Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany.
J Mol Med (Berl). 2018 Aug;96(8):831-843. doi: 10.1007/s00109-018-1658-1. Epub 2018 Jun 20.
Impaired salt and water absorption is a hallmark of diarrhea in IBD. In the present study, the therapeutic effect of continuous anti-TNFα treatment on the progression of inflammation and colonic transport dysfunction during chronic dextran sulfate sodium (DSS)-induced colitis was investigated. Chronic colitis was induced by three DSS exposure cycles. Mice received TNFα monoclonal antibody treatment twice weekly after the end of the first 5-day DSS drinking period. Mice developed chronic DSS-induced colitis characterized by a typical immune cell infiltration composed of CD3 T cells and CD68 macrophages, both expressing high levels of the pro-inflammatory cytokines IL-1β and TNFα, a loss of NHE3 and PDZK1 in the brush border region of the absorptive enterocyte and a decrease of colonic fluid absorption in vivo, measured by colonic single pass perfusion. Concomitant anti-TNFα treatment resulted in a significant reduction of mucosal immune cell infiltration and expression of the pro-inflammatory cytokines IL-1β and TNFα. It also resulted in a normalization of NHE3-mediated fluid absorption and a restoration of NHE3 and PDZK1 location in the apical and subapical region of the enterocytes. Here, we show for the first time that in this chemically induced murine colitis model, anti-TNFα treatment significantly decreased inflammatory activity, improved mucosal integrity and restored transport function despite an ongoing inflammatory insult. Anti-TNFα treatment may therefore be beneficial in patients with IBD even in spite of an absence of complete mucosal healing.
Chronic DSS treatment caused a loss of NHE3 and PDZK1 in the brush border region of the absorptive enterocyte and decreases colonic fluid absorption. In DSS-induced colitis, anti-TNFα treatment reduced mucosal immune cell infiltration and expression of the pro-inflammatory cytokines IL-1β and TNFα. In DSS-induced colitis, anti-TNFα treatment normalized NHE3-mediated fluid absorption and restored NHE3 and PDZK1 location in the enterocytes. In DSS-induced colitis, anti-TNFα treatment decreased inflammatory activity, improved mucosal integrity, and restored transport function.
探讨持续抗 TNF-α治疗对葡聚糖硫酸钠（DSS）诱导的慢性结肠炎中炎症进展和结肠转运功能障碍的治疗效果。
采用三周期 DSS 暴露法诱导慢性结肠炎，在第一个 5 天 DSS 饮水中止后每周两次给予 TNFα 单克隆抗体治疗。
DSS 诱导的慢性结肠炎表现为典型的免疫细胞浸润，由 CD3 T 细胞和 CD68 巨噬细胞组成，均高表达促炎细胞因子 IL-1β 和 TNFα，吸收上皮细胞刷状缘区的 NHE3 和 PDZK1 丢失，体内结肠单通道灌流测量的结肠液体吸收减少。同时进行抗 TNF-α治疗可显著减少黏膜免疫细胞浸润和促炎细胞因子 IL-1β 和 TNFα 的表达，还可使 NHE3 介导的液体吸收正常化，并使 NHE3 和 PDZK1 恢复到肠上皮细胞的顶端和亚顶端区域。
在该化学诱导的小鼠结肠炎模型中，抗 TNF-α治疗可显著降低炎症活性，改善黏膜完整性并恢复转运功能，尽管存在持续的炎症刺激。因此，即使在黏膜愈合不完全的情况下，抗 TNF-α治疗对 IBD 患者也可能有益。
