胰高血糖素样肽-2减少肝移植后肠源性感染的机制研究

Liver transplantation (LT) may eventually become the definitive therapeutic modality for irreversible liver failureand hepatocellular carcinoma (HCC). However, infection (especially enterogenic infection) following orthotopic liver transplantation limits the success and clinical Prognosis of LT. Glucagon-like peptide-2 (GLP-2) is a newly found enteric epithelium growth factor and has a specific growth promotion effect on intestinal tract. It is the product of glucagongenes of a kind of endocrine cells called L cells. GLP-2 could promote repair and healing of damaged intestinal tissues caused by several chronic bowel diseases and intestinal mueosa injuries. Therefore, GLP-2 had value in clinical applications of reducing gut injuries caused by possible kinds of diseases. Our previous studies demonstrated the protection of GLP-2 in small intestine with ischemia-reperfusion injury in mice. The applicant finished grants from the National Nature Science Foundation of China( No. 30801127) and observed that GLP-2 supplementation could promote recovery of structure and function of intestine following orthotopic transplantation. In this study the applicant tries to prove that GLP-2 can stimulate intestinal mucosal growth and inhibit its apoptosis, promote recovery of structure and function of intestine and reduce intestinal bacterial infections following orthotopic liver transplantation. This study will investigate the protective mechanisms of GLP-2 on the primay cultivated intestinal epithelial cells. Our exploratory research observed that the effect of GLP-2 might be mediated though GLP-2 receptors and GLP-2 supplementation could promote and recovery of structure of intestine following orthotopic liver transplantation. This ground-breaking work will, we believe, dramatically promote the current level of understanding of the molecular determinants of GLP-2 and the patients of LT can get benefits from this research results.

肝移植术后的肠源性感染是阻碍受体及移植肝存活率提高的重要因素。生长因子胰高血糖素样肽-2(GLP-2)可特异促肠道生长且作用更强。课题组前期实验已证明GLP-2可减轻肠缺血/再灌注损伤(Dig Dis Sci2005)，申请者刚完成的国科金（30801127）证实GLP-2促进移植小肠功能恢复(NDT2009,JGH2008,Transpl P 2008)。在上述研究基础上，申请者提出在肝移植后应用GLP-2，应有利于肝移植后损伤小肠粘膜的再生和修复，减少肠源性感染，同时应用我们建立的"肠上皮原代培养模型"检测GLP-2作用后细胞凋亡、增殖途径中关键信号表达变化，可阐明其的作用机理。探索实验表明GLP-2通过特异受体发挥作用(中国应用生理学杂志2010)，GLP-2确能改善肝移植后损伤小肠的结构(JGH2012)。预期的研究结果，可为防治肝移植后肠源性感染的难题提供新的可行方法和理论支持。

肝移植过程中无肝期由于门静脉阻断会造成小肠淤血，供肝移植成功后开放血流后再灌注过程会造成小肠出现淤血再灌注损伤，导致小肠出现氧化应激、凋亡等一系列损伤。GLP-2是新近发现的肠上皮生长因子，与已发现的生长因子不同，GLP-2的作用具有肠道特异性，且促生长作用更强。前期的研究结果已证明GLP-2可减轻小肠缺血/再灌注损伤（Dig Dis Sci 2005）并有利于肠粘膜的再生和修复，进而促进肠功能的恢复。故作者通过阻断门静脉再开放模拟肝移植小肠淤血再灌注过程，并通过术前、术后应用GLP-2，同时通过形态学及超微结构观察小肠在不同组间的变化，检测GLP-2作用后细胞凋亡、增殖途径中关键信号表达的变化，可阐明GLP-2的作用机理。预期的研究结果，可加深对GLP-2肠道保护机制的认知水平，并促进肝移植患者术后小肠功能恢复，为防止患者术后并发症提供新的防治手段。