Deregulated unfolded protein response in chronic wounds of diabetic ob/ob mice: A potential connection to inflammatory and angiogenic disorders in diabetes-impaired wound healing (original) (raw)
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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.
Journal of Investigative Dermatology, 2007
To date, diabetes-associated skin ulcerations represent a therapeutic problem of clinical importance. The insulin-resistant type II diabetic phenotype is functionally connected to obesity in rodent models of metabolic syndrome through the release of inflammatory mediators from adipose tissue. Here, we used the impaired wound-healing process in obese/obese (ob/ob) mice to investigate the impact of obesity-mediated systemic inflammation on cutaneous wound-healing processes. Systemic administration of neutralizing monoclