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

https://doi.org/10.1016/j.jcmgh.2020.10.007Get rights and content
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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

Fibrinogen
Vascular Permeability
Colitis
GPRP Acetate

Abbreviations used in this paper

DSS
dextran sulfate sodium
eNOS
endothelial nitric oxide synthase
Fg
fibrinogen
GPRP
Gly-Pro-Arg-Pro acetate
IBD
inflammatory bowel disease
IFN-γ
interferon gamma
IL
interleukin
p-AKT
phosphorylated AKT
TNF-α
tumor necrosis factor alpha
TNBS
trinitrobenzene sulfonic acid
TUNEL
terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling
UC
ulcerative colitis
VEGF
vascular endothelial growth factor
VP
vascular permeability

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Conflicts of Interest The authors disclose no conflicts.

Funding This study was supported by grants from the Key Scientific Research Project of Colleges in Education Department of Guangdong Province (2018KZDXM057, J.Y.), the National Science and Technology Major Project of China (2016ZX08011-005, A.T.), Overseas Expertise Introduction Center for Discipline Innovation (111 center, D18010, J.Y.), Youth Program of Guangxi Natural Science Foundation of China (2019JJB140217, C.Z.), and Special Project Guangxi Science and Technology Base and Talent (2019AC20274, C.Z.).

Authors share co-first authorship.