Proteases and the Diabetic Foot Syndrome: Mechanisms and Therapeutic Implications

Lobmann, Ralf; Schultz, Gregory S.; Lehnert, Hendrik

doi:10.2337/diacare.28.2.461

Cited by 173 publications

(124 citation statements)

References 122 publications

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“…By contrast, the inflammatory reaction in diabetic lesions with poor cicatrization appears to slow recovery by generating an intense proteolytic response, which is mediated by elastase and neutrophils, TNF and IL-1. This inflammatory reaction results from bacterial contamination and recurrent trauma in tissues; however, is not associated with pain (15,18,26,44).…”

Section: Discussionmentioning

confidence: 99%

TUNEL-positive cells in the surgical border of an amputation due to infected diabetic foot

et al. 2011

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Abstract. Diabetic infected foot is the outcome of progressive vascular and neurological damage caused by persistent chronic hyperglycemia. Due to acute hypoxia and infection, the tissues develop extensive necrosis and gangrene, which often require amputation. The decision regarding the level of amputation relies mainly on the personal experience of the surgeon who must identify the healthy tissue without necrosis. However, tissue cells under stress may succumb before clear evidence of necrosis is present. In this study, dying cells with DNA damage were identified in the necrotic lesions and surgical borders of amputations. Therefore, the main purpose of this study was to identify apoptosis in the surgical borders of amputations required to treat infected diabetic foot. Apoptosis was identified by terminal deoxynucleotidyl transferase-mediated bio-dUTP nick-end labeling (TUNEL) in the superficial and deep tissues of wounds, and in the surgical borders of 10 consecutive adult patients with diabetes mellitus type 2 (DM2) who underwent amputation due to infected diabetic foot. The severity of the disease was classified by the Acute Physiological and Chronic Health Evaluation II (APACHE II) score on admission, and laboratory data were collected and bacteriological cultures were obtained from the lesions. The ankle/arm blood pressure index was measured, the blood flow in the affected limb was evaluated by high-resolution ultrasonography and color Doppler and pulse oximetry were performed during surgery. A total of 5 males and 5 females, aged 45-84 years (58.8±14.1), were included. The APACHE II score was 2-18 points (8±5.7). A total of 9 patients developed sepsis and 2 succumbed. A total of 5 patients required above-ankle amputation, and 5 required toe disarticulation. The ankle/ arm blood pressure index ranged from 0.23-0.85 (0.51±0.23). Apoptotic cells were found in ulcers and abscesses, and in areas without necrosis. In the surgical borders of the amputations, apoptotic cells were found in skeletal muscle, blood vessels and periphe ral nerves, particularly Schwann cells. Morphometric analysis revealed that the extent of apoptosis was 2-3 logarithms higher in the surgical borders of the infected diabetic foot compared to the venous ulcers, which were used as the reference. In conclusion, apoptosis was identified in regenerating tissues within diabetic foot wounds and in the surgical borders of amputations, where the surgeon considered the tissues to be undamaged. This information suggests that apoptosis may be present before visible signs of necrosis appear in the diabetic foot and may be caused by hypoxia, acidosis or proinflammatory cytokines. The extent of apoptosis in tissues proximal to necrotic areas may anticipate the development of diabetic foot and help the surgeon to make decisions regarding the need and extent of amputation.

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Section: Discussionmentioning

confidence: 99%

TUNEL-positive cells in the surgical border of an amputation due to infected diabetic foot

et al. 2011

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“…Many researchers have indicated that a retarded remodeling process is caused by abnormally elevated levels of a matrix metalloproteinase (MMP), a superfamily of proteases that can degrade various kinds of extracellular matrix. [2][3][4] In nondiabetic wounds, MMPs are important for remodeling defective tissues by increasing the migration of fibroblasts and endothelial cells of the connective tissues. Their expression levels are tightly…”

Section: Introductionmentioning

confidence: 99%

Cationic star-shaped polymer as an siRNA carrier for reducing MMP-9 expression in skin fibroblast cells and promoting wound healing in diabetic rats

