1. Academic Validation
  2. Fibrinogen/AKT/Microfilament Axis Promotes Colitis by Enhancing Vascular Permeability

Fibrinogen/AKT/Microfilament Axis Promotes Colitis by Enhancing Vascular Permeability

  • Cell Mol Gastroenterol Hepatol. 2021;11(3):683-696. doi: 10.1016/j.jcmgh.2020.10.007.
Chong Zhang 1 Honglv Chen 2 Qiaoling He 2 Yiqin Luo 2 Andong He 2 Ailin Tao 3 Jie Yan 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China; Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Guilin Medical University, Guilin, China.
  • 2 State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
  • 3 State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China. Electronic address: taoailin@gzhmu.edu.cn.
  • 4 State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China. Electronic address: jieyan@gzhmu.edu.cn.
Abstract

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.

Keywords

Colitis; Fibrinogen; GPRP Acetate; Vascular Permeability.

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