Abstract
Venous leg ulcer (VLU) is a huge healthcare problem with poorly understood pathophysiology. Transforming growth factor-β (TGF-β) and endoglin (Eng), are inflammatory and wound healing mediators. Eng, co-receptor for TGF-β type-II receptors, may be cleaved forming soluble Eng (sEng), antagonizing TGF-β signaling, a crucial process in vascular pathologies. We evaluated the accumulation in wound fluid (WF) of TGF-β isoforms and sEng in healing stages, showing the effects of sulodexide treatments, a glycosaminoglycan with clinical efficacy in VLU healing. Patients with inflammatory (Infl) and granulating (Gran) VLU were recruited. WFs and THP-1 monocytes exposed to Infl and Gran WF (treated/untreated with sulodexide) were analyzed for TGF-β isoforms and sEng by multiplex immunoassay. In both Infl and Gran WF, TGF-β1 and β2 were similar; TGF-β3 was significantly increased in Infl compared to Gran WFs (p = 0.033). sEng was significantly elevated in Gran compared to Infl WFs (p = 0.002). In THP-1 monocytes there was a significant increase in sEng after co-treatment of WF and sulodexide. The increase in TGF-β3 found in Infl WF highlights its negative effect on wound healing, while the increased levels of sEng in Gran WF affects the leukocyte adhesion/transmigration through the endothelium, reducing the inflammatory response and favoring the wound healing. Glycosaminoglycan sulodexide potentiates the effects of sEng release from monocyte, representing an important therapeutic option for wound healing.
Highlights
Venous leg ulcer (VLU) is the final complication of chronic venous disease (CVeD), a common lower extremity vascular pathology of great medical and socioeconomic impact, affecting a large part of the population worldwide [1]
From our recent biochemical studies on chronic venous wound fluids assessing cytokines, chemokines, and metalloproteinases [2,4,5], we focused this study on the role of Transforming Growth Factor-β (TGF-β) isoforms and soluble endoglin, as critical inflammatory mediators [6,7] in both vascular diseases [8,9,10] and wound healing [11,12], and their production/release in different stages of healing in VLU
We studied the release of TGF-beta isoforms and soluble Eng (sEng) from wound fluid (WF)-stimulated monocytes, with and without the treatment of sulodexide (Alfa Wassermann, Bologna, Italy), a glycosaminoglycan mixture known for its antithrombotic and pro-fibrinolytic activities, as well as for the anti-inflammatory and
Summary
Venous leg ulcer (VLU) is the final complication of chronic venous disease (CVeD), a common lower extremity vascular pathology of great medical and socioeconomic impact, affecting a large part of the population worldwide [1]. Whereas normal healing of acute wounds is traditionally divided into four overlapping and timely-limited phases (i.e., hemostasis, inflammation, granulation, and remodeling), chronic wounds seem to be blocked mainly in a persistent inflammatory state, which prevents the progression toward the phases and the wound closure [2]. In this regard, “non-healing ulcers are wounds which do not show any reduction in size within six months”; this definition includes both ulcers blocked in the inflammatory phase of wound healing (inflammatory ulcers), and ulcers which, due to conservative or surgical therapeutical procedures, turned granulation phase but did not start to reduce in size (granulating ulcers) [4,5]
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