Omics profiles in chronic venous ulcer wound fluid: innovative applications for translational medicine

Abstract

Chronic venous disease represents a healthcare problem due to high prevalence and recurrence rates. Studies on chronic venous ulcer wound fluid (CVUWF) have demonstrated increased inflammation and proteolysis which can cause tissue destruction and delayed healing. This review discusses: nearly all known metabolites discovered in the past 25 years in CVUWF studies; the omics approaches characterizing the microenvironment of human venous leg ulcers; and the use of biocompounds as prognostic biomarkers and as possible targets for therapeutic approaches. A biomarker is a biological compound that can be functional or non-functional, specific or non-specific in the diagnosis/prognosis to a disease state and may be quantified to determine progression or regression of disease. Omics studies in CVUWF provide the impetus for future identification of biomarkers within the intricate network in chronic venous disease and set the basis for determining the appropriate combination of molecules that are expressed with the healing status of venous leg ulcers.

Keywords::

• biomarker
• chronic venous disease
• cytokine
• genomic
• inflammation
• metabolomic
• proteinase
• proteomic
• venous leg ulcer
• wound fluid

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Chronic venous disease (CVeD) is a highly prevalent disorder among the worldwide population, which causes deleterious alteration of quality of life of patients and an enormous financial burden to healthcare spending.

• Chronic venous leg ulcers (CVLU) are the final outcome of lower extremity CVeD. Although the biomolecular characteristics of leg ulcer microenvironment are not fully understood, great efforts have been made to identify pathways of ulcer healing/non-healing processes.

• The chronic wound fluid represents the metabolic and degrading activities of the venous ulcer microenvironment, which are mainly characterized by an unabated cycle of inflammatory and proteolytic processes.

• Even though a large number of biocompounds have been found through different ‘Omic’ approaches in both healing and non-healing CVLU fluids, there is an urgent need to discover clinically useful biomarkers of the wound initiation and/or progression.

• Genomic and transcriptomic approaches revealed that, other than the well-known environmental risk factors, a strong association between CVeD and gene mutation and/or altered gene expression is present.

• Proteomics and metabolomics highlighted a plethora of biocompounds with different molecular functions and linked to specific subcellular constituents, identifying biomarkers involved in crucial biological processes of the venous microenvironment able to discriminate healing and non-healing venous ulcers.

• Degradomic studies have provided consistent and significant evidence of the balance between matrix degradation and tissue remodeling/repair, highlighting the important role of the proteolytic-antiproteolytic switch for healing/non-healing processes.

• Cytokinome profile of CVLU showed a complex interplay among inflammatory cells, inflammatory cytokines and growth factors, differentially expressed in healed and non-healed venous ulcer microenvironment. A complex network connects cytokines/chemokines and proteases/antiproteases and proteinases/antiproteinases in CVLU.

• Omic approaches of intra- and intercellular networks provide a means to characterize useful panel(s) of biomarkers, which represent key factors for predicting/monitoring healing outcome and tools for developing novel targeted therapies, ultimately increasing the potential to the application of translational medicine.

Notes

PAI: Plasminogen activator inhibitor 1; uPA: Urokinase-dependent plasminogen activator.