Department of Internal Medicine, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
BMC Gastroenterol. 2011 Oct 6;11:109. doi: 10.1186/1471-230X-11-109.
Hematopoietic stem cell transplantation is increasingly performed for hematologic diseases. As a major side effect, acute graft versus host disease (GvHD) with serious gastrointestinal symptoms including diarrhea, gastrointestinal bleeding and high mortality can be observed. Because surveillance and biopsies of human gastrointestinal GvHD are difficult to perform, rare information of the alterations of the gastrointestinal barrier exists resulting in a need for systematic animal models.
To investigate the effects of GvHD on the intestinal barrier of the small intestine we utilized an established acute semi allogenic GvHD in C57BL/6 and B6D2F1 mice.
By assessing the differential uptake of lactulose and mannitol in the jejunum, we observed an increased paracellular permeability as a likely mechanism for disturbed intestinal barrier function. Electron microscopy, immunohistochemistry and PCR analysis indicated profound changes of the tight-junction complex, characterized by downregulation of the tight junction protein occludin without any changes in ZO-1. Furthermore TNF-α expression was significantly upregulated.
This analysis in a murine model of GvHD of the small intestine demonstrates serious impairment of intestinal barrier function in the jejunum, with an increased permeability and morphological changes through downregulation and localization shift of the tight junction protein occludin.
造血干细胞移植越来越多地用于治疗血液疾病。作为一种主要的副作用，急性移植物抗宿主病（GvHD）可出现严重的胃肠道症状，包括腹泻、胃肠道出血和高死亡率。由于对人类胃肠道 GvHD 的监测和活检较为困难，因此对于胃肠道屏障的改变，我们了解甚少，这就需要建立系统性的动物模型。
为了研究 GvHD 对小肠肠屏障的影响，我们利用 C57BL/6 和 B6D2F1 小鼠建立了一种已确立的急性半同种异体 GvHD 模型。
通过评估乳果糖和甘露醇在空肠中的差异摄取，我们观察到细胞旁通透性增加，这可能是肠屏障功能紊乱的机制之一。电镜、免疫组织化学和 PCR 分析表明，紧密连接复合物发生了深刻的变化，紧密连接蛋白 occludin 的下调而 ZO-1 没有变化。此外，TNF-α 的表达显著上调。
本研究通过对 GvHD 小鼠小肠模型的分析，证明了空肠中肠屏障功能严重受损，通过紧密连接蛋白 occludin 的下调和定位改变导致通透性增加和形态学变化。
