5-脱氧5-甲基硫代腺苷对极限肝切除术后残留肝细胞的保护作用及机制

The inhibited proliferation of hepatocytes was regarded as the key cause of liver failure following extended liver resection and the key cause of small for size syndrome (SFSS) following living donor liver transplantation. However, in our previous work, we have found that using somatostatin can significantly inhibit liver regeneration but decrease the injury of hepatocytes and improve liver function and survival of rats following 90% liver resection, which suggested us that it was progressive injury of hepatocytes instead of the inhibited hepatocytes proliferation playing the key function of resulting in liver failure after extended hepatedtomy. Metabonomic suggested that the major alteration of metabolites after somatostatin administration were focus on methionine cycle. Moreover we speculated that 5- deoxy 5-methylthioadenosine (MTA) have the protective function to the remnant liver through data analysis, which was confirmed by 90% hepatectomized rats model. Building on that earlier research, we will detect and compare the content of MTA between patients with SFSS and patients without SFSS. Then we will validate that whether MTA have the function of protecting hepatocytes from injury using extended hepatectomy models of small Bama pig and rat, and detect the mechanism. Finally, we will try using microfluidic chip technology to validate the protective function of MTA on maintaining the membrane fluidity and cytoskeleton.

肝再生障碍一直被认为是肝切除术后肝功能衰竭和活体肝移植术后小肝综合征（SFSS）发生的最主要原因，然而在前期工作中，我们发现对90%肝切除大鼠注射生长抑素后，在肝再生被抑制的同时，大鼠肝功能却明显好转，肝细胞损伤坏死程度也减轻，表明肝细胞再生障碍并不是导致肝功能衰竭的关键因素，残存肝细胞的进行性损伤坏死才是最主要原因。代谢组学研究结果提示生长抑素的使用主要引起了残存肝组织蛋氨酸循环的改变，我们通过数据分析，并于大鼠90%肝切除模型中初步验证了5-脱氧5-甲基硫代腺苷（MTA）对肝功能的保护作用。本项目拟在前期研究的基础上，首先检测临床活体肝移植SFSS受者和非SFSS受者肝组织中MTA含量的差异；进而在小型巴马猪及大鼠极限肝切除模型中检测MTA是否有改善肝脏组织学结构及其功能的作用，并研究其机制；最后拟通过微流控芯片技术在细胞层面验证MTA对细胞膜的流动性及细胞骨架的保护作用。

肝再生障碍一直被认为是肝切除术后肝功能衰竭和活体肝移植术后小肝综合征（SFSS）发生的最主要原因，然而在前期工作中，我们发现对90%肝切除大鼠注射生长抑素后，在肝再生被抑制的同时，大鼠肝功能却明显好转，肝细胞损伤坏死程度也减轻，表明肝细胞再生障碍并不是导致肝功能衰竭的关键因素，残存肝细胞的进行性损伤坏死才是最主要原因。代谢组学研究结果提示生长抑素的使用主要引起了残存肝组织蛋氨酸循环的改变，我们通过数据分析，并于大鼠90%肝切除模型中初步验证了5-脱氧5-甲基硫代腺苷（MTA）对肝功能的保护作用。后期研究中我们发现MTA主要通过保护肝细胞避免肝血窦剪切力的损伤，同时降低炎性反应来避免肝细胞的二次损伤来维持肝细胞大量丢失后（肝切除、药物性肝损伤、活体肝移植受体）的肝脏功能，避免肝衰的发生。该研究成果为肝功能衰竭的机制提供了新思路，也为肝衰竭的治疗提供了实验依据及有力支撑。通过上述研究，课题组共发表了SCI全文论著2篇。因此，本项目在执行年度内严格执行申请标书的研究计划，研究结果和结论与申请书中预期一致。

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