摘要
肝脏纤维化是威胁人类健康的重大疾病。长期饮酒、脂肪肝和慢性病毒性肝炎感染是可能引起肝脏纤维化的三个重要原因。肝脏发生纤维化是许多慢性肝病发展的终末状态,严重的肝脏纤维化将导致肝硬化甚至肝癌(hepatocellular carcinoma, HCC)的发生。肝脏纤维化过程中有许多细胞参与,包括肝脏实质细胞与非实质细胞。其中最受关注的效应细胞是肝脏星形细胞(hepatic stellate cell, HSC),HSC活化后分泌大量的胶原,导致细胞外基质(extracellular matrix, ECM)的大量累积。近年也有研究发现,肝实质细胞也参与了肝脏纤维化。同时,众所周知肝脏具有天然免疫的优势状态,这些在肝脏中大量存在的天然免疫细胞或多或少影响了肝脏纤维化的发展。
我国拥有大量的乙肝(Hepatitis B virus, HBV)携带者,乙肝病毒感染是导致患者发生肝脏纤维化的重要原因。乙肝感染如何加速肝脏纤维化,肝脏中的免疫细胞如何参与其中尚无定论,其中一个重要原因是缺少可以利用的小鼠模型。在本文研究中,我们对C57BL/6鼠和HBV转基因(HBV-tg)鼠长期用肝脏毒物四氯化碳(carbon tetrachloride,CCl4)诱导肝脏纤维化,对肝脏损伤、病理学和纤维化相关分子进行检测,在机制研究中采用细胞群体的比例和数目分析、细胞清除、纯化、转输、HSC与NKT细胞共培养、分离肝实质细胞进行原代培养等方法。通过上述研究手段,我们取得的主要结果是:
1、HBV-tg鼠可以自发肝脏纤维化
通过检测肝脏损伤(alanine aminotransferase ,ALT,病理HE染色),我们发现六个月大的HBV-tg鼠肝损伤明显比相同年龄的对照鼠C57BL/6严重。对肝脏切片的天狼猩红(Sirius Red)染色和纤维化相关分子的荧光定量PCR检测,发现六个月大的HBV-tg鼠与C57BL/6鼠相比明显自发肝脏纤维化。
2、HBV-tg鼠对CCl4长期诱导的肝脏纤维化更加敏感
每周两次注射CCl4连续注射2周-14周诱导C57BL/6鼠和HBV-tg鼠产生肝脏纤维化。发现HBV-tg鼠的肝脏纤维化更加严重。我们首次发现,HBV-tg鼠可以作为很好的模拟人的乙肝携带者发展为肝脏纤维化的小鼠模型。
3、HBV-tg鼠NKT细胞通过活化HSC促进了肝脏纤维化
研究发现,给Rag1-/-鼠转输来自HBV-tg鼠的淋巴细胞可以引起Rag1-/-鼠肝脏纤维化,而转输来自C57BL/6鼠的淋巴细胞则不可以。进一步研究发现,在急性或慢性CCl4诱导下,HBV-tg鼠的肝脏NK细胞和NKT细胞比例和数目均比C57BL/6鼠多。通过细胞清除、转输等实验发现,HBV-tg鼠的肝脏NKT细胞对HSC活化具有促进作用。同时NKT细胞也促进了纤维化相关分子表达,从而加重了HBV-tg鼠的肝脏纤维化。
4、NKT细胞通过分泌细胞因子促进HSC的活化
NKT细胞怎样活化HSC?我们发现与C57BL/6鼠相比,HBV-tg鼠在CCl_4刺激下肝脏NKT细胞总数增多,同时分泌细胞因子IFN-γ,IL-4和IL-13的NKT细胞数目增多。将HBV-tg鼠通过流式分选出的肝脏NKT细胞,与通过肝脏灌流分离出来的HSC共培养,发现NKT细胞可以活化HSC。如果在共培养体系中加入抗IL-4和IL-13的中和抗体,这种活化作用会消失;如果加入抗IFN-γ的中和抗体没有这种作用。说明NKT细胞通过分泌Th2类细胞因子(eg,IL-4,IL-13)活化HSC。
5、HBV-tg鼠的肝实质细胞可以自发上皮间质转变(epithelial-mesenchyma-transition,EMT)
HBV-tg鼠中除了NKT细胞对肝脏纤维化具有促进作用,我们发现其肝实质细胞也发挥了促进作用。来自六个月大的C57BL/6鼠和HBV-tg鼠的肝实质细胞通过肝脏灌流分离出来体外培养,可以明显看出来自HBV-tg鼠的肝实质细胞比来自C57BL/6鼠的肝实质细胞表现出更显著的间质细胞表型。经过定量PCR检测EMT的标志分子波形蛋白(vimentin),发现其在HBV-tg鼠的肝实质细胞中表达上调,更加证明HBV-tg鼠的肝实质细胞可以自发EMT。对两种鼠分离得到的肝实质细胞进行纤维化相关分子检测,发现这些分子在六个月大的HBV-tg鼠中表达增高,表明HBV-tg鼠肝实质细胞发生EMT对肝脏纤维化具有促进作用。
6、HBV-tg鼠的肝实质细胞在CCl_4诱导纤维化过程中通过发生EMT促进纤维化的发生
对CCl_4诱导肝脏纤维化的HBV-tg鼠和C57BL/6鼠原代分离肝实质细胞进行体外培养,在不同的时间点进行拍照比较,可以看出来自HBV-tg鼠的肝实质细胞具有更加典型的成纤维细胞表型,进一步通过定量PCR检测vimentin,HBV-tg鼠的肝实质细胞表达vimentin增加,说明HBV-tg鼠的肝实质细胞在诱导肝脏纤维化过程中更容易发生EMT。对纤维化相关分子检测,也发现在某些时间点这些分子表达上调。这个结果说明在CCl_4诱导肝脏纤维化过程中,肝实质细胞也起到促进作用。
7、NK细胞具有抑制HBV-tg鼠EMT的作用
我们发现对HBV-tg鼠注射CCl_4 24小时,肝脏EMT标志分子vimentin表达会增高。通过细胞清除实验发现NK细胞对EMT具有一定的抑制作用。推测NK细胞可能通过作用在CCl_4诱导下肝实质细胞表达上调的DR5发挥抑制作用。
