Hepatology：控制调节性T细胞有望阻断脂肪肝恶化进程
单纯性脂肪肝一般较为稳定，可是一旦转变为脂肪性肝炎，发生肝纤维化、肝硬化的几率将大大增加。一项中美科学家的最新合作研究发现：在这个转变过程中，一种称为调节性T细胞的免疫细胞可能起到至关重要的作用。
近年来，肥胖、糖尿病、高酯血症、酗酒等各种原因导致的脂肪肝人群数量不断增加，且逐渐成为发达国家和发展中国家慢性肝病的第一、第二位病因。国际肝病研究领域权威学术杂志《肝脏病学》（Hepatology）本月刊登了我国和美国医学家合作的最新发现，这是此研究领域第一篇报道脂肪性肝炎与调节性T细胞之间关系的论文。
课题负责人之一、上海市消化疾病研究所副所长、上海市脂肪性肝病诊治研究中心副主任、仁济医院消化内科马雄副教授介绍说，在临床上，将非酒精性脂肪性肝病分为单纯性脂肪肝、脂肪性肝炎和脂肪性肝炎相关肝硬化。单纯性脂肪肝相对稳定，其中１０－２０％会进展为脂肪性肝炎，脂肪性肝炎患者中将有２５－３５％发生肝纤维化、肝硬化。曾有学者预言，脂肪性肝炎在未来的２０至３０年中将成为肝功能衰竭的主要病因。因此，如何在单纯性脂肪肝进展为脂肪性肝炎的过程中实施“半路拦截”已成为临床医学的研究热点。
单纯性脂肪肝进展为脂肪性肝炎的机制尚未被完全阐明，包括氧应激和肝内免疫调节紊乱等多种因素被认为与此过程有关。调节性T细胞（CD4+CD25+Foxp3+ T细胞）参与肝脏免疫调节。马雄领衔的研究小组与美国约翰·霍普金斯（Johns Hopkins）大学医学院李治平博士为代表的研究小组合作，重点观察了调节性T细胞在脂肪性肝炎发病过程中所起的作用。
研究发现，经高脂饮食８周后发生显著脂肪肝的小鼠，肝内调节性T细胞数量下降至正常饮食小鼠的１／２左右。科研人员还首次发现，调节性T细胞在体外经历氧化氢模拟的氧应激状态就会显得“弱不禁风”，凋亡指数明显上升。进一步研究则发现导致这种现象的原因可能是调节性T细胞内部一种抗凋亡基因bcl-2表达水平较低。相反，如果在肝脏遭受氧应激之前给予一定的抗氧化剂，那么肝内调节性T细胞凋亡将减少，并能减轻脂肪肝内炎症。
马雄表示：调节性T细胞可能是阻断单纯性脂肪肝转变为脂肪性肝炎的最后一道“防线”。调控肝脏内调节性T细胞的数量、或者调控细胞凋亡特性很可能将发展为治疗脂肪性肝炎的新途径。
据悉，关于非酒精性脂肪性肝病的系列研究自２００６年起已连续得到我国国家自然基金项目的资助，此次发现正是其中的一项主要研究成果。如何通过调控调节性T细胞凋亡特性进一步提高细胞抗凋亡能力、提高脂肪肝治疗效果的研究课题，即将作为２００８年国家自然基金项目启动。（新华网）
原始出处:
Hepatology
Volume 46, Issue 5 , Pages 1519 - 1529
Received: 24 January 2007; Accepted: 17 May 2007
Liver Injury/Regeneration
Xiong Ma 1 4, Jing Hua 1 4, Abdiaziz R. Mohamood 2, Abdel Rahmin A. Hamad 2, Rajani Ravi 3, Zhiping Li 1 4 * 
1Department of Gastroenterology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Digestive Disease, Shanghai, China
2Department of Pathology, Johns Hopkins University, Baltimore, MD
3Department of Oncology, Johns Hopkins University, Baltimore, MD
4Department of Medicine, Johns Hopkins University, Baltimore, MD
email: Zhiping Li (zhipingli@jhmi.edu)
*Correspondence to Zhiping Li, Johns Hopkins University, 912 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205
Potential conflict of interest: Nothing to report.fax: 410-955-9677.
Funded by:
American Gastroenterological Association Fellowship/Faculty Transition Award American Gastroenterological Association Roche Research Scholar Award in Liver Diseases Shanghai Leading Academic Discipline Project; Grant Number: Y0205 National Natural Science Foundation of China; Grant Number: 30571730 Hopkins Digestive Disease Basic Research Development Center; Grant Number: R24DK064388-04
| Abstract |
In nonalcoholic fatty liver disease, the pathogenesis of progression from simple steatosis to steatohepatitis has not been fully clarified. Many factors, including oxidative stress and hepatic immune regulation, contribute to the inflammation in steatosis. Because regulatory T cells (Tregs) are important components of immune regulation, we have now investigated their role in the pathogenesis of nonalcoholic steatohepatitis. Wild-type C57BL/6 mice were fed a high-fat (HF) diet to induce steatosis, and the hepatic lymphocyte population was analyzed by flow cytometry. HF-induced steatosis was associated with the depletion of hepatic Tregs and led to up-regulation of the inflammatory tumor necrosis factor- signaling pathway. When challenged by exogenous lipopolysaccharide, the HF-fed mice developed liver inflammation. In contrast, the adoptive transfer of Tregs decreased inflammation in HF-fed mice. In comparison with effector T cells, Tregs had a lower expression of bcl-2 and, therefore, increased susceptibility to oxidative stress-induced apoptosis. The treatment of mice with the antioxidant Mn(III)tetrakis(4-benzoic acid)porphyrin chloride reduced Treg apoptosis, increased the number of hepatic Tregs, and decreased hepatic inflammation in HF-fed mice. Conclusion: Our results indicate that increased oxidative stress in a fatty liver causes the apoptosis of Tregs, reduces the number of hepatic Tregs, and leads to a lowered suppression of inflammatory responses. This scenario is likely one of the pathogenetic mechanisms that facilitate the transformation of simple steatosis into steatohepatitis when a fatty liver is exposed to second or third hits. (HEPATOLOGY 2007.) |
相关报道:
脂肪肝的研究进展
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