Inflammatory and Angiogenic Abnormalities in Diabetic Wound Healing: Role of Neuropeptides and Therapeutic Perspectives

Abstract

Diabetic foot ulceration (DFU) is one of the most costly and debilitating complications of diabetes and is the leading cause of non-traumatic amputations, affecting 15% of the diabetic population. Impaired wound healing in diabetic patients without large-vessel disease has been attributed to microvascular dysfunction, neuropathy, and abnormal cellular and inflammatory responses. These abnormalities have been examined mainly in animal models although a few studies have been undertaken in diabetic patients. This review provides an overview of the inflammatory and vascular abnormalities in DFU and emphasises the role of angiogenic growth factors, endothelial progenitor cells (EPCs), and neuropeptides as mediators of wound healing and potential therapeutic agents for these chronic, non-healing ulcers.

The effect of bone marrow-derived mesenchymal stem cells on the healing of experimental skin wound in diabetic adult male albino rats

“…In the reticular layer the collagen fibers limited penetration of new blood vessels into the wound leading to restriction to the entry of inflammatory cells [25]. A similar profile had been observed in monocytes from diabetic patients, with impaired chemotaxis and phagocytosis [26].…”

Substance P promotes diabetic wound healing by modulating inflammation and restoring cellular activity of mesenchymal stem cells

“…Analysis for immune cells isolated from diabetic mice was found to be the great infiltration by inflammatory M1 macrophages . M1 macrophages primarily secrete pro‐inflammatory cytokines including TNF‐α, IL‐1b, IL‐6, and IL‐18, whereas M2 macrophages exert immunosuppressive effects via IL‐10, TGF‐β1, and VEGF.…”

“…Impaired wound healing in diabetes is characterized by blunted acute inflammation and abnormal angiogenesis. Proper wound healing requires a highly regulated self‐limited inflammatory response, whereas diabetic wounds have long lasting inflammatory responses at the late stages of wound healing due to altered chemokine and growth factor expression . Type 1 DM wounds show increased expression of inflammatory cytokines including tumor necrosis factor‐α (TNF‐α), interleukin (IL)−1, and IL‐6 and decreased IL‐10 leading to a prolonged inflammatory phase .…”

The role of microRNAs in the healing of diabetic ulcers

“…The results of previous studies showed that the expression of miR-146a has a reverse correlation with glycosylated haemoglobin, insulin resistance, tumour necrosis factor, receptor-associated factor (TRAF)-6, the level of NF-kB mRNA, and the TNF-α and IL-6 levels in blood. 95 Based on all these studies, it can be concluded that the inflammatory phase is directly and indirectly controlled by miRNAs.…”

“…89 Based on studies by Balasubramanyam et al, there is an increase in the activity of the NF-Kβ pathway and the reduction of mir-146a in diabetic patients. 95 The results of studies by Kovacs et al showed that miR-146 could be an appropriate therapeutic target for diabetes and its complications, such as retinopathy, by exerting an inhibitory effect on the route of NF-Kβ. 165 The question that was posed at this juncture was whether the increase of mir-146a could be accompanied by a reduction in pro-inflammatory factors or not.…”