Treatment of SLE with N-acetylcysteine

N-乙酰半胱氨酸治疗 SLE

• 批准号: 8098843
• 负责人: Andras Perl
• 金额: $ 38.47万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8098843
• 关键词: 8-hydroxy-2' -deoxyguanosine; Acetylcysteine; Adverse effects; Adverse event; Anions; Antibodies; Antigen-Antibody Complex; Antioxidants; Apoptosis; Autoantibodies; Autoimmune Diseases; Azathioprine; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; Binding; Biogenesis; Bone Marrow; CD28 gene; CD3 Antigens; Cell Death; Cell Extracts; Cessation of life; Chronic; Clinical; Clinical Trials Data Monitoring Committees; Complex; Cysteine; DNA; Data; Dendritic Cells; Detection; Development; Disease; Dose; Double-Blind Method; Drug toxicity; Environment; Etiology; European; Exhibits; Fluorescence; Functional disorder; Gene Expression Profile; Glomerulonephritis; Glutamic Acid; Glutathione; Glycine; Hamman-Rich syndrome; Health Food; High Pressure Liquid Chromatography; Human; Immunoglobulin D; Immunosuppressive Agents; In Vitro; Inflammation; Inflammatory; Interferons; Kidney Diseases; Life; Literature; Liver; Liver Failure; Lung diseases; Lupus; Lymphocyte; Lymphopenia; MS4A1 gene; Maintenance; Measures; Membrane Potentials; Memory B-Lymphocyte; Mitochondria; Monitor; Multiple Abnormalities; Mus; Muscle Fatigue; Necrosis; Nucleosides; Oral; Outcome; Outer Mitochondrial Membrane; Oxidative Stress; Participant; Pathogenesis; Patients; Peripheral; Pharmaceutical Preparations; Phase; Placebo Control; Placebos; Plasmablast; Play; Predisposition; Prednisone; Process; Production; Public Health; Randomized; Reactive Oxygen Species; Reduced Glutathione; Regulation; Reporting; Respiratory physiology; SOD2 gene; Severity of illness; Sirolimus; Specificity; Symptoms; Systemic Lupus Erythematosus; T-Cell Activation; T-Lymphocyte; Tacrolimus Binding Protein 1A; Tacrolimus Binding Proteins; Testing; Therapeutic; Toxic effect; Transaldolase; arm; base; human TLR7 protein; improved; in vivo; lupus prone mice; mTOR protein; mitochondrial dysfunction; monochlorobimane; monocyte; peripheral blood; prevent; primary outcome; reactive oxygen intermediate; receptor

DESCRIPTION (provided by applicant): N-acetylcysteine (NAC) is available in health food stores and widely used as an antioxidant. NAC is the acetylated form of L-cysteine, a rate-limiting factor in synthesis of glutathione (GSH), tripeptide made up of cysteine, glutamic acid, and glycine, which plays key roles in maintenance of a reducing intracellular environment, regulation of the mitochondrial transmembrane potential, and production of reactive oxygen intermediates (ROI). The pathogenesis of systemic lupus erythematosus (SLE), a potentially fatal autoimmune disease of unknown etiology, is characterized by abnormal T-cell activation and death, processes which are crucially dependent on the controlled production of ROI and of ATP in the mitochondria. We found that lupus T cells exhibit persistent mitochondrial hyperpolarization (MHP), increased mitochondrial biogenesis, and increased ROI production as well as depletion of ATP and GSH which decrease activation-induced apoptosis and instead predispose T cells for necrosis, thus activating B cells and dendritic cells and stimulating inflammation in SLE. GSH is also depleted in lymphocytes of lupus-prone mice and NAC and other antioxidants reduce autoantibody production, prevent the development of glomerulonephritis, and prolong the survival of lupus-prone mice. Current therapy of SLE patients is based on the use of prednisone and immunosuppressants which have limited efficacy and serious side-effects. In a recent European study, NAC, added to prednisone and azathioprine, resulted in clinical improvement of patients with idiopathic pulmonary fibrosis. NAC has been shown to improve fatigue and muscle endurance, a major complaint in patients with SLE. NAC can effectively raise intracellular GSH of lymphocytes both in vitro and in vivo. Therefore, the specific aims of this double-blind placebo-controlled dose-comparison study will test the hypothesis that treatment with NAC will result in elevation of intracellular GSH and reverse the MHP, ATP depletion and predisposition of lupus T cells to necrosis and, consequently, diminish activation of B cells and dendritic cells, production of auto-antibodies, and disease activity in patients with SLE. Under Specific Aim 1, we will determine the daily oral dose of NAC that is well tolerated and capable of normalizing or moderating the depletion of GSH and MHP in T cells of patients with SLE over a period of 3 months. Under Specific Aim 2, we will determine the impact of an optimal NAC dose on disease activity and prednisone use in patients with SLE over a period of 12 months. As clinical outcomes, we will assess lupus disease activity by SELENA/SLEDAI and BILAG, liver and bone marrow function, overall fatigue, and muscle endurance. As immunological outcomes, we will assess intracellular GSH content, MHP, ATP, Ca2+ fluxing, predisposition to necrosis and mitochondrial gene expression signature of T cells, activation of B cells, and production of NO and interferon-a by monocytes and dendritic cells. The results of this study will establish whether administration of NAC can restore or at least significantly modulate low GSH and dysfunction of T cells, activation of B cells and dendritic cells, and thus improve the disease manifestations in SLE. PUBLIC HEALTH REVELANCE: Systemic lupus erythematosus (SLE) is a chronic inflammatory disease which often has debilitating and potentially life-threatening consequences. The cause of SLE is unknown and current therapies lack specificity and carry significant side effects. Existing data in the literature provide evidence that a natural antioxidant, glutathione, is depleted in T cells of patients with SLE which may be a key factor underlying abnormal activation and predisposition of T lymphocytes to pro-inflammatory cell death via necrosis. Administration of N-acetylcysteine (NAC), that serves as a precursor of GSH, improves the clinical outcome of murine lupus, and limits the toxicity of pro-oxidant/immunosuppressant medications (4) commonly used in patients with SLE. NAC is widely available in health food stores and large doses (up to 8 g/day) can be safely administered to humans(1). In a one-year study of patients with inflammatory lung disease treated with prednisone and azathioprine, addition of NAC (1.8g/day) diminished disease severity and reduced drug toxicity in comparison to placebo. Moreover, oral NAC has been found to improve muscle fatigue (5-7) which is reported to be the most disabling symptom in 53% of patients with SLE (8). Thus, establishing a dose ranging between 1.8-7.2 g/day that is well-tolerated and capable of raising intracellular GSH in lupus patients and determining its immunological and therapeutic impact in SLE appear to be well justified.

