Division of Gastroenterology, University Hospital, Leuven, Belgium.
Inflamm Bowel Dis. 2010 Aug;16(8):1322-31. doi: 10.1002/ibd.21211.
Epithelial barrier disturbance is thought to contribute to the pathogenesis of inflammatory bowel diseases; however, it remains unclear whether it is a primary defect participating to the onset of inflammation or only a consequence of sustained inflammation.
A time course study of epithelial barrier functions and immune mediators was performed in the CD4(+)CD45RB(hi) T cell transfer model of colitis using Ussing chambers.
In nonreconstituted severe combined immunodeficiency (SCID) mice, no epithelial dysfunction was observed. However, after transfer of CD4(+)CD45RB(hi) T cells or total CD4(+) T cells, colon of SCID mice displayed a decreased epithelial resistance, even before overt microscopic inflammation had occurred. Sustained colitis of CD4(+)CD45RB(hi) T cell reconstituted mice was also associated with enhanced subepithelial resistance, enhanced paracellular permeability, and decreased net ion transport. All these reflect a disturbance of barrier function and may contribute to diarrhea. Epithelial resistance was positively correlated with interleukin 10 (IL-10) and transforming growth factor beta (TGF-beta) levels and net ion transport inversely correlated with tumor necrosis factor alpha (TNF-alpha) levels, pointing to the protective effect of IL-10 and TGF-beta and to a damaging effect of TNF-alpha. Indomethacin, a nonselective COX inhibitor, decreased epithelial resistance independent of T cells and inflammation, but its effect was more pronounced in inflamed colon.
Induction of colitis by transfer of CD4(+)CD45RB(hi) T cells in SCID mice leads to changes in the colonic epithelium before colitis develops. Decreased epithelium resistance might contribute to the development of colitis; however, it is not sufficient to lead to chronic inflammation.
上皮屏障功能紊乱被认为与炎症性肠病的发病机制有关；然而，尚不清楚它是参与炎症发生的主要缺陷，还是持续炎症的结果。
使用 Ussing 室在 CD4+CD45RB（高）T 细胞转移结肠炎模型中进行了上皮屏障功能和免疫介质的时程研究。
在未重建的严重联合免疫缺陷（SCID）小鼠中，未观察到上皮功能障碍。然而，在转移 CD4+CD45RB（高）T 细胞或总 CD4+T 细胞后，SCID 小鼠的结肠显示出上皮电阻降低，甚至在出现明显的显微镜下炎症之前。CD4+CD45RB（高）T 细胞重建小鼠的持续性结肠炎也与增强的黏膜下阻力、增强的细胞旁通透性和减少的净离子转运相关。所有这些都反映了屏障功能的紊乱，并可能导致腹泻。上皮电阻与白细胞介素 10（IL-10）和转化生长因子-β（TGF-β）水平呈正相关，而净离子转运与肿瘤坏死因子-α（TNF-α）水平呈负相关，这表明 IL-10 和 TGF-β 具有保护作用，而 TNF-α 具有破坏作用。非选择性 COX 抑制剂吲哚美辛可独立于 T 细胞和炎症降低上皮电阻，但在炎症结肠中其作用更为明显。
在 SCID 小鼠中转移 CD4+CD45RB（高）T 细胞诱导结肠炎导致结肠炎发生前结肠上皮发生变化。降低的上皮电阻可能有助于结肠炎的发展；然而，它不足以导致慢性炎症。
