DLPC Treatment of Alcoholic and Non-Alcoholic Fibrosis

超出所提供的空间。过度的肝纤维化导致终末期肝硬化，具有高发病率和死亡率。目前尚无有效的治疗方法。拟议研究的目的是确定二亚油酰磷脂酰胆碱（DLPC）作为一种有效，安全和化学定义的治疗剂，阐明其作用方式并规范其正确使用。我们以前观察到，从大豆中提取的多烯磷脂酰胆碱（PPC）完全防止非人灵长类动物酒精诱导的肝硬化。DLPC是PPC的主要磷脂种类，并且我们先前的一些体外和当前的体内研究表明它是其活性成分。我们现在计划扩展这些实验，包括DLPC对枯否细胞中氧化应激的影响的体外研究，可能涉及细胞因子作为这些细胞、肝细胞和星状细胞之间的介质。此外，经济和足够纯的DLPC现在已经变得可用，使我们能够进行体内实验，以确定PPC在脂肪变性和纤维化方面的有益作用是否可以用DLPC再现。还将研究预防细胞凋亡的机制。此外，我们将评估DLPC是否可以逆转既存的纤维化，无论是在大鼠中由CCH或异源白蛋白或在我们的狒狒模型中由酒精产生。目前，PPC治疗用途的速率限制因素之一是剂量（每日3片，3.3 gm片剂）。理论上，如果DLPC被证实是活性化合物，它可以以更高的剂量给药，至少是PPC的两倍。因此，我们将测试使用更高剂量的DLPC是否可以实现比PPC更大的对肝纤维化的作用。我们还将尝试通过将DLPC与无毒的活化氨基酸S-腺苷硫代磷酸结合来增强DLPC的作用，因为这两种化合物作用于有效防御乙醇引起的氧化应激以及维持细胞膜的正常结构和功能所需的不同但相互依赖的步骤。如果所提出的方法是成功的，它可以提供计划多中心，安慰剂对照临床试验，以确定SAMe + DLPC联合治疗预防酒精性肝病及其治疗在人类中的有效性。性能站点==================================

EXCEED THE SPACE PROVIDED. Excess liver fibrosis leads to end-stage cirrhosis with high morbidity and mortality. Presently, no effective treatment is available. The objectives of the proposed research are to establish dilinoleoylphosphatidylcholine (DLPC) as an effective, safe, and chemically defined therapeutic agent, clarify its mode of action and codify its proper use. We previously observed that polyenylphosphatidylcholine (PPC) extracted from soybeans fully prevents alcohol-induced cirrhosis in non-human primates. DLPC is the main phospholipid species of PPC and some of our prior hi vitro and current in vivo studies suggest that it is its active component. We now plan to extend these experiments, including in vitro studies of the effect of DLPC on oxidative stress in Kupffer cells, with possible involvement of cytokines as mediators between these cells, hepatocytes and stellate cells. Furthermore, economical and sufficiently pure DLPC has now become available to allow us to carry out experiments in vivo to determine whether the beneficial effects of PPC in terms of steatosis and fibrosis can be reproduced with DLPC. The mechanisms of the prevention of apoptosis will also be investigated. In addition, we will assess whether DLPC can reverse preexisting fibrosis, either produced by CCH or heterologous albumin in the rat or by alcohol in our baboon model. Currently one of the rate limiting factors of the therapeutic use of PPC is the dose (3 daily 3.3 gm tablets). Theoretically, if DLPC is confirmed to be the active compound, it could be given at a much higher dose, at least twice that of PPC. Therefore, we will test whether an effect on liver fibrosis greater than that of PPC could be achieved with a higher dose of DLPC. We will also attempt to boost the effect of DLPC by combining it with the non-toxic activated ammo-acid S-adenosyhnethionine, since both compounds act on different, but interdependent, steps required for an effective defense against the oxidative stress caused by ethanol and also for the maintenance of the normal structure and function of cellular membranes. If the proposed approach is successful, it may provide the preclinical studies needed to plan a multicenter, placebo controlled clinical trial to define the effectiveness of the SAMe + DLPC combination for the prevention of alcoholic liver disease and its treatment in man. PERFORMANCE SITE ========================================Section End===========================================