说明(申请人提供)：N-乙酰半胱氨酸(NAC)在健康食品店可买到，并被广泛用作抗氧化剂。NAC是L-半胱氨酸的乙酰化形式，是谷胱甘肽合成的限速因子，谷胱甘肽是由半胱氨酸、谷氨酸和甘氨酸组成的三肽，在维持还原的细胞内环境、调节线粒体跨膜电位和产生活性氧中间体(ROI)中发挥关键作用。系统性红斑狼疮(SLE)是一种病因不明的潜在致命性自身免疫性疾病，其发病机制以T细胞异常激活和死亡为特征，这一过程关键依赖于线粒体中ROI和ATP的受控产生。我们发现，狼疮T细胞表现出持续的线粒体超极化(MHP)，增加了线粒体的生物合成，增加了ROI的产生，并耗尽了ATP和GSH，从而减少了激活诱导的凋亡，反而使T细胞易于坏死，从而激活了B细胞和树突状细胞，刺激了SLE的炎症。狼疮易感小鼠的淋巴细胞中GSH也被耗尽，NAC和其他抗氧化剂减少自身抗体的产生，防止肾小球肾炎的发展，并延长狼疮易感小鼠的生存时间。目前系统性红斑狼疮的治疗主要以强的松和免疫抑制剂为主，疗效有限，副作用严重。在最近的一项欧洲研究中，NAC与泼尼松和硫唑嘌呤一起使用，导致特发性肺纤维化患者的临床改善。NAC已被证明可以改善疲劳和肌肉耐力，这是SLE患者的主要症状。NAC在体内外均能有效提高淋巴细胞胞内GSH水平。因此，这项双盲安慰剂对照剂量对照研究的具体目标将检验这样的假设，即NAC治疗将导致细胞内GSH升高，并逆转狼疮T细胞的MHP、ATP耗竭和易坏死性，从而减少B细胞和树突状细胞的激活，自身抗体的产生，以及SLE患者的疾病活动性。在具体目标1下，我们将确定耐受性良好的NAC的每日剂量，该剂量能够在3个月的时间内正常或缓和SLE患者T细胞中GSH和MHP的消耗。在具体目标2下，我们将确定最佳NAC剂量对SLE患者在12个月期间疾病活动性和泼尼松使用的影响。作为临床结果，我们将通过赛琳娜/SLEDAI和BILAG来评估狼疮疾病的活动性，肝脏和骨髓功能，总体疲劳和肌肉耐力。作为免疫学结果，我们将评估细胞内GSH含量、MHP、ATP、钙离子流动、T细胞的坏死倾向和线粒体基因表达特征、B细胞的激活以及单核细胞和树突状细胞产生NO和干扰素-α。这项研究的结果将确定NAC能否恢复或至少显著调节T细胞的低GSH和功能障碍、B细胞和树突状细胞的激活，从而改善SLE的疾病表现。 公共卫生：系统性红斑狼疮(SLE)是一种慢性炎症性疾病，通常会导致虚弱并可能危及生命的后果。系统性红斑狼疮的病因尚不清楚，目前的治疗方法缺乏特异性，并带有显著的副作用。现有文献提供的证据表明，SLE患者T细胞中一种天然抗氧化剂谷胱甘肽被耗尽，这可能是导致T淋巴细胞异常激活和易于通过坏死导致促炎性细胞死亡的关键因素。给予N-乙酰半胱氨酸(NAC)，作为GSH的前体，可以改善小鼠狼疮的临床结果，并限制SLE患者常用的促氧化剂/免疫抑制药物的毒性。NAC在保健食品店广泛可用，大剂量(每天高达8g)可安全地用于人类(1)。在一项对使用泼尼松和硫唑嘌呤治疗的炎症性肺病患者进行的为期一年的研究中，与安慰剂相比，添加NAC(1.8g/天)可以减轻疾病的严重性，并降低药物毒性。此外，口服NAC被发现可以改善肌肉疲劳(5-7)，据报道，这是53%的SLE患者最令人无力的症状(8)。因此，建立一个耐受性良好且能够提高狼疮患者细胞内GSH水平的剂量范围在1.8-7.2g/天，并确定其对SLE的免疫学和治疗效果似乎是合理的。