8、HBV-tg鼠发生EMT对乙肝诱发肝癌具有促进作用
我们发现HBV-tg鼠的肝实质细胞容易发生EMT。最新的研究显示,EMT对癌症发生具有促进作用。同时我们发现HBV-tg鼠晚期会自发肝脏肿瘤;通过每周两次CCl_4注射连续诱导14周的HBV-tg鼠全部发生肝脏肿瘤。所以我们提出HBV-tg鼠也是一种研究乙肝导致肝癌的很好模型。
结论:HBV-tg鼠是研究乙肝携带加速肝脏纤维化的重要小鼠模型。HBV-tg鼠的免疫细胞对肝脏纤维化具有促进作用,其中肝脏NKT细胞主要通过分泌细胞因子活化HSC。另一方面,HBV-tg鼠的肝实质细胞通过发生EMT参与肝脏纤维化,并对肝癌发生具有促进作用。
Liver fibrosis is huge threaten to human health. Long term alcohol drinking, fatty liver and chronic virus hepatitis infection are the three major causes of liver fibrosis. Liver fibrosis is a common end for many chronic liver diseases. Serious liver fibrosis could lead to cirrhosis or even hepatocellular carcinoma (HCC). There are many kinds of cell participate in liver fibrosis, including parenchyma and non-parenchyma cells. Among which the most significant cell is hepatic stellate cell (HSC). Upon activation, HSC secrete a lot of collagen, inducing extracellular matrix (ECM) deposition. Recent studies suggested that the hepatocyte also has a role in liver fibrosis. At the same time, liver is predominant for the innate immunity, the innate cells in the liver could affect the progress of liver fibrosis.
These are many Chinese hepatitis B virus (HBV) carriers, which is the main causes for later liver fibrosis. How HBV infection accelerates liver fibrosis and the immune cells function are not completed studied. One of the most important reasons is the lack of suitable mice model. In this study, we compared liver fibrosis after the long term hepatotoxin carbon tetrachloride (CCl_4) administration in C57BL/6 mice and HBV-tg mice. We tested the liver injury, pathological changes and fibrosis related molecules. To find the mechanism, we used cell counting and ratio analysis, cell depletion, purification, adoptive transfer, co-culture of HSC and NKT cells, isolate and culture primary hepatocyte etc. Through the above methods, we have these results:
1. Spontaneous liver fibrosis in HBV-tg mice
We found the six month old HBV-tg mice had spontaneous liver injury compared with C57BL/6 mice by detecting alanine aminotransferase(ALT)and pathology. The six month old HBV-tg mice also had much more liver fibrosis than C57BL/6 mice by liver Sirius red staining and qPCR of fibrosis related genes.
