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

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种影响超过100万美国人的自身免疫性疾病，主要是女性，受遗传和环境风险因素的影响，缩短寿命。其临床特征包括肾小球肾炎、心血管疾病（CVD）、皮疹、浆液炎、溶血性贫血、中枢神经系统损伤和骨质流失。一些动物模型被用于研究SLE，包括NZB x NZW F1 （B/W）和MRL/lpr小鼠。我们已经证明，任意（AL）食物摄入富含18:2亚油酸（LA）的n-6脂肪酸（玉米油）可促进两种小鼠SLE的快速发展，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脂肪酸的普通鱼油会带来一些好处，但仅仅限制热量摄入（CR）就能显著延缓疾病的发作。然而，我们最近注意到，用AL喂养浓缩鱼油（EPA/DHA 50%）对肾脏疾病的保护作用与CR相似。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，导致促炎IL-18细胞因子的减少。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生。在特定目标1中提出的新研究是确定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；特异性目的2：测定OMACOR鱼油喂养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、NF-kB表达等信号通路的变化；特异性目的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小鼠肾脏疾病和骨质流失的相互作用。这些与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治疗肾脏疾病和骨质流失的疗效。拟议的研究还将有助于开展临床研究，以预防SLE患者的肾脏和心血管疾病以及骨质流失。

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.