Inflammation and neuropeptides: the connection in diabetic wound healing

Pradhan, Leena; Nabzdyk, Christoph S.; Andersen, Nicholas D.; LoGerfo, Frank W.; Veves, Aristidis

doi:10.1017/s1462399409000945

Cited by 220 publications

(202 citation statements)

References 238 publications

(336 reference statements)

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“…We confirmed our mouse findings in the neuroischemic diabetic rabbit ear model that heals with minimal contraction, is characterized by chronic inflammation and increased baseline M1/ M2 ratio, 21 and is probably the closest animal model to the human neuroischemic diabetic foot ulceration. 3,20,21 Because SP had a similar effect in both mouse and rabbit models, we believe that they satisfactorily represent the human condition and that the data support the progression to phase 1/2 clinical trials.…”

Section: Discussionmentioning

confidence: 74%

Substance P Promotes Wound Healing in Diabetes by Modulating Inflammation and Macrophage Phenotype

Leal

Carvalho

Tellechea

et al. 2015

The American Journal of Pathology

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179

155

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Diabetic foot ulceration is a major complication of diabetes. Substance P (SP) is involved in wound healing, but its effect in diabetic skin wounds is unclear. We examined the effect of exogenous SP delivery on diabetic mouse and rabbit wounds. We also studied the impact of deficiency in SP or its receptor, neurokinin-1 receptor, on wound healing in mouse models. SP treatment improved wound healing in mice and rabbits, whereas the absence of SP or its receptor impaired wound progression in mice. Moreover, SP bioavailability in diabetic skin was reduced as SP gene expression was decreased, whereas the gene expression and protein levels of the enzyme that degrades SP, neutral endopeptidase, were increased. Diabetes and SP deficiency were associated with absence of an acute inflammatory response important for wound healing progression and instead revealed a persistent inflammation throughout the healing process. SP treatment induced an acute inflammatory response, which enabled the progression to the proliferative phase and modulated macrophage activation toward the M2 phenotype that promotes wound healing. In conclusion, SP treatment reverses the chronic proinflammatory state in diabetic skin and promotes healing of diabetic wounds. (Am J Pathol 2015 http://dx

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Section: Discussionmentioning

confidence: 74%

Substance P Promotes Wound Healing in Diabetes by Modulating Inflammation and Macrophage Phenotype

Leal

Carvalho

Tellechea

et al. 2015

The American Journal of Pathology

Self Cite

179

155

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“…74 In contrast, patients with advanced PDN typically have elevated vibration perception thresholds indicative of sensory loss, a condition ultimately responsible for foot ulceration and amputation. 75,76 Thus, studies of mechanical hyper-and hypoalgesia and development of agents to prevent and treat both disorders have clinical relevance. In experimental studies, mechanical withdrawal thresholds in diabetic rat and mouse models are assessed by paw (rats) and tail (mouse) pressure Randall-Selitto test or with a von Frey aesthesiometer and rigid von Frey filaments.…”

Section: Pathogenesis and Experimental Treatments: Diabetes-associatementioning

confidence: 99%

Diabetic Painful and Insensate Neuropathy: Pathogenesis and Potential Treatments

2009

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Summary:Advanced peripheral diabetic neuropathy (PDN) is associated with elevated vibration and thermal perception thresholds that progress to sensory loss and degeneration of all fiber types in peripheral nerve. A considerable proportion of diabetic patients also describe abnormal sensations such as paresthesias, allodynia, hyperalgesia, and spontaneous pain. One or several manifestations of abnormal sensation and pain are described in all the diabetic rat and mouse models studied so far (i.e., streptozotocin-diabetic rats and mice, type 1 insulinopenic BB/Wor and type 2 hyperinsulinemic diabetic BBZDR/Wor rats, Zucker diabetic fatty rats, and nonobese diabetic, Akita, leptin-and leptin-receptor-deficient, and highfat diet-fed mice). Such manifestations are 1) thermal hyperalgesia, an equivalent of a clinical phenomenon described in early PDN; 2) thermal hypoalgesia, typically present in advanced PDN; 3) mechanical hyperalgesia, an equivalent of pain on pressure in early PDN; 4) mechanical hypoalgesia, an equivalent to the loss of sensitivity to mechanical noxious stimuli in advanced PDN; 5) tactile allodynia, a painful perception of a light touch; and 5) formalin-induced hyperalgesia. Rats with short-term diabetes develop painful neuropathy, whereas those with longer-term diabetes and diabetic mice typically display manifestations of both painful and insensate neuropathy, or insensate neuropathy only. Animal studies using pharmacological and genetic approaches revealed important roles of increased aldose reductase, protein kinase C, and poly(ADPribose) polymerase activities, advanced glycation end-products and their receptors, oxidative-nitrosative stress, growth factor imbalances, and C-peptide deficiency in both painful and insensate neuropathy. This review describes recent achievements in studying the pathogenesis of diabetic neuropathic pain and sensory disorders in diabetic animal models and developing potential pathogenetic treatments. Key Words: Animal models, diabetic insensate neuropathy, diabetic painful neuropathy, formalin-induced hyperalgesia, mechanical hyper-and hypoalgesia, pathogenetic treatments of diabetic neuropathic pain and sensory loss, symptomatic treatments of diabetic pain, tactile allodynia, thermal hyper-and hypoalgesia.