Luo

Yang

et al. 2014

IJN

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Background Excessive expression of matrix metalloproteinase-9 (MMP-9) is deleterious to the cutaneous wound-healing process in the context of diabetes. The aim of the present study was to explore whether a cationic star-shaped polymer consisting of β-cyclodextrin (β-CD) core and poly(amidoamine) dendron arms (β-CD-[D 3 ] 7 ) could be used as the gene carrier of small interfering RNA (siRNA) to reduce MMP-9 expression for enhanced diabetic wound healing. Methods The cytotoxicity of β-CD-(D 3 ) 7 was investigated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (MMT) method in the rat CRL1213 skin fibroblast cell line. The transfection efficiency of β-CD-(D 3 ) 7 /MMP-9-small interfering RNA (siRNA) complexes was determined by confocal microscopy and flow cytometry. Quantitative real time (RT) polymerase chain reaction was performed to measure the gene expression of MMP-9 after the transfection by β-CD-(D 3 ) 7 /MMP-9-siRNA complexes. The β-CD-(D 3 ) 7 /MMP-9-siRNA complexes were injected on the wounds of streptozocin-induced diabetic rats. Wound closure was measured on days 4 and 7 post-wounding. Results β-CD-(D 3 ) 7 exhibited low cytotoxicity in fibroblast cells, and easily formed the complexes with MMP-9-siRNA. The β-CD-(D 3 ) 7 /MMP-9-siRNA complexes were readily taken up by fibroblast cells, resulting in the downregulation of MMP-9 gene expression ( P <0.01). Animal experiments revealed that the treatment by β-CD-(D 3 ) 7 /MMP-9-siRNA complexes enhanced wound closure in diabetic rats on day 7 post-wounding ( P <0.05). Conclusion β-CD-(D 3 ) 7 may be used as an efficient carrier for the delivery of MMP-9-siRNA to reduce MMP-9 expression in skin fibroblast cells and promote wound healing in diabetic rats.

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“…Furthermore, when s f 50.002 the influx of inflammation to the wound site did not elicit more damage than the initial level of D50.5. These experiments correlate to the use of agents such as recombinant platelet-derived growth factor 37 and basic fibroblast growth factor (bFGF). 38 The Akita et al 38 study reported a 20% decrease in healing time with the use of bFGF, which is on the same order of magnitude as the decrease seen in our model experiment.…”

Section: Resultsmentioning

confidence: 99%

“…Impaired fibroblast production results in a nonhealing state, but under conditions where the production is increased we have wounds that heal at notably faster rates. 37,38 This provides a framework from which to test a new hypothesis in a living model.…”

Section: Discussionmentioning

confidence: 99%

An in silico approach to the analysis of acute wound healing

Menke¹,

Cain

Reynolds

et al. 2010

Wound Repair and Regeneration

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The complex interactions that characterize acute wound healing have stymied the development of effective therapeutic modalities. The use of computational models holds the promise to improve our basic approach to understanding the process. By modifying an existing ordinary differential equation model of systemic inflammation to simulate local wound healing, we expect to improve the understanding of the underlying complexities of wound healing and thus allow for the development of novel, targeted therapeutic strategies. The modifications in this local acute wound healing model include: evolution from a systemic model to a local model, the incorporation of fibroblast activity, and the effects of tissue oxygenation. Using these modifications we are able to simulate impaired wound healing in hypoxic wounds with varying levels of contamination. Possible therapeutic targets, such as fibroblast death rate and rate of fibroblast recruitment, have been identified by computational analysis. This model is a step toward constructing an integrative systems biology model of human wound healing.A soft tissue injury elicits a well-prescribed wound healing response.1,2 The process of wound healing is designed to restore anatomic and functional characteristics of the tissue; however, little progress has been made in improving the wound healing response time or in preventing complications such as fibrosis, infections, and formation of nonhealing wounds.3 In this paper, we describe a computational model of acute wound healing designed to allow a system-level analysis of the wound healing response using ordinary differential equations (ODEs). As a first step to a more comprehensive model, we have explored the combined effects of bacterial infections, inflammation, and tissue hypoxia on the rate and success of wound healing since these processes are well-known as affecters of healing. As this model matures, it will provide the opportunity to test new mechanisms and novel therapeutics of wound healing strategies in silico.Despite burgeoning interest in the field of computational biology, work of limited scope has been published on modeling the acute wound. Most of these studies show the difficulties of adequately accounting for the myriad of potential interactions. 4 For example, in their respective works on epidermal wound healing, Stekel et al., 5 Walker et al., 6 and Morel et al. 7 do not attempt to simulate healing by fibroblasts and do not implement inflammatory changes in their models. Dallon et al. 8 constructed an ODE model of collagen deposition focusing on the fibroblasts and their relationship to the underlying extracellular matrix, but do not account for inflammation or repair of underlying tissue damage. Schugart et al. 9 recently published a model of wound angiogenesis as a function of tissue oxygen tension but the model does not specifically address the wound healing process.Reynolds et al. 10,11 created an ODE model designed to simulate inflammation and repair on a systemic level in the setting of a systemic ins...

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Proteases and the Diabetic Foot Syndrome: Mechanisms and Therapeutic Implications

Cited by 173 publications

References 122 publications

TUNEL-positive cells in the surgical border of an amputation due to infected diabetic foot

TUNEL-positive cells in the surgical border of an amputation due to infected diabetic foot

Cationic star-shaped polymer as an siRNA carrier for reducing MMP-9 expression in skin fibroblast cells and promoting wound healing in diabetic rats

An in silico approach to the analysis of acute wound healing

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