Background & Aims

Increased vascular permeability (VP) has been indicated to play an important role in the pathogenesis of inflammatory bowel disease (IBD). However, the pathological causes of increased intestinal VP in IBD remain largely unknown.

Method

Fibrinogen level was measured in dextran sulphate sodium (DSS)-induced colitis and patients with ulcerative colitis. Gly-Pro-Arg-Pro acetate (GPRP), an Fg inhibitor, was used to detect the effect of Fg inhibition on the pathogenesis of DSS-induced colitis, as indicated by tissue damage, cytokine release and inflammatory cell infiltration. Miles assay was used to detect vascular permeability.

Results

Through tandem mass tag–based quantitative proteomics, fibrinogen (Fg) was found to be upregulated in the colon of DSS-treated mice, which was consistent with increased Fg level in colon sample of patients with ulcerative colitis. Gly-Pro-Arg-Pro acetate (GPRP), an Fg inhibitor, significantly alleviated DSS-induced colitis as indicated by improvement of body weight loss and mortality. GPRP decreased colonic inflammation and VP in DSS-treated mice. In vivo, Fg enhanced VP as indicated by Miles assay, which was significantly inhibited by GRPR, AKT (serine/threonine kinase 1) inhibitors and low doses of Jasplakinolide which induced actin polymerization, while was dramatically enhanced by Cytochalasin D (an actin polymerization inhibitor). Moreover, activation of AKT was found in vessels of DSS-treated mice. In vitro, Fg induced activation of AKT and depolymerization of microfilament and promoted cell-to-cell disaggregation. Furthermore, inhibition of AKT decreased Fg-induced microfilament depolymerization.

Conclusions

Our findings highlight the importance of Fg in regulating colitis by modulation of VP via activating AKT and subsequent depolymerization of microfilament and suggest Fg as an attractive target for anti-colitis treatment.

中文翻译：

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纤维蛋白原/AKT/微丝轴通过增强血管通透性促进结肠炎

背景与目标

已表明血管通透性 (VP) 增加在炎症性肠病 (IBD) 的发病机制中起重要作用。然而，IBD 中肠道 VP 增加的病理原因在很大程度上仍然未知。

方法

在葡聚糖硫酸钠 (DSS) 诱发的结肠炎和溃疡性结肠炎患者中测量纤维蛋白原水平。Gly-Pro-Arg-Pro 醋酸盐 (GPRP) 是一种 Fg 抑制剂，用于检测 Fg 抑制对 DSS 诱导的结肠炎发病机制的影响，如组织损伤、细胞因子释放和炎症细胞浸润所示。Miles测定用于检测血管通透性。

结果

通过基于串联质量标签的定量蛋白质组学，发现 DSS 治疗小鼠结肠中的纤维蛋白原 (Fg) 上调，这与溃疡性结肠炎患者结肠样本中 Fg 水平升高一致。Gly-Pro-Arg-Pro 醋酸盐 (GPRP)，一种 Fg 抑制剂，显着减轻了 DSS 诱导的结肠炎，如体重减轻和死亡率的改善所示。GPRP 减少了 DSS 治疗小鼠的结肠炎症和 VP。 在体内，如 Miles 试验所示，Fg 增强了 VP，这被 GRPR、AKT（丝氨酸/苏氨酸激酶 1）抑制剂和诱导肌动蛋白聚合的低剂量 Jasplakinolide 显着抑制，而细胞松弛素 D（肌动蛋白聚合抑制剂）显着增强）。此外，在 DSS 治疗小鼠的血管中发现了 AKT 的激活。在体外，Fg 诱导 AKT 的激活和微丝的解聚，并促进细胞间的解聚。此外，AKT 的抑制减少了 Fg 诱导的微丝解聚。

结论

我们的研究结果强调了 Fg 通过激活 AKT 和随后的微丝解聚来调节 VP 在调节结肠炎中的重要性，并表明 Fg 作为抗结肠炎治疗的有吸引力的靶点。