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）可在保健食品商店中获得，并广泛用作抗氧化剂。 NAC是L-半胱氨酸的乙酰化形式，L-半胱氨酸是谷胱甘肽（GSH）合成的限制因子，由半胱氨酸，谷氨酸和甘氨酸组成的三肽，三肽，它在维持细胞内环境，减少肠内环境，调节跨性别（RORI）的生产（ROCGEN）中，它在维持内细胞环境中起着关键作用。全身性红斑狼疮（SLE）的发病机理（SLE）是一种潜在的致命性病理学自身免疫性疾病，其特征是异常的T细胞活化和死亡，这是依赖于Mitochonochoncondria中ROI和ATP的受控产生的过程。我们发现，狼疮T细胞表现出持久的线粒体超极化（MHP），线粒体生物发生的增加，ROI产生增加以及ATP和GSH的消耗，从而减少了激活诱导的凋亡诱导的凋亡，而相反，相反，相反，相反，它诱发了BINDRICE细胞和刺激性细胞和刺激性的刺激性。 GSH还会在狼疮易发的小鼠和NAC和其他抗氧化剂的淋巴细胞中耗尽，减少了自身抗体的产生，防止肾小球肾炎的发展，并延长了狼疮prone小鼠的存活。 SLE患者的当前治疗是基于使用疗效和严重副作用的泼尼松和免疫抑制剂的使用。在最近的一项欧洲研究中，NAC添加到泼尼松和硫唑嘌呤中，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患者的主要抱怨。 NAC可以在体外和体内有效地提高淋巴细胞的细胞内GSH。因此，这项双盲安慰剂对照剂量比较研究的具体目的将检验以下假说：NAC治疗将导致细胞内GSH的升高并逆转MHP，ATP枯竭，狼疮T细胞的衰减和耐药性对NECROSIOS对NECROSIS的耐药性，从而使B细胞和细胞的活性降低，使B细胞和疾病的活性降低。在特定的目标1下，我们将确定NAC的每日口服剂量，该NAC的耐受性良好，能够在3个月的时间内将SLE患者的T细胞中GSH和MHP的耗竭归一化或调节。在特定的目标2下，我们将确定最佳NAC剂量对疾病活动和泼尼松使用的影响在12个月内对SLE患者的影响。作为临床结果，我们将评估Selena/Sledai和Bilag，肝脏和骨髓功能，整体疲劳和肌肉耐力的狼疮疾病活性。作为免疫学结果，我们将评估细胞内GSH含量，MHP，ATP，Ca2+通量，对坏死的易感性和T细胞的线粒体基因表达信号，B细胞的激活，NO和Interferon-A的产生和Interferon-A由单核细胞和树突状细胞产生。这项研究的结果将确定NAC的给药是否可以恢复或至少可以显着调节T细胞的低gsh和功能障碍，B细胞的激活和树突状细胞的激活，从而改善SLE中的疾病表现。 公共卫生启示：全身性红斑狼疮（SLE）是一种慢性炎症性疾病，经常具有使人衰弱且潜在的威胁生命的后果。 SLE的原因是未知的，目前的疗法缺乏特异性并带有明显的副作用。文献中的现有数据提供了证据，表明在SLE患者的T细胞中耗尽了天然抗氧化剂谷胱甘肽，这可能是通过坏死的T淋巴细胞对促炎细胞死亡的T淋巴细胞倾向的关键因素。作为GSH的先驱的N-乙酰半胱氨酸（NAC）的给药可改善鼠狼疮的临床结果，并限制了在SLE患者中常用的促氧化剂/免疫抑制剂药物的毒性（4）。 NAC在保健食品商店中广泛使用，可以安全地给人类使用大剂量（最多8克/天）（1）。在一项为期一年的研究中，对接受泼尼松和硫唑嘌呤治疗的炎症性肺部疾病患者的添加（1.8G/天）与安慰剂相比，NAC（1.8G/天）降低了疾病的严重程度和药物毒性降低。此外，已经发现口服NAC可以改善肌肉疲劳（5-7），据报道，在53％的SLE患者中，这是最残疾的症状（8）。因此，建立范围在1.8-7.2 g/天之间的剂量良好，能够在狼疮患者中提高细胞内GSH，并确定其在SLE中的免疫学和治疗影响似乎是有道理的。