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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 4  |  Issue : 2  |  Page : 17-21

Pro-inflammatory chemokine interleukin-17A may increase venous thrombus resolution by increasing venous thrombus neovascularization


Department of Vascular Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiaotong University School of Medicine; Vascular Center of Shanghai Jiaotong University, Shanghai, China

Date of Submission16-Jun-2019
Date of Decision20-Sep-2019
Date of Acceptance19-Oct-2019
Date of Web Publication27-Nov-2019

Correspondence Address:
Lu Xinwu
Department of Vascular Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Vascular Center of Shanghai Jiaotong University, 639 Zhizaoju Road, Shanghai 200011
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ts.ts_8_19

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  Abstract 


Objectives: The aim of this study was to assess the effect of the pro-inflammatory interleukin (IL)-17A in deep venous thrombosis (DVT) resolution. Materials and Methods: A total of 45 DVT patients, 30 primary deep venous insufficiencies (DVI) patients, and 18 healthy volunteers were divided into three groups: (a) Control group, (b) DVT group, and (c) DVI group. The venous blood samples of the lower extremity with DVT were collected to evaluate the expression of IL-17A in plasma. Samples of superficial venous thrombus and superficial vein without thrombosis were collected to evaluate the expression of IL-17A in tissue. Male C57/BL mice DVT model was established and was randomly divided into five groups: (1) Control group, no treatment or surgical intervention; (2) Sham group, no treatment and sham operation; (3) DVT group, each mouse intravenous (iv) injected with phosphate-buffered saline (PBS); (4) IL-17A group, each mouse was iv injected with IL-17A; and (5) IL-17A-neutralizing antibody (NA) group, each mouse was iv injected with IL17A NA. Inferior vena cava (IVC) with thrombi were collected to measure their length and weight and analysis CD31(+) endothelial cells in thrombus of internal cerebral vein. Results: Western blot suggested that the expression of IL-17A in superficial vein with thrombosis was higher than superficial vein without thrombosis from human samples (P < 0.05). Comparing the plasma IL-17A levels in human samples, it was found that the expression of IL-17A in DVT and DVI groups was higher than those control group (P < 0.05). In C57/BL mice DVT model, immunofluorescence showed that CD31(+) endothelial cells in thrombus in IL-17A intervention group were more than those in other groups (P < 0.05). The weight of IVC with thrombi in IL-17A intervention group were less than those in other groups (P < 0.05), however, without statistical difference compared with the DVT group and IL-17A-NA group. Conclusions: Venous thrombus neovascularization can be increased by pro-inflammatory chemokine IL-17A but do not appear to decrease thrombus size.

Keywords: Angiogenesis, deep venous thrombosis, inflammation, neovascularization


How to cite this article:
Ruihua W, Xiaoyu W, Bo L, Xinwu L. Pro-inflammatory chemokine interleukin-17A may increase venous thrombus resolution by increasing venous thrombus neovascularization. Transl Surg 2019;4:17-21

How to cite this URL:
Ruihua W, Xiaoyu W, Bo L, Xinwu L. Pro-inflammatory chemokine interleukin-17A may increase venous thrombus resolution by increasing venous thrombus neovascularization. Transl Surg [serial online] 2019 [cited 2019 Dec 10];4:17-21. Available from: http://www.translsurg.com/text.asp?2019/4/2/17/271822




  Introduction Top


Deep venous thrombosis (DVT) is one of the major causes of disability and death worldwide for its major complication pulmonary embolism (PE). Both of which lead to about 300,000 deaths in the US each year despite the improvement of diagnosis, treatment, and prophylaxis.[1],[2]

DVT formation has been thought to be caused by blood stagnancy, venous endothelium injury, and hypercoagulability traditionally.[3] It involves three consecutive stages: (1) blood stagnancy and hypoxia; (2) endothelium activation; (3) activation of blood coagulation and thrombus development following with blood cells recruitment.[4]

Thrombosis is formed via two mechanisms designated as extrinsic and intrinsic pathways traditionally. Therefore, the current method of DVT prophylaxis focuses on the coagulation system mainly. Medicine targeting Vitamin K-dependent clotting factors (e.g., warfarin;), active FXa (e.g., rivaroxaban), thrombin (e.g., dabigatran). All these medicines may cause bleeding because the narrow therapeutic window of anticoagulants. Some recent studies have shown that several inflammatory markers increased in DVT patients, suggest that DVT is also closely related to inflammatory processes.[5],[6],[7],[8]

