The pro‐inflammatory environment in recalcitrant diabetic foot wounds

Abstract

Lower extremity ulceration is one of the serious and long-term diabetic complications rendering a significant social burden in terms of amputation and quality-of-life reduction. Diabetic patients experience a substantial wound-healing deficit. These lesions are featured by an exaggerated and prolonged inflammatory reaction with a significant impairment in local bacterial invasion control. Experimental and clinical evidences document the deleterious consequences of the wound's pro-inflammatory phenotype for the repair process. From a biochemical standpoint, hyperinflammation favours wound matrix degradation, thus, amplifying a pre-existing granulation tissue productive cells' invasiveness and recruitment deficit. Tumour necrosis factor perpetuates homing of inflammatory cells, triggers pro-apoptotic genes and impairs reepithelialisation. Advanced glycation end-products act in concert with inflammatory mediators and commit fibroblasts and vascular cells to apoptosis, contributing to granulation tissue demise. Therapeutic approaches aimed to downregulate hyperinflammation and/or attenuate glucolipotoxicity may assist in diabetic wound healing by dismantling downstream effectors. These medical interventions are demanded to reduce amputations in an expanding diabetic population.

Wound Fluid Diagnostics in Diabetic Foot Ulcers

“…The wound fluid proteome of healing tissue is characterised by proteins involved in tissue growth and protection from inflammatory activity, whereas non-healing wounds are characterised by a chronic inflammatory environment primarily consisting of leukocyte proteases and inflammatory mediators (Eming et al 2010). This is particularly striking since the non-healing state in diabetic foot ulcers has previously been linked to persistent inflammatory activity (Acosta et al 2008). Thus, the wound fluid of chronic wounds seems to be characterised by an altered wound micro-milieu and may, therefore, provide deeper insights into the causes of delayed wound healing.…”

“…With regard to chronic non-healing wounds, a connection with persistent inflammatory activity is a guiding principle, which is observed in various entities of impaired healing (Acosta et al 2008;Pukstad et al 2010). In a longitudinal study in chronic venous leg ulcers, decreases in IL-1 and IL-1 were observed in healing ulcers, whereas increases in IL-8 and MIP-1 were associated with non-healing.…”

“…Especially in diabetes, it is established that a local over-secretion of pro-inflammatory cytokines (notably TNF , IL-6 and IL-1) is observed, impacting the wound healing microenvironment and opposing healing (Acosta et al 2008). These factors have been multiply observed in the context of failure to heal and are linked with other processes observed in the wound environment, such as elevated proteolysis and the degradation of growth factors and their receptors.…”

Type 2 Diabetes Mellitus (T2DM): Biological Overview from Pathways to Organelles and its Translation toward a Torpid Wound Healing Process

“…The systemically elevated levels of pro-inflammatory response markers and the wound expression of cytokines and chemokines are among the culprits of the abnormal repair mechanism [106]. Another factor to be considered is that diabetes per se is a metabolic disease in which fuel metabolism is perturbed given the rupture of one of the most important anabolic axis of the organism: insulin/insulin-like growth factor type-I.…”

“…However, the reluctance to trigger and sustain the out-growth of a productive granulation tissue with an appropriate extracellular matrix is typical in diabetic patients, particularly if ischemia concurs. As mentioned, these wounds are characterized by a proliferative arrest, pro-inflammatory, pro-oxidant and pro-degradative phenotype in which a spill-over of proteases degrades extracellular matrix ingredients, growth factors and their receptors [106].…”