DLPC TREATMENT OF ALCOHOLIC AND NON ALCOHOLIC FIBROSIS

肝脏（肝硬化）和肝外组织（即肝硬化）中的过度纤维化 肺），导致具有高发病率的毁灭性终末期疾病， mortality. 目前尚无有效的治疗方法。 的目的 拟建立二亚油酰磷脂酰胆碱（DLPC） 作为一种有效、安全和化学定义明确的治疗药物，请澄清 并将其正确使用编成法典。 调查员此前 观察到从大豆中提取的多烯磷脂酰胆碱（PPC） 完全预防非人类灵长类动物酒精诱导的肝硬化。 DLPC是 PPC的主要磷脂种类，并且基于初步实验， 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任何明显的体内应用。 然而，较便宜的合成DPLC现在可用于 调查员 将在体内和体外对该纯制剂进行测试， 它确实是PPC的活性磷脂物质。 DLPC和PPC的抗肝纤维化作用的程度和机制将 在肝纤维化以及由CC 14诱导的肝硬化中进行研究， 大鼠异源白蛋白。 对于肺纤维化，一只硅尘鼠 模型将被使用。 调查将包括评估 减少胶原蛋白合成和增强胶原蛋白的相对作用 预防纤维化的方法。 此外，实验将 进行逆转先前存在的纤维化。 α 1（I）原胶原 并通过活性测定胶原蛋白分解 (and金属蛋白酶1和胶原酶抑制剂，如组织 金属蛋白酶抑制剂（TIMPs）。 还将开展研究， 在培养的脂肪细胞和/或与枯否细胞共培养的脂肪细胞中，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TGF-β、TNF-α和IL-6。 抗氧化应激的药物，如S-腺苷甲硫氨酸（SAMe） 或维生素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。 到 确定开始治疗的最佳时间，将评估， 在可用的常规获得的临床标本中， 用于在非侵入性测试中检测前列腺病变，例如 金属蛋白酶循环组织抑制剂（TIMP-1）的测量 和前胶原肽（PIIIP）。 如果成功，拟议的研究将 将DLPC确立为第一种安全且化学成分明确的药物， 防止进展（并可能促进退化） 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.