Liver Fibrosis, Inflammation & Oxidative Stress Markers

肝纤维化、炎症

• 批准号: 6952293
• 负责人: CHARLES S LIEBER
• 金额: $ 12.3万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-27 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6952293
• 关键词: alcoholic liver cirrhosis; biomarker; biopsy; clinical research; collagenase; cytochrome P450; enzyme activity; histopathology; human tissue; inflammation; keratin; laminin; malonaldehyde; oxidative stress; peroxidation; procollagen; tenascin; tissue inhibitor of metalloproteinases; transforming growth factors; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Liver cirrhosis is a major cause of mortality in alcoholics. Recent experimental pathophysiotogic studies suggest several therapeutic approaches but their clinical verification is hampered by the requirement of liver biopsies to establish the stage of the disease, the therapeutic indications and documentation of outcome. Various circulating markers have been proposed as substitute for biopsies. The specific aim of the present study is to validate these markers, taking advantage of over 2,000 sequential liver biopsies and corresponding blood samples collected in 789 alcoholics studied for up to 6 years in VA Cooperative Study 391, including monthly measurements of carbohydrate deficient transferrin to substantiate the self-reported alcohol consumption. This recently conducted trial assessed the effects of polyunsaturated phosphatidylcholine (PPC), a soybean extract, on alcoholic liver disease, with superimposed hepatitis C in 1/3 of the patients. The liver pathology varied from fatty liver to perivenular and septal fibrosis and cirrhosis, with variable degrees of inflammation. Correlation of these lesions with the following proposed circulating markers of fibrosis will be determined: laminin, tenascin, procollagen type tll and collagen IV and VI. The activity of enzymes that degrade fibrotic tissue, such as metalloproteinases and their inhibitors, will also be measured. In addition, hepatic parameters with the potential to prognosticate progression of liver disorders, such as cytokeratins, will be assessed. Cytokines that affect fibrogenesis as well as inflammation, e.g. TNFalpha and TGF-beta will also be evaluated. One major pathogenic factor is oxidative stress resulting from free radicals generated by alcohol-induced cytochrome P450 (CYP2E1). Accordingly, the correlation of markers of oxidative stress (4-hydroxynonenal, F2-isoprostanes and malondialdehyde) with the degree of CYP2E1 induction in the liver will be evaluated. Once validated, these markers could serve in future studies to detect subjects vulnerable to drugs activated to toxins by CYP2E1. As controls for the markers of a specific lesion (such as cirrhosis), we will use the values of the same markers in patients without the specific liver disease. In conclusion, an available bank of sequential liver biopsies and monthly blood samples, collected in association with detailed clinical information, offers a unique opportunity to establish which circulating markers can serve as partial substitute for liver biopsies, thereby optimizing the diagnosis, prevention and treatment of alcoholic liver injury.

描述（由申请人提供）： 肝硬化是酗酒者死亡率的主要原因。最近的实验性病理学研究研究表明了几种治疗方法，但由于肝脏活检的要求，它们的临床验证受到阻碍，以建立该疾病的阶段，治疗迹象和预后文献。已经提出了各种循环标记作为活检的替代品。本研究的具体目的是验证这些标记物，利用2,000多个顺序肝活检和在VA合作研究391中研究长达6年的789种酗酒者中收集的相应的血液样本，包括每月测量碳水​​化合物缺陷的转铁蛋白，以证实自我报复的酒精消耗。最近进行的试验评估了一种大豆提取物多不饱和磷脂酰胆碱（PPC）对酒精性肝病的影响，并在1/3患者中叠加丙型肝炎。肝脏病理学因脂肪肝而异，炎症和肝硬化，炎症程度变化。这些病变与以下提出的纤维化循环标记的相关性将确定：层粘连蛋白，田酸胶质素，procollagen型TLL和胶原蛋白IV和VI。还将测量降解纤维化组织（例如金属蛋白酶及其抑制剂）的酶的活性。此外，将评估具有预后肝脏疾病进展（例如细胞角蛋白）潜力的肝参数。影响纤维发生和炎症的细胞因子，例如TNFALPHA和TGF-BETA也将进行评估。一种主要的致病因素是由酒精诱导的细胞色素P450产生的自由基引起的氧化应激（CYP2E1）。因此，将评估氧化应激标记（4-羟基诺纳尔，F2-异丙烷和丙二醛）与肝脏中CYP2E1诱导程度的相关性。一旦得到验证，这些标记物可以在以后的研究中使用，以检测受到CYP2E1激活毒素药物的受试者。作为特定病变标记的对照（例如肝硬化），我们将使用没有特定肝病的患者中相同标记的值。 总之，与详细的临床信息相关的一组可用的顺序肝活检和每月的血液样本提供了一个独特的机会，可以确定哪种循环标记可以用作肝脏活检的部分替代品，从而优化了酒精肝损伤的诊断，预防和治疗。