Interleukin (IL)-17, which composed of six major isoforms (IL-17A, -B, -C, -D, -E, and -F), is a member of a novel group of pro-inflammatory cytokines. IL-17A is the most widely studied cytokine of the IL-17 family. IL-17A modulates endothelial cells, epithelial cells and macrophages release of a broad range of cytokines and inflammatory molecules, including IL-1, IL-6, IL-8, vascular endothelial growth factor, prostaglandin E1, intercellular adhesion molecule-1, tumor necrosis factor (TNF),[8],[9],[10],[11] IL-17 induces secretion of TNF-α and IL-1β from macrophages.[12] Moreover, IL-17 stimulates the migration of vascular endothelial cells and promotes tumor angiogenesis.[13] Furthermore, some recent studies demonstrated that increased serum IL-17 levels are expressing in DVT.[8],[14],[15] However, whether the IL-17A-mediated changes in DVT formation and resolution has not been established.

In the current study, we established a mouse model of DVT that imitates the formation of thrombus via reduced blood flow of inferior vena cava (IVC). The model was used to explore the expression of IL-17A in thrombus and the role of IL-17A in DVT resolution.


  Materials and Methods Top


Patients

A total of 45 DVT patients, 30 primary deep venous insufficiency (DVI) patients with superficial venous thrombosis and 18 healthy volunteers were recruited from the Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, China. The participants were divided into three groups: (a) Control group (n = 18) (herein, a healthy person refers to anyone in good health in terms of physical, mental, social, and other aspects); (b) DVT group (n = 45, case history: 7–90 days); and (c) DVI group (n = 18, patients without venous thrombosis or any inflammatory disease). The DVT and DVI patients were diagnosed by vascular ultrasound. The study protocol was approved by the Committee for the Protection of Human Subjects at the Shanghai Jiao Tong University, School of Medicine (Shanghai, China). Written informed consent was obtained from every participant.

The venous blood samples of the lower extremity with DVT or DVI and peripheral venous blood samples of healthy volunteers were collected. Samples of superficial venous thrombus and normal superficial vein without thrombosis were collected.

Animals

Male C57/BL mice (6–8 weeks old) were purchased from the Shanghai Research Center for Model Organisms (Shanghai, People's Republic of China). All mice were used under a protocol approved by the Animal Experiment and Care Committee.

Murine deep venous thrombosis model and treatment grouping

Mouse model of stagnant-flow venous thrombosis was established as described previously.[16] C57/BL mice were anesthetized with 3% pentobarbital sodium, 50 mg/kg. With a blunt dissection, IVC was exposed and separated from the aorta under a stereoscope. A hemostatic forceps was used to the clip IVC twice, in order to damage the venous endothelium. 5-0 Prolene thread was placed longitudinally along the IVC, and then, a 4-0 Prolene suture was tied around both the IVC and Prolene thread together. At last, the 5-0 Prolene suture was pulled out to allow partial blood flow through the obstruction. No branches were ligated [Figure 1].
Figure 1: Murine inferior vena cava stagnant-flow venous thrombosis model was established

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Mice were randomly divided into five groups: (1) Control group, no treatment and surgery; (2) Sham group, surgery only; (3) DVT group, iv injected with phosphate-buffered saline (PBS); (4) IL-17A group, injected with 50 μg/kg of mouse IL-17A (Abcam, UK) diluted in PBS; and (5) IL-17A-neutralizing antibody (NA) group, iv injected with 5 mg/kg of IL-17A-NA (Abcam, UK) diluted in PBS.

All C57/BL mice were sacrificed 7 days after the surgery. IVC with thrombus were collected to measure the weight and length, before fixed with 4% paraformaldehyde [Figure 1].

Statistical analysis

Statistical analysis was performed using an unpaired two-tailed Student's t-test with a confirmation by parametric and F-tests. Difference was considered to be statistically significant when the P value was <0.05.


