DLPC TREATMENT OF ALCOHOLIC AND NON ALCOHOLIC FIBROSIS

肝组织(肝硬变)和肝外组织(即 肺部)，导致灾难性的终末期疾病，发病率高， 死亡率。目前，还没有有效的治疗方法。目的 建议的研究是建立二甘油酰磷脂酰胆碱(DLPC) 作为一种有效、安全和化学定义的治疗剂， 它的行动模式，并将其适当使用编成法典。调查员之前 观察到从大豆中提取的多烯基磷脂酰胆碱(PPC) 在非人类灵长类动物中完全防止酒精引起的肝硬变。DLPC是 PPC的主要磷脂种类，根据初步实验， 它大概是它的活性成分，但到目前为止， 纯化的化合物排除了在体内任何可察觉的使用。 然而，价格较低的合成DPLC现在可供 调查员。这种纯制剂将在体内和体外进行测试，以 确定它确实是PPC的活性磷脂物种。 DLPC和PPC抗纤维化作用的程度和机制 在肝纤维化以及CC14或C14诱导的肝硬化中的研究 大鼠体内异源白蛋白。对于肺纤维化，二氧化硅粉尘大鼠 将使用模型。调查将包括对 胶原蛋白合成减少和胶原蛋白增强的相对作用 在预防纤维化方面的分项工作。此外，实验将是 就逆转先前存在的纤维化进行了研究。α-1(I)前胶原 将被确定，胶原蛋白的分解将通过活性来测量 金属蛋白酶1和胶原酶抑制物如组织的(和mRNA) 金属蛋白酶抑制剂(TIMPs)。还将进行研究 在培养的脂肪细胞和/或与Kupffer细胞或 肝细胞。将使用相同的系统来确定DLPC和 PPC影响纤维化细胞因子如转化生长因子-β、肿瘤坏死因子-α和白介素6。 抗氧化应激药物，如S-腺苷蛋氨酸(同) 或者维生素E，可能还有抗细胞因子，将被研究以确定 它们是否增强了DLPC或PPC的有益效果。至 确定开始治疗的最佳时间，将进行评估， 在可获得的、常规获得的临床标本中，诊断价值 用于在非侵入性测试中检测肝硬变前病变，例如 循环金属蛋白酶组织抑制物(TIMP-1)的检测 和前胶原肽(PIIIP)。如果成功，拟议的研究将 将DLPC确立为第一种安全的、化学定义的制剂，能够 防止糖尿病的进展(并可能促进其退化) 肝和肺纤维化。

Excess fibrosis, in both liver (cirrhosis) and extrahepatic tissues (i.e. lungs), leads to devastating end-stage diseases with high morbidity and mortality. Presently, no effective treatment is available. The purpose of the proposed research is to establish dilinoleoylphosphatidylcholine (DLPC) as an effective, safe, and chemically defined therapeutic agent, clarify its mode of action and codify its proper use. The investigator 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, based on preliminary experiments, it is presumably its active component, but this far the high cost of the purified compound precluded any appreciable in vivo use. However, less expensive synthetic DPLC is now available to the investigator. This pure preparation will be tested in vivo and in vitro to firmly establish that it is indeed the active phospholipid species of PPC. The extent and mechanisms of the antifibrotic effect of DLPC and PPC will be studied in liver fibrosis, as well as cirrhosis induced by CC14 or heterologous albumin in rats. For pulmonary fibrosis, a silica dust rat model will be used. The investigations will include the assessment of the relative role of decreased collagen synthesis and enhances collagen breakdown in the prevention of fibrosis. In addition, experiments will be conducted on the reversal of preexisting fibrosis. alpha 1 (I) procollagen will be determined and collagen breakdown will be measured by the activity (and mRNA) of metalloproteinase 1 and collagenase inhibitors such as tissue inhibitors of metalloproteinases (TIMPs). Studies will also be carried out in cultured lipocytes and/or in lipocytes co-cultured with Kupffer cells or hepatocytes. The same systems will be used to ascertain whether DLPC and PPC affect fibrogenic cytokines such as TGF-Beta, TNF-alpha and IL-6. Agents which oppose oxidative stress, such as S-adenosylmethionine (SAMe) or vitamin E, and possibly anticytokines, will be studied to determine whether they potentiate the beneficial effects of DLPC or PPC. To ascertain the optimal time for initiation of treatment, one will evaluate, in available, routinely obtained clinical specimens, the diagnostic value for detecting precirrhotic lesions in non-invasive tests, such as measurements of circulating tissue inhibitor of metalloproteinases (TIMP-1) and procollagen peptides (PIIIP). If successful, the proposed studies will establish DLPC as the first safe and chemically defined agent capable of preventing the progression (and possibly of promoting the regression) of hepatic and pulmonary fibrosis.