Fries Walter, Muja Carmelo, Crisafulli Carmela, Cuzzocrea Salvatore, Mazzon Emanuela
Dipartimento di Medicina Interna e Terapia Medica, Policlinico Universitario, Pad C, III piano, Via Consolare Valeria, 1, 98100 Messina, Italy.
Am J Physiol Gastrointest Liver Physiol. 2008 Apr;294(4):G938-47. doi: 10.1152/ajpgi.00469.2007. Epub 2008 Feb 7.
An alteration of the intestinal barrier is considered to represent an early step in pathogenesis of Crohn's disease. The integrity of intestinal barrier function is guaranteed among other factors by enterocyte tight junction (TJ) proteins. Clinical and experimental data indicate the TNF-alpha to be the major responsible factor for these defects. In the present study we investigated the very early effects of DNBS-ethanol colitis on ileal enterocyte TJ proteins [occludin, zonula occludens-1 (ZO-1), claudin-2] in controls, mice treated with infliximab (IFX) or with etanercept (ETC), and in knockout mice for the TNF-alpha receptor 1 (TNFR-1(-/-)). Circulating TNF-alpha levels were effectively reduced by IFX and ETC (P < 0.01, both) at 3 and at 6 h. DNBS colitis induced disappearance of occludin and ZO-1 from enterocyte cell-cell contact, whereas claudin-2, absent under control conditions, appeared in the ileal epithelium. These alterations were prevented equally by both treatments, IFX and ETC, and in TNFR-1(-/-) animals. DNBS colitis induced a very rapid loss of occludin and ZO-1 from ileal TJ together with an upregulation of claudin-2. Our data are consistent with the hypothesis that TNF-alpha is involved in early TJ rearrangement and that its effects are mediated through TNFR-1. Despite clinical differences, both anti-TNF treatments were equally effective in the present setting.
肠屏障的改变被认为是克罗恩病发病机制的早期步骤。肠屏障功能的完整性在其他因素中由肠上皮细胞紧密连接（TJ）蛋白来保证。临床和实验数据表明肿瘤坏死因子-α（TNF-α）是这些缺陷的主要责任因素。在本研究中，我们调查了二硝基苯磺酸（DNBS）-乙醇诱导的结肠炎对对照组、接受英夫利昔单抗（IFX）或依那西普（ETC）治疗的小鼠以及肿瘤坏死因子-α受体1基因敲除小鼠（TNFR-1(-/-)）回肠肠上皮细胞TJ蛋白[闭合蛋白、闭合小环蛋白-1（ZO-1）、claudin-2]的早期影响。在3小时和6小时时，IFX和ETC均有效降低了循环中的TNF-α水平（两者P均<0.01）。DNBS结肠炎导致闭合蛋白和ZO-1从肠上皮细胞间接触中消失，而在对照条件下不存在的claudin-2出现在回肠上皮中。IFX和ETC这两种治疗以及TNFR-1(-/-)动物均能同样有效地预防这些改变。DNBS结肠炎导致回肠TJ中闭合蛋白和ZO-1迅速丢失，同时claudin-2上调。我们的数据与TNF-α参与早期TJ重排且其作用通过TNFR-1介导的假说一致。尽管在临床上存在差异，但在本研究中两种抗TNF治疗同样有效。