2. HBV-tg mice are oversensitive to CCl_4-induced liver fibrosis
C57BL/6 and HBV-tg mice were injected CCl_4 twice a week and lasted from 2 to 14 weeks. We found much more liver fibrosis in HBV-tg mice than C57BL/6 mice. For the first time, we suggest HBV-tg mice for a good mice model to study HBV related liver fibrosis.
3. NKT cell activate HSC and aggravate liver fibrosis in HBV-tg mice
Experiments showed that Rag1-/- mice adoptively transferred lymphocytes from HBV-tg mice could induce liver fibrosis but not the cells from C57BL/6 mice. Further studies showed the percentage and number of liver NK and NKT cells are much more in HBV-tg mice than C57BL/6 mice after CCl_4 injection. We found in HBV-tg mice NKT cells could activate HSC by using cell depletion and adoptive transfer experiments. And NKT cell could also up-regulated fibrosis related genes, thus increasing liver fibrosis in HBV-tg mice.
4. NKT cells activate HSC through secreting of cytokines
How NKT cells activate HSC? We found NKT cell number increased in HBV-tg mice than C57BL/6 mice after CCl_4 injection. The number of NKT cell secreting IFN-γ, IL-4 and IL-13 were also more in HBV-tg mice. NKT cell could activate HSC in an in vitro co-culture of sorted liver NKT cells and perfused liver HSC. If we added neutralizing cytokine antibodies against IL-4 or IL-13, the activation was disappeared but not the antibody against IFN-γ. These results suggested NKT cell activate HSC by the Th2 cytokines (eg, IL-4, IL-13).
5. Hepatocyte from HBV-tg mice has spontaneous epithelial-mesenchyma-transition (EMT).
Besides NKT cell accelerating liver fibrosis, we also found the hepatocyte promoted liver fibrosis in HBV-tg mice. When cultured and compared the hepatocyte from six months of age C57BL/6 mice and HBV-tg mice, we found more mesenchyma cell phenotype from HBV-tg mice than C57BL/6 mice. The EMT marker vimentin also increased in the hepatocyte from HBV-tg mice than C57BL/6 mice by qPCR, which is a solid evidence for the EMT in HBV-tg mice. We also found the fibrosis related genes up regulated in hepatocyte from six month old HBV-tg mice than that of C57BL/6 mice, which demonstrated that the EMT from HBV-tg mice hepatocyte could contribute to liver fibrosis.
6. The hepatocyte from CCl_4 induced liver fibrosis has EMT and contributes to liver fibrosis
The hepatocyte was perfused and cultured from CCl_4 induced liver fibrosis of C57BL/6 mice and HBV-tg mice, and was visualized at different time points. The hepatocyte from HBV-tg mice showed more fibroblast like phenotype. The EMT marker vimentin was increased suggested the more EMT in hepatocyte of HBV-tg mice during CCl_4 induced liver fibrosis. The fibrosis related genes were also increased more in HBV-tg mice than C57BL/6 mice at some of the time points. These results showed the hepatocyte also contribute to CCl_4 induce liver fibrosis.
7. NK cells inhibit EMT in HBV-tg mice
We found EMT marker vimentin increased in HBV-tg mice after CCl_4 injection for 24 hours. NK cells could inhibit EMT by cell depletion experiment. We hypothesis that NK cells could inhibit hepatocyte EMT through the DR5 up-regulated in CCl_4 injected hepatocyte.
8. EMT in HBV-tg mice contribute to HBV induced HCC
The above results suggested there is more EMT in HBV-tg mice. Recent studies showed EMT could accelerate the carcinoma. We found the old HBV-tg mice could spontaneously develop liver tumor and two times a week CCl_4 injection for 14 weeks could induce liver tumor from all of the HBV-tg mice. So we suggested HBV-tg mice as a good animal model for study HBV induced carcinoma.
Conclusion: HBV-tg mice is an important mice model for study HBV related liver fibrosis. The immune cells could accelerate liver fibrosis, especially liver NKT cells activate HSC through secreting of cytokines. On the other hand, the hepatocyte from HBV-tg mice could undergo EMT and participate in liver fibrosis, which is a contribution for HCC.
引文
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