Background: 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.
Methods:
A time course study of epithelial barrier functions and immune mediators was performed in the CD4 þ CD45RB hi T cell transfer model of colitis using Ussing chambers.
Results:
In nonreconstituted severe combined immunodeficiency (SCID) mice, no epithelial dysfunction was observed. However, after transfer of CD4 þ CD45RB hi T cells or total CD4 þ T cells, colon of SCID mice displayed a decreased epithelial resistance, even before overt microscopic inflammation had occurred. Sustained colitis of CD4 þ 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 b (TGF-b) levels and net ion transport inversely correlated with tumor necrosis factor alpha (TNF-a) levels, pointing to the protective effect of IL-10 and TGF-b and to a damaging effect of TNF-a. Indomethacin, a nonselective COX inhibitor, decreased epithelial resistance independent of T cells and inflammation, but its effect was more pronounced in inflamed colon.
Conclusions: Induction of colitis by transfer of CD4 þ 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.