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“…Diabetes is a chronic progressive disease with rising incidence worldwide over the last three decades [1,2]. Diabetes patients often deal with non-closure of wounds and non-healing foot ulcerations, which contribute to the high mortality rate for this disease [3,4].…”

Section: Introductionmentioning

confidence: 99%

“…One of the major complications of diabetes mellitus is abnormal wound closure and healing, particularly in the case of foot ulcers. This can result in clinical problems, including lower-limb amputation, prolonged hospitalization and lifethreatening sepsis [1]. Factors thought to play key roles in the delay of wound closure and healing in diabetes mellitus include: cellular dysfunction; alterations in growth factor; alterations in the signals that impair the migration and proliferation of keratinocytes and fibroblasts, the production of extracellular matrix, and angiogenesis; and the susceptibility of wound tissue to bacteria and infection [6,13,14].…”

Section: Introductionmentioning

confidence: 99%

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Enhancement of wound closure in diabetic mice by ex vivo expanded cord blood CD34+ cells

Chotinantakul¹,

Dechsukhum²,

Dejjuy³

et al. 2013

Cellular and Molecular Biology Letters

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Diabetes can impair wound closure, which can give rise to major clinical problems. Most treatments for wound repair in diabetes remain ineffective. This study aimed to investigate the influence on wound closure of treatments using expanded human cord blood CD34 + cells (CB-CD34 + cells), freshly isolated CB-CD34 + cells and a cytokine cocktail. The test subjects were mice with streptozotocin-induced diabetes. Wounds treated with fresh CB-CD34 + cells showed more rapid repair than mice given the PBS control. Injection of expanded CB-CD34 + cells improved wound closure significantly, whereas the injection of the cytokine cocktail alone did not improve wound repair. The results also demonstrated a significant decrease in epithelial gaps and advanced re-epithelialization over the wound bed area after treatment with either expanded CB-CD34 + cells or freshly isolated cells compared with the control. In addition, treatments with both CB-CD34 + cells and the cytokine cocktail were shown to promote recruitment of CD31 + -endothelial cells in the wounds. Both the CB-CD34 + cell population and the cytokine treatments also enhanced the recruitment of CD68-positive cells in the early stages (day 3) of treatment compared with PBS control, although the degree of this enhancement was found to decline in the later stages (day 9). These results demonstrated that expanded CB-CD34 + cells or freshly isolated CB-CD34 + cells could accelerate wound repair by increasing the recruitment of macrophages and capillaries and the reepithelialization over the wound bed area. Our data suggest an effective role in wound closure for both ex vivo expanded CB-CD34 + cells and freshly isolated cells, and these may serve as therapeutic options for wound treatment for diabetic patients. Wound closure acceleration by expanded CB-CD34 + cells also breaks the insufficient quantity obstacle of stem cells per unit of cord blood and other stem cell sources, which indicates a broader potential for autologous transplantation.

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Inflammation and neuropeptides: the connection in diabetic wound healing

Cited by 220 publications

References 238 publications

Substance P Promotes Wound Healing in Diabetes by Modulating Inflammation and Macrophage Phenotype

Substance P Promotes Wound Healing in Diabetes by Modulating Inflammation and Macrophage Phenotype

Diabetic Painful and Insensate Neuropathy: Pathogenesis and Potential Treatments

Enhancement of wound closure in diabetic mice by ex vivo expanded cord blood CD34+ cells

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