Comment to: Raffetto JD, Ligi D, Maniscalco R, Khalil RA, Mannello F. Why Venous Leg Ulcers Have Difficulty Healing: Overview on Pathophysiology, Clinical Consequences, and Treatment. J Clin Med. 2020 Dec 24;10(1):29. doi: 10.3390/jcm10010029. PMID: 33374372; PMCID: PMC7795034.
Venous leg ulcer (VLU) is the most common type of ulcer in the lower extremity with a prevalence of VLU up to 2% of the population and up to 5% of individuals over 65 years old. VLU often occurs in association with post-thrombotic syndrome, advanced chronic venous disease, varicose veins, and venous hypertension.
Raffetto et al. recently published a review providing a foundation of information that defines causes of VLU and other ulcers that may be mistaken for VLUand delayed healing of and difficulty healing VLU that is commonplace in clinical practice. The paper also presents critical factors in propagating the VLU refractory state of continued inflammation (pathophysiological molecular insights on important regulators and inflammatory mediators), surgical treatments and innovations, and drug therapies whose discovery and knowledge lead over time to better-targeted therapies and finally with information on the means to prevent progression, occurrence, and recurrence of VLU.
VLU has been demonstrated over the years to be a complex system involving mechanisms affecting venous macrovasculature (abnormalities with hemodynamics, leading to venous hypertension that involves superficial venous insufficiency that can overwhelm the deep system, junctions, and reentry points in compartments of the lower extremity and cause outflow obstruction via the iliofemoral venous system, calf muscle pump dysfunction, and perforator venous insufficiency) and microvasculature. The latter includes glycocalyx and endothelium and is affected by changes in shear stress and activation of leukocytes and adhesion molecules occurring in both large and microscopic veins. The microvascular system is composed of a network of capillaries, post-capillary venules, interstitium, and lymphatics that respond to overexpressed inflammatory pathways and upregulation of cytokines, chemokines, matrix metalloproteinases (MMPs), iron-free radicals, and activated oxygen and nitrogen species that all have detrimental effects to the surrounding tissues and possibly systemic effects (Figure 1).
Figure 1. Representation of chronic venous disorder pathophysiology, from Raffetto et al. GAG: glycosaminoglycans, MCP-1: monocyte chemoattractant protein, MIP-1: macrophage inflammatory protein, ICAM-1: intercellular adhesion molecule, VCAM-1: vascular cell adhesion molecule, NO: nitric oxide, Fe2+/Fe3+: ferrous/ferric ions, ROS: reactive oxygen species, NOS: nitrogen oxidative species, TAM: Tyro Axl MerTK receptor family tyrosine kinase, TLR: toll like receptors
Treatment of VLU includes compression therapy and endovenous ablation to occlude the axial reflux. With good wound care and compression therapy, VLU usually heals within 6 months. VLU healing involves numerous processes including hemostasis, inflammation, proliferation, and remodeling and the contribution of different cells including leukocytes, platelets, fibroblasts, vascular smooth muscle cells, endothelial cells, and keratinocytes as well as the release of various biomolecules including transforming growth factor-β, cytokines, chemokines, MMPs, tissue inhibitors of MMPs (TIMPs), elastase, urokinase plasminogen activator, fibrin, collagen, and albumin. Alterations in any of these physiological wound closure processes could delay VLU healing.
If not treated adequately, VLU could progress to non-healed or granulating VLU, causing physical immobility, reduced quality of life, cellulitis, severe infections, osteomyelitis, and neoplastic transformation. Recalcitrant VLU shows prolonged healing time with advanced age, obesity, nutritional deficiencies, colder temperature, preexisting venous disease, deep venous thrombosis, and larger wound areas. VLU also has a high, 50-70% recurrence rate, likely due to noncompliance with compression therapy, failure of surgical procedures, incorrect ulcer diagnosis, progression of venous disease, and poorly understood pathophysiology. Understanding the molecular pathways underlying VLU has led to new lines of therapy with significant promise including biologics such as bilayer living skin construct, fibroblast derivatives, and extracellular matrices and non-biologic products such as poly-N-acetyl glucosamine, human placental membranes amnion/chorion allografts, ACT1 peptide inhibitor of connexin 43, sulodexide, growth factors, silver dressings, MMP inhibitors, and modulators of reactive oxygen and nitrogen species, the immune response and tissue metabolites.
Although sulodexide was demonstrated nearly two decades ago to be effective in increasing VLU healing, its novel molecular mechanisms and the pleiotropic effects are just recently understood. It is important to assess the effects of the drug in patients with VLU and healed ulcer disease, which provides insight into the mechanisms and targets of sulodexide. In a study evaluating the anti-inflammatory effects of sulodexide in healed VLU patients who were treated for 8 weeks. At 8 weeks of treatment with sulodexide, there was a significant decrease in inflammatory molecules (IL-6 and MMP-9). Also, evaluation of endothelial cells treated with sulodexide-treated serum from patients significantly decreased IL-6 and intracellular free radicals. Taken together, these data demonstrate that sulodexide results in a reduction in intravascular inflammation and is endothelial-protective.
The effect of inflammation and oxidative stress in HUVEC cells was evaluated in the serum from CVD-healed ulcer patients before and after treatment with sulodexide, showing that sulodexide reduces inflammatory mediators in CVD serum (IL-6, MCP-1, and ICAM-1) and oxidative stress, suppresses the effect of IL-1 and reduces population doubling time and hypertrophy, indicating decreased aging and senescence.
Sulodexide was also shown to mitigate apoptosis by inhibiting intrinsic and extrinsic caspase pathways and increased cell viability, by reducing ROS, by reducing the synthesis and release of inflammatory cytokines (TNF-α, IL1, IL6, and IL8), by promoting cell autophagy in maintaining cellular function, and by reducing DNA damage. The implications are that sulodexide prevents endothelial dysfunction and injury that may have significant implications in CVD, DVT, and PTS. Importantly, these scientific discoveries allow for further research in the pathophysiology of VLU and the possibility for synergistic effects with sulodexide in treating and healing VLU.
