表（FAS）每月评估疾病活动度。通过流式细胞术检测Δψm和mTOR。42名与患者年龄、性别和种族相匹配的健康受试者作为对照进行研究。所有接受2.4 g/天NAC的患者都能耐受，而接受4.8 g/天NAC的患者中有33%出现可逆性恶心。安慰剂或1.2 g/d NAC对疾病活动没有影响。综合考虑，2.4 g和4.8 g NAC降低：1)1个月（p=0.0007）， 2个月（p=0.0009）， 3个月（p=0.0030）和4个月（p=0.0046）后SLEDAI；2) 1个月（p=0.029）和3个月（p=0.0009）后BILAG；3)术后2个月（p=0.002）和3个月（p=0.004） FAS。NAC在所有T细胞中升高Δψm (p=0.0001)，显著降低mTOR活性（p=0.0001），增强细胞凋亡（p=0.0004），逆转CD4−/CD8−T细胞的扩增（1.35±0.12倍；p=0.008），刺激CD4+/CD25+ T细胞中Foxp3表达（p=0.045），降低抗dna产生（p=0.049）。这项初步研究表明NAC通过阻断T淋巴细胞中的mTOR安全地改善狼疮疾病的活动性。
Systemic lupus erythematosus (SLE) patients exhibit T-cell dysfunction which can be regulated through the mitochondrial transmembrane potential (Δψm) and mammalian target of rapamycin (mTOR) by glutathione. Therefore, the safety, tolerance, and efficacy of glutathione-precursor N-acetylcysteine (NAC) were examined in this randomized double-blind placebo-controlled study. 36 SLE patients received daily placebo or 1.2 g, 2.4 g or 4.8 g of NAC. Disease activity was monthly evaluated by BILAG, SLEDAI and fatigue assessment scale (FAS) before, during, and after 3-month treatment. Δψm and mTOR were assessed by flow cytometry. 42 healthy subjects matched for patients’ age, gender, and ethnicity were studied as controls. NAC was tolerated by all patients up to 2.4 g/day while 33% of those receiving 4.8 g/day had reversible nausea. Placebo or 1.2 g/day NAC did not influence disease activity. Considered together, 2.4 g and 4.8 g NAC reduced: 1) SLEDAI after 1 month (p=0.0007), 2 months (p=0.0009), 3 months (p=0.0030) and 4 months (p=0.0046); 2) BILAG after 1 month (p=0.029) and 3 months (p=0.0009); and 3) FAS after 2 months (p=0.002) and 3 months (p=0.004). NAC increased Δψm (p=0.0001) in all T cells, it profoundly reduced mTOR activity (p=0.0001), enhanced apoptosis (p=0.0004) and reversed expansion of CD4−/CD8− T cells (1.35 ± 0.12-fold; p=0.008), stimulated Foxp3 expression in CD4+/CD25+ T cells (p=0.045), and reduced anti-DNA production (p=0.049). This pilot study suggests that NAC safely improves lupus disease activity by blocking mTOR in T lymphocytes.
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