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.

描述（由申请人提供）：N-乙酰半胱氨酸（NAC）可在健康食品商店购买，并广泛用作抗氧化剂。NAC是L-半胱氨酸的乙酰化形式，是谷胱甘肽（GSH）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，其在维持还原性细胞内环境、调节线粒体跨膜电位和产生活性氧中间体（ROI）中起关键作用。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，其发病机制的特征在于异常的T细胞活化和死亡，这些过程关键地依赖于线粒体中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）、线粒体生物发生增加、ROI产生增加以及ATP和GSH的耗竭，这减少了活化诱导的凋亡，反而使T细胞易于坏死，从而活化B细胞和树突状细胞并刺激SLE中的炎症。GSH在狼疮易感小鼠的淋巴细胞中也被耗尽，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期。目前对SLE患者的治疗是基于使用泼尼松和免疫抑制剂，其疗效有限且副作用严重。在最近的一项欧洲研究中，NAC加用泼尼松和硫唑嘌呤，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内GSH含量。因此，这项双盲安慰剂对照剂量比较研究的具体目的是检验以下假设：NAC治疗将导致细胞内GSH升高，逆转MHP、ATP耗竭和狼疮T细胞坏死倾向，从而减少SLE患者B细胞和树突状细胞的活化、自身抗体的产生和疾病活动。根据具体目标1，我们将确定NAC的每日口服剂量，该剂量耐受性良好，并且能够在3个月的时间内使SLE患者的T细胞中GSH和MHP的消耗正常化或缓和。在具体目标2下，我们将确定最佳NAC剂量对SLE患者12个月内疾病活动和泼尼松使用的影响。作为临床结局，我们将通过SELENA/SLEDAI和BILAG、肝脏和骨髓功能、总体疲劳和肌肉耐力评估狼疮疾病活动性。作为免疫学结果，我们将评估细胞内GSH含量、MHP、ATP、Ca 2+流动、T细胞的坏死倾向和线粒体基因表达特征、B细胞的活化以及单核细胞和树突状细胞的NO和干扰素-α的产生。本研究的结果将确定给予NAC是否可以恢复或至少显著调节低GSH和T细胞功能障碍、B细胞和树突状细胞的活化，从而改善SLE的疾病表现。 公共卫生部门：系统性红斑狼疮（SLE）是一种慢性炎症性疾病，通常具有衰弱和潜在的危及生命的后果。SLE的病因尚不清楚，目前的治疗缺乏特异性，并有明显的副作用。文献中的现有数据提供证据表明，天然抗氧化剂谷胱甘肽在SLE患者的T细胞中耗尽，这可能是T淋巴细胞异常激活和倾向于通过坏死促炎细胞死亡的关键因素。N-乙酰半胱氨酸（NAC）作为GSH的前体，可改善小鼠狼疮的临床结局，并限制SLE患者常用的促氧化剂/免疫抑制剂药物（4）的毒性。NAC在健康食品商店中广泛使用，大剂量（高达8 g/天）可以安全地给予人类（1）。在一项对接受泼尼松和硫唑嘌呤治疗的炎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（1.8 g/天）可减轻疾病严重程度并降低药物毒性。此外，已发现口服NAC可改善肌肉疲劳（5-7），据报道，肌肉疲劳是53% SLE患者的最大致残症状（8）。因此，建立耐受性良好且能够提高狼疮患者细胞内GSH的1.8-7.2 g/天剂量范围并确定其在SLE中的免疫学和治疗影响似乎是合理的。