Transglutaminase type II plays a protective role in hepatic injury
Transglutaminase type II plays a protective role in hepatic injury
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DOI：
10.1016/s0002-9440(10)63925-9
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发表时间：
2003-04-01
影响因子：
6
通讯作者：
Piacentini, M
中科院分区：
文献类型：
--
作者：
Nardacci, R;Iacono, OL;Piacentini, M
“组织”转谷氨酰胺酶（TG2）基因的上调已被证明发生在各种病理中，并可导致严重的肝损伤；然而，其在肝损伤发生中的作用尚未明确。为了解决这个问题，我们使用了两种实验设置：四氯化碳（CCl4）诱导野生型和TG2敲除小鼠的肝损伤；以及从一大群丙型肝炎病毒（HCV）感染患者中获得的肝活检。缺乏TG2的小鼠无法清除因长期接触CC14（5周）而形成的肝坏死组织，其中60%在治疗结束前死亡。相比之下，野生型小鼠在中毒后能够恢复。 CCl4 处理的 TG2 缺失小鼠表现出肝小叶结构紊乱以及细胞外基质 (ECM) 成分和炎症细胞的逐渐积累，而在对照动物的肝脏中未观察到这一点。与这种保护作用一致，我们观察到，与未感染的对照相比，HCV 感染者 (METAVIR = F2) 在肝纤维化的初始阶段，TG2 水平要高得多（高达 15 倍），在未感染的对照中，酶蛋白定位于面向汇管周围浸润的肝细胞中。相比之下，酶水平在晚期阶段下降（METAVIR = F3 和 174），并且其定位仅限于 ECM。我们的数据表明，TG2 通过促进组织稳定性和修复在肝损伤中发挥保护作用。
The up-regulation of "tissue" transglutaminase (TG2) gene has been shown to occur in various pathologies and can lead to severe liver injury; however, its role in the onset of liver damage has not yet been clarified. To address this issue, we have used two experimental settings: carbon tetrachloride (CCl4)-induced liver injury in wild-type and TG2 knockout mice; and liver biopsies obtained from a large cohort of hepatitis C virus (HCV)-infected patients. Mice lacking TG2 failed to clear the hepatic necrotic tissue formed in response to prolonged CC14 exposure (5 weeks) and 60% of them died before the end of the treatment. By contrast, wild-type mice were able to recover after the toxic insult. CCl4-treated TG2 null mice showed a derangement of the hepatic lobular architecture and a progressive accumulation of extracellular matrix (ECM) components and inflammatory cells which were not observed in the liver of control animals. Consistent with this protective role, we observed that TG2 levels were much higher (up to 15-fold) during the initial stages of liver fibrosis in HCV-infected individuals (METAVIR = F2) compared with uninfected controls, in which the enzyme protein localized in the hepatocytes facing the periportal infiltrate. By contrast, the enzyme levels decreased in the advanced stages (METAVIR = F3 and 174) and their localization was limited to the ECM. Our data demonstrate that TG2 plays a protective role in the liver injury by favoring tissue stability and repair.