Inflammatory signals and network connections implicate cell-mediated immunity in chronic venous insufficiency

Lena Vodovotz; Ruben Zamora; Derek A Barclay; Yoram Vodovotz; Jinling Yin; Julie Bitner; John Florida; Efthymios D Avgerinos; Ulka Sachdev

doi:10.21037/atm-21-688

Inflammatory signals and network connections implicate cell-mediated immunity in chronic venous insufficiency

Ann Transl Med. 2021 Nov;9(22):1643. doi: 10.21037/atm-21-688.

Authors

Lena Vodovotz¹, Ruben Zamora^{1

2}, Derek A Barclay¹, Yoram Vodovotz^{1

2}, Jinling Yin¹, Julie Bitner^{1

3}, John Florida³, Efthymios D Avgerinos^{1

3}, Ulka Sachdev^{1

3}

Affiliations

¹ Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
² Center for Inflammation and Regeneration Modeling, McGowen Institute for Regenerative Modeling, Pittsburgh, PA, USA.
³ Division of Vascular Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Abstract

Background: The role of inflammation in superficial venous reflux in varicose veins (VVs) is unknown. Computational network modeling has deduced inflammation in experimental and clinical settings. We measured immune mediators in plasma from competent and incompetent leg veins inferring the role of cellular immunity based on cytokine networks.

Methods: Temperature was assessed using infrared thermography (IRT) to measure inflammation. Blood was obtained during sclerotherapy or endovenous thermal ablation for VVs. Control subjects underwent phlebotomy from saphenous and forearm veins. Vein segments were harvested during surgery. Demographics, clinical, etiology, anatomy and pathophysiology classification, venous clinical severity scores (VCSSs), and body mass index (BMI) were collected. Twenty-five mediators were measured in serum and vein segments. Means were compared using Mann-Whitney U test. Pearson correlations equaling or exceeding a threshold prompted connections among nodes, and mapped as networks. Spearman correlations were performed between interleukin (IL)-17A and both granulocyte macrophage colony stimulation factor, and IL-10 as indicators of pathogenic and nonpathogenic Th17 cell involvement.

Results: Age, BMI, and VCSSs differed significantly between groups. Temperatures were higher over diseased veins. Plasma concentrations of 20 cytokines differed between control and patient subjects (P<0.05), and most were lower in patients. C-X-C motif chemokine ligand-9 (aka monokine-induced by gamma interferon), C-X-C motif chemokine ligand 10 (aka IFNγ induced protein 10), and soluble IL-2 receptor-alpha were higher in patients, but not connected to other mediators in networks. In contrast, IL-17A, IL-12p70, and interferon gamma were the only mediators that were more highly interconnected in venous insufficiency. IL-17A and granulocyte macrophage colony stimulating factor (GM-CSF) were highly correlated in chronic venous insufficiency (CVI) but not in controls. In tissue, refluxing VVs significantly higher IL-15 expression than competent saphenous veins.

Conclusions: Venous insufficiency associates with age, BMI, skin temperature, and plasma cytokines associated with interferon gamma and possibly IL-17A signaling. The vein wall may be a source of activation of cellular activation, given elevated IL-15 expression. Correlations between IL-17A and GM-CSF suggested a potential role for pathogenic Th17 cells in VVs. Differentially expressed inflammatory networks induced by venous hypertension may reflect or drive venous damage and ulceration.

Keywords: T helper cells (Th cells); Venous disease; computational modeling; inflammation.