Garg Sarita, Zheng Junying, Wang Junru, Authier Simon, Pouliot Mylene, Hauer-Jensen Martin
a Department of Pharmaceutical Sciences, Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas;
b CIToxLAB, Laval, Quebec, Canada; and.
Radiat Res. 2016 Jan;185(1):50-9. doi: 10.1667/RR14157.1. Epub 2015 Dec 31.
Dysfunction of the intestinal epithelial barrier and leakage of luminal antigens and bacteria across the barrier have been linked to various human diseases. Intestinal permeability is regulated by intercellular structures, termed "tight junction" (Tj), which are disrupted after total-body irradiation (TBI). In this study, we investigated radiation-induced alterations in Tj-related proteins in the jejunum, ileum and colon of a non-human primate (NHP) model. NHPs were total-body irradiated with 6.7 and 7.4 Gy and intestines were procured at day 4, 7 and 12. Radiation exposure was found to induce significant increases in claudin-10 mRNA early (day 4) in all three gut segments and claudin-4 mRNA levels were repressed through day 12. TNF-alpha was highly induced in the jejunum and colon at early time points, but little induction was found in the ileum. Claudin-1 was induced only in the colon on day 4 postirradiation. Unlike the colon and jejunum, the ileum levels of claudin-7 were significantly downregulated through day 12 postirradiation. Western blot analysis revealed increased levels of claudin-2 on day 4 and of JAM-1 on day 7 postirradiation in all three gut segments. E-cadherin was downregulated on day 4 postirradiation in all segments, but remained reduced in the jejunum only until day 12. Taken together, these data suggest that exposure to radiation causes segment-specific alterations in the expression of Tj-related proteins. Interruption of Tjs may be a key factor contributing to injury to the intestinal mucosal barrier and increased intestinal permeability.
肠道上皮屏障功能障碍以及管腔抗原和细菌跨越屏障的渗漏与多种人类疾病有关。肠道通透性由称为“紧密连接”（Tj）的细胞间结构调节，全身照射（TBI）后这些结构会被破坏。在本研究中，我们调查了非人类灵长类动物（NHP）模型空肠、回肠和结肠中Tj相关蛋白的辐射诱导变化。用6.7和7.4 Gy对NHP进行全身照射，并在第4、7和12天获取肠道。发现辐射暴露在所有三个肠道段中早期（第4天）均诱导claudin-10 mRNA显著增加，并且claudin-4 mRNA水平在第12天之前受到抑制。TNF-α在早期时间点在空肠和结肠中高度诱导，但在回肠中几乎没有诱导。Claudin-1仅在照射后第4天在结肠中被诱导。与结肠和空肠不同，回肠中claudin-7的水平在照射后第12天之前显著下调。蛋白质印迹分析显示，在所有三个肠道段中，照射后第4天claudin-2水平升高，第7天JAM-1水平升高。E-钙黏蛋白在所有段中照射后第4天均下调，但仅在空肠中直到第12天仍保持降低。综上所述，这些数据表明辐射暴露会导致Tj相关蛋白表达的节段特异性变化。紧密连接的中断可能是导致肠黏膜屏障损伤和肠道通透性增加的关键因素。
