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: 7537225
• 负责人: GABRIEL J J FERNANDES
• 金额: $ 32.59万
• 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/7537225
• 关键词: Affect; American; Animal Model; Animals; 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; Genetic Predisposition to Disease; 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; Omacor; Omega-3 Fatty Acids; Onset of illness; Osteoporosis; Patients; Peripheral; Peritoneal Macrophages; Pharmaceutical Preparations; Pharmacotherapy; Production; Reporting; Research Personnel; Risk; Serositis; Signal Pathway; Spleen; Supplementation; Systemic Lupus Erythematosus; T memory cell; T-Lymphocyte; Therapeutic; Time; Tissues; Transcription Factor AP-1; Treatment Protocols; Woman; aged; base; bone loss; cytokine; feeding; immune function; insight; macrophage; 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(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100多万美国人，其中大部分是女性，它受到遗传和环境风险因素的影响，并缩短寿命。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、中枢神经系统损害和骨质丢失。一些动物模型被用于研究SLE，包括NZB×NZW F1(B/W)和MRL/LPR小鼠。我们已经证明，自由进食富含18：2亚油酸(LA)的n-6脂肪酸(玉米油)可促进两种品系小鼠SLE的快速发展，包括MRL/LPR小鼠的骨质丢失。虽然喂食含有22-30%EPA/DHA(20：5+22：6)n-3脂肪酸的普通鱼油对AL有一定的益处，但仅限制卡路里(CR)可显著延缓疾病的发生。然而，我们最近注意到，当喂食AL时，浓缩鱼油(EPA/DHA 50%)可预防类似于CR的肾脏疾病。高浓度n-3脂肪酸(FA)能抑制靶组织中核因子-kB和共刺激分子的增加，增加靶组织中的抗氧化酶，导致促炎细胞因子IL-18的减少。我们现在假设，最近通过处方获得的OMACOR鱼油(EPA/DHA 90%)用于治疗高甘油三酯血症患者，将减少巨噬细胞和T细胞的促炎细胞因子，从而防止或推迟自身免疫性疾病的发生。拟议的针对特定目的1的新研究旨在确定抑制B/W和MRL/LPR小鼠肾脏疾病和延长其最长寿命所需的最低剂量OMACOR鱼油；特定目的2是确定服用OMACOR鱼油的B/W和MRL/LPR小鼠巨噬细胞和T细胞中抗炎和促炎细胞因子、核因子-kB表达和其他信号通路的变化；特定目的3是确定OMACOR n-3脂肪酸与免疫抑制环磷酰胺和甲基强的松龙药物治疗在SLE发病后控制MRL/LPR小鼠肾脏疾病和骨丢失中的相互作用。FDA批准的OMACOR n-3 FA的这些新研究将确定其单独治疗肾脏疾病和骨丢失的疗效，或与免疫抑制药物联合使用。拟议的研究还将有助于深入了解开展预防SLE患者肾脏和心血管疾病以及骨丢失的临床研究。