Substance P Promotes Wound Healing in Diabetes by Modulating Inflammation and Macrophage Phenotype (original) (raw)
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Topical application of substance P promotes wound healing in streptozotocin-induced diabetic rats
Cytokine, 2015
Substance P (SP) is known to stimulate angiogenesis, fibroblasts proliferation and expressions of cytokines and growth factors involved in wound healing. However, SP level reduces in dermis in diabetics and, hence, it was hypothesized that exogenously applied SP could be helpful in improving wound healing in diabetic rats. Excision skin wound was created on the back of diabetic rats and rats were divided into three groups i.e. (i) saline-, (ii) gel-and (iii) SP-treated. Normal saline, pluronic gel and SP (10 À6 M) in gel were topically applied once daily for 19 days. SP treatment significantly increased the wound closure, levels of interleukin-10, and expressions of vascular endothelial growth factor, transforming growth factor-beta1, heme oxygenase-1 and endothelial nitric oxide synthase, whereas it significantly decreased the expression of tumor necrosis factor-alpha, interleukin-1beta and matrix metalloproteinases-9 in the granulation/healing tissue. The inflammatory cells were present for long time in normal saline-treated group. Histological evaluation revealed better extracellular matrix formation with marked fibroblast proliferation and collagen deposition in SP-treated group. Early epithelial layer formation, increased microvessel density and greater growth associated protein-43 positive nerve fibers were also evidenced in SP-treated group. In conclusion, SP treatment markedly accelerated cutaneous wound healing in diabetic rats.
The Open Circulation & Vascular Journal, 2012
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 macrophage-activating lipopeptide-2 accelerates wound healing in diabetic mice
Experimental Dermatology, 2004
Wound healing in healthy individuals proceeds at an optimal rate. However, in patients, with -e.g.-locally impaired blood flow or diabetes, chronic wounds develop and often become infected. Chronic wounds mean a low quality of life for the afflicted patients, not to mention enormous costs. Rather than using recombinant growth factors to accelerate wound healing, we employed the toll-like receptor agonist macrophage-activating lipopeptide-2 (MALP-2) to improve the healing of full-thickness excision skin wounds in an animal model with obese, diabetic mice. A gene array experiment suggested that MALP-2 stimulates the release of various mediators involved in wound healing. Further data to be presented in this study will show (i) that MALP-2 is capable of stimulating the appearance of the monocyte chemoattractant protein-1 at the wound site, (ii) that this leads to increased leucocyte and, in particular, macrophage infiltration and (iii) that MALP-2-treated wounds closed 2 weeks earlier than vehicle-treated controls. MALP-2, thus, appears to stimulate the early inflammatory process needed to set in motion the ensuing consecutive natural steps of wound healing resulting in wound closure.
Inflammation and neuropeptides: the connection in diabetic wound healing
Expert Reviews in Molecular Medicine, 2009
This article provides a broad overview of the interaction between neuropeptides and inflammatory mediators as it pertains to diabetic wound healing. Abnormal wound healing is a major complication of both type I and type II diabetes and is the most frequent cause of non-traumatic lower limb amputation. Wound healing requires the orchestrated integration of complex biological and molecular events. Inflammation, proliferation and migration of cells followed by angiogenesis and re-epithelization are essential phases of wound healing. The link between wound healing and the nervous system is clinically apparent as peripheral neuropathy is reported in 30-50% of diabetic patients and is the most common and sensitive predictor of foot ulceration. The bidirectional connection between the nervous and the immune systems and the role it plays in wound healing has emerged as one of the focal features of the wound healing dogma. The mediators of this connection include neuropeptides and the cytokines released from different cells including immune and cutaneous cells. Therefore, to develop successful wound healing therapies, it is vital to understand in depth the signaling pathways in the neuro-immune axis and their implication in diabetic wound healing.
A Chemical Biological Strategy to Facilitate Diabetic Wound Healing
ACS Chemical Biology, 2014
A complication of diabetes is the inability of wounds to heal in diabetic patients. Diabetic wounds are refractory to healing due to the involvement of activated matrix metalloproteinases (MMPs), which remodel the tissue resulting in apoptosis. There are no readily available methods that identify active unregulated MMPs. With the use of a novel inhibitor-tethered resin that binds exclusively to the active forms of MMPs, coupled with proteomics, we quantified MMP-8 and MMP-9 in a mouse model of diabetic wounds. Topical treatment with a selective MMP-9 inhibitor led to acceleration of wound healing, re-epithelialization, and significantly attenuated apoptosis. In contrast, selective pharmacological inhibition of MMP-8 delayed wound healing, decreased reepithelialization, and exhibited high apoptosis. The MMP-9 activity makes the wounds refractory to healing, whereas that of MMP-8 is beneficial. The treatment of diabetic wounds with a selective MMP-9 inhibitor holds great promise in providing heretofore-unavailable opportunities for intervention of this disease.
Molecular Targets for Promoting Wound Healing in Diabetes
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery, 2007
Diabetic foot ulceration stands as one of the most costly and debilitating complications of diabetes and remains the leading cause of nontraumatic lower extremity amputation in the United States. Traditionally, ischemia, neuropathy, trauma, and infection were considered the culprits of the recurring chronic wound and treatment revolved largely around wound debridement and revascularization. However, recent investigations have uncovered an impaired cutaneous wound healing process in diabetes caused by cellular and molecular alterations in the diabetic microenvironment and have subsequently identified an array of potential molecular targets for intervention. Here, we review recent patents describing upcoming molecular technologies at various stages of development for treating foot ulceration in the diabetic patient. Target classes reviewed include immunomodulators, neuropeptides, and growth factors, and targets reviewed include lactoferrin, thymosin beta 4, T cell immune response cDNA 7, substance P, neuropeptide Y, vascular endothelial growth factor, fibroblast growth factor, nerve growth factor, connective tissue growth factor, hepatocyte growth factor, homeobox genes, and treprostinil. In the course of this presentation, the biology of wound healing and the pathobiology of impaired wound healing in diabetes are emphasized to illustrate how these future molecular therapeutics are intended to counteract disease pathology and promote normal wound repair.
The pro-inflammatory environment in recalcitrant diabetic foot wounds
International Wound Journal, 2008
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.