Therapeutic Value of Fish Oil Rx on SLE and Bone Loss in Mice

鱼油 Rx 对小鼠 SLE 和骨丢失的治疗价值

• 批准号: 8007407
• 负责人: GABRIEL J J FERNANDES
• 金额: $ 32.34万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8007407
• 关键词: Affect; American; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antioxidants; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Bone Density; Caloric Restriction; Cardiovascular Diseases; Cessation of life; Clinical; Clinical Research; Corn Oil; Cyclophosphamide; Development; Diet; Diet therapy; Disease; Dose; Eating; Environmental Risk Factor; Enzymes; Exanthema; FDA approved; Fatty Acids; Female; Fish Oils; Free Radicals; Gene Expression; Genetic Predisposition to Disease; Genetic Risk; Glomerulonephritis; Hemolytic Anemia; Human; Immune response; Immunoglobulin A; Immunoglobulins; Immunosuppressive Agents; Impairment; Inbred MRL lpr Mice; Inflammatory; Interleukin-18; Kidney; Kidney Diseases; Life; Linoleic Acids; Liver; Longevity; Lymphocyte; Maintenance; Measures; Methylprednisolone; Molecular; Mouse Strains; Mus; NF-kappa B; Neuraxis; Omega-3 Fatty Acids; Onset of illness; Osteoporosis; Patients; Peritoneal Macrophages; Pharmaceutical Preparations; Pharmacotherapy; Production; Regimen; Reporting; Research Personnel; Risk; Serositis; Signal Pathway; Spleen; Supplementation; Systemic Lupus Erythematosus; T memory cell; T-Lymphocyte; Therapeutic; Time; Tissues; Transcription Factor AP-1; Woman; aged; base; bone loss; cytokine; feeding; immune function; insight; macrophage; peripheral tolerance; prevent; protective effect

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is an autoimmune disease affecting over 1 million Americans, mostly women, which is influenced by both genetic and environmental risk factors and shortens the life span. Its clinical features include glomerulonephritis, cardiovascular disease (CVD), skin rashes, serositis, hemolytic anemia, impairment of the central nervous system and bone loss. Several animal models are in use to study SLE including NZB x NZW F1 (B/W) and MRL/lpr mice. We have demonstrated that ad libitum (AL) food intake with n-6 fatty acids (corn oil) enriched in 18:2 linoleic acid (LA) promotes rapid development of SLE in both strains of mice including bone loss in MRL/lpr mice. Although feeding AL a regular fish oil containing 22- 30% EPA/DHA (20:5 + 22:6) n-3 fatty acids provides some benefit, calorie restriction (CR) alone significantly delayed the onset of the disease. We recently noted, however, that concentrated fish oil (EPA/DHA 50%) when fed AL protects against kidney disease similar to CR. Concentrated n-3 fatty acid (FA) supplementation was able to inhibit the increase in NF-kB, and co-stimulatory molecules, and increase antioxidant enzymes in target tissues resulting in a decrease of proinflammatory IL-18 cytokine. We now hypothesize that recently available through prescription, OMACOR fish oil (EPA/DHA 90%), to treat hyperglyceridemic patients, will reduce pro-inflammatory cytokines from macrophages and T cells, thereby preventing or delaying the onset of autoimmune disease. The proposed new studies in specific aim 1 is to establish the minimal dose of OMACOR fish oil required to suppress renal disease and prolong maximal lifespan in B/W and MRL/lpr mice; Specific aim 2 is to determine the changes in anti- and pro-inflammatory cytokines, NF-kB expression and other signaling pathways in macrophages and T cells of B/W and MRL/lpr mice fed OMACOR fish oil; Specific aim 3 is to determine the interaction of OMACOR n-3 fatty acids along with immunosuppressive cyclophosphamide and methylprednisolone drug therapy after the onset of SLE in controlling renal disease and bone loss in MRL/lpr mice. These new studies with FDA approved OMACOR n-3 FA will establish its efficacy against renal disease and bone loss alone, or in combination with immunosuppressive drugs. The proposed studies will also help to gain insight to undertake clinical studies to prevent renal and CVD as well as bone loss in SLE patients.

描述（由申请人提供）：系统性红斑狼疮 (SLE) 是一种自身免疫性疾病，影响超过 100 万美国人，其中大多数是女性，该疾病受到遗传和环境风险因素的影响，会缩短寿命。其临床特征包括肾小球肾炎、心血管疾病（CVD）、皮疹、浆膜炎、溶血性贫血、中枢神经系统损伤和骨质流失。多种动物模型用于研究 SLE，包括 NZB x NZW F1 (B/W) 和 MRL/lpr 小鼠。我们已经证明，随意（AL）摄入富含 18:2 亚油酸（LA）的 n-6 脂肪酸（玉米油）可促进两种小鼠品系的 SLE 快速发展，包括 MRL/lpr 小鼠的骨质流失。虽然给 AL 喂食含有 22-30% EPA/DHA (20:5 + 22:6) n-3 脂肪酸的普通鱼油可以带来一些好处，但单独限制热量 (CR) 会显着延迟疾病的发作。然而，我们最近注意到，与 CR 类似，喂食 AL 时浓缩鱼油（EPA/DHA 50%）可以预防肾脏疾病。补充浓缩 n-3 脂肪酸 (FA) 能够抑制 NF-kB 和共刺激分子的增加，并增加靶组织中的抗氧化酶，从而减少促炎性 IL-18 细胞因子。我们现在假设，最近通过处方使用 OMACOR 鱼油（EPA/DHA 90%）来治疗高甘油酯血症患者，将减少巨噬细胞和 T 细胞的促炎细胞因子，从而预防或延缓自身免疫性疾病的发作。拟议的具体目标 1 的新研究是确定 OMACOR 鱼油在 B/W 和 MRL/lpr 小鼠中抑制肾脏疾病和延长最大寿命所需的最小剂量；具体目标2是确定喂食OMACOR鱼油的B/W和MRL/lpr小鼠的巨噬细胞和T细胞中抗炎和促炎细胞因子、NF-kB表达和其他信号通路的变化；具体目标 3 是确定 MRL/lpr 小鼠 SLE 发病后 OMACOR n-3 脂肪酸与免疫抑制环磷酰胺和甲泼尼龙药物治疗在控制肾脏疾病和骨质流失方面的相互作用。这些 FDA 批准的 OMACOR n-3 FA 的新研究将确定其单独或与免疫抑制药物联合使用对肾脏疾病和骨质流失的功效。拟议的研究还将有助于深入开展临床研究，以预防 SLE 患者的肾脏和心血管疾病以及骨质流失。