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

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，影响超过100万美国人，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、浆膜炎、溶血性贫血、中枢神经系统受损和骨质流失。几种动物模型用于研究SLE，包括NZ B 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中SLE的快速发展，包括MRL/lpr小鼠中的骨丢失。虽然给AL喂食含有22- 30%EPA/DHA（20：5 + 22：6）n-3脂肪酸的常规鱼油提供了一些益处，但单独的卡路里限制（CR）显著延迟了疾病的发作。然而，我们最近注意到，当喂食AL时，浓缩鱼油（EPA/DHA 50%）可以防止类似于CR的肾脏疾病。浓缩的n-3脂肪酸（FA）补充能够抑制NF-κ B和共刺激分子的增加，并增加靶组织中的抗氧化酶，导致促炎性IL-18细胞因子的减少。我们现在假设，最近通过处方，OMACOR鱼油（EPA/DHA 90%），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，从而预防或延迟自身免疫性疾病的发作。具体目标1中拟定的新研究是确定抑制B/W和MRL/lpr小鼠肾脏疾病和延长最长寿命所需的OMACOR鱼油的最小剂量;具体目标2是确定喂食OMACOR鱼油的B/W和MRL/lpr小鼠巨噬细胞和T细胞中抗炎和促炎细胞因子、NF-κ B表达和其他信号传导途径的变化;具体目标3是确定SLE发作后OMACOR n-3脂肪酸沿着免疫抑制性环磷酰胺和甲基强的松龙药物治疗在控制MRL/lpr小鼠中的肾病和骨丢失方面的相互作用。FDA批准的OMACOR n-3 FA的这些新研究将确定其单独或与免疫抑制药物联合治疗肾脏疾病和骨丢失的疗效。拟议的研究还将有助于深入了解进行临床研究，以预防SLE患者的肾脏和CVD以及骨丢失。

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.