  Results Top


The expression of interleukin-17A in plasma from human samples

Comparing the plasma IL-17A levels of the three groups: Control group (n = 18); DVT group (n = 45) and DVI group (n = 18), it was found that the expression of IL-17A in DVT and DVI groups were higher than those control group with statistical difference [Figure 2].
Figure 2: Comparing the plasma interleukin-17A level in deep venous thrombosis, deep venous insufficiency, and control individuals, we found that the interleukin-17A level was significantly higher in deep venous thrombosis (P = 0.001) and deep venous insufficiency (P = 0.001) patients than controls

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The expression of interleukin-17A in human superficial venous thrombus

Western Blot suggested that the expression of IL-17A in superficial vein with thrombosis was higher than superficial vein without thrombosis with statistical difference [Figure 3].
Figure 3: Western blot showed that the expression level of interleukin-17A in venous wall from thrombophlebitis lesion than adjacent normal venous wall (P = 0.000)

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CD31(+) endothelial cells in thrombus of inferior vena cava from mouse model

Immunofluorescence showed that CD31(+) endothelial cells in thrombus in IL-17A intervention group were more than those in other groups with statistical difference [Figure 4].
Figure 4: In vivo study showed that interleukin-17 neutralizing antibody (interleukin-17-neutralizing antibody) inhibited angiogenesis in thrombus of internal cerebral vein (interleukin-17A group vs. deep venous thrombosis group, P = 0.018; interleukin-17A group vs. interleukin-17A-neutralizing antibody group, P = 0.026)

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The expression of CD31 protein in thrombus of inferior vena cava from mouse model

Western Blot results showed that the expression of CD31 protein in IL-17A intervention group were more than those in other groups with statistical difference [Figure 5].
Figure 5: Western blot further showed that CD31 expression level in inferior vena cava thrombus was significantly lower in interleukin-17- neutralizing antibody treated mice than that in control-Sham mice (interleukin-17A group vs. deep venous thrombosis group, P = 0.001; interleukin-17A group vs. interleukin-17A-neutralizing antibody group, P = 0.003)

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The weight of inferior vena cava with thrombi from mouse model

The weight of IVC with thrombi in IL-17A intervention group were less than those in other groups, however without statistical difference compared with the DVT group and IL-17A-NA group [Figure 6].
Figure 6: The weight of inferior vena cava with thrombi in interleukin-17A intervention group were less than those in other groups, however without statistical difference (interleukin-17A group vs. deep venous thrombosis group, P = 0.11; interleukin-17A group vs. interleukin-17A-neutralizing antibody group, P = 0.26)

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  Discussion Top


Venous thromboembolism (DVT and PE) is a major health problem with an incidence of 0.75–2.69 cases/1000 annually.[17] Fibrinolysis,[18] angiogenesis,[19] and inflammation [20] are all involved in thrombus resolution. During the venous remodeling process, the thrombus retracts from the vein wall and neovascular channels are formed.

A number of studies investigating the effect of neovascularization and inflammation for thrombus resolution, showed that interdependence of inflammatory cell recruitment and angiogenesis in thrombus revascularization and resolution.[21],[22],[23],[24],[25] Therefore, DVT is an immunity and inflammation-related process rather than merely coagulation-dependent thrombosis.

IL-17 has a broad range of pro-inflammatory potential in host defense, inflammatory disease, and autoimmunity such as atherosclerosis.[26],[27],[28] IL-17 expression was reported in human coronary and symptomatic carotid atherosclerotic lesions.[29],[30] IL-17A is known to be important constituents of fresh and lytic thrombus after acute myocardial infarction.[31],[32] IL-17A was highly expressed in deep vein thrombosis from mouse model.[33]

In our study, the expression of IL-17A in human superficial venous thrombus was higher than that superficial vein without thrombosis with statistical difference, the expression of IL-17A in plasma of DVT and DVI groups were higher than those control groups with statistical difference. Therefore, IL-17A, as a powerful pro-inflammatory cytokine, has an impact on DVT formation and resolution.

IL-17A has been recognized as a new angiogenic factor in recent years. IL-17A acts on inflammation-related tumors and promotes the growth, invasion, and metastasis of tumors by promoting angiogenesis of endothelial cells.[10],[13],[34] In our study, the expression of CD31 protein in IL-17A intervention group were more than those in other groups with statistical difference in the mouse DVT model. The results showed that IL-17A could increase neovascularization in the thrombus of IVC in mouse, which could be resisted by IL-17A neutralizing antibody. In this study, the weight of IVC with thrombi in IL-17A intervention group was less than those in other groups in the mouse DVT model, however, without statistical difference. These results suggest that angiogenesis may be one of the mechanisms of IL-17A promoting thrombolysis and recanalization.

Our study has shown that venous thrombus neovascularization can be increased by pro-inflammatory chemokine IL-17A but do not appear to decrease thrombus size. Further work is needed to clarify the basic mechanisms of thrombus resolution, with the aim of accelerating thrombolysis through the immune system in its pathogenesis. And more studies are needed to explain the role of angiogenesis in DVT resolution.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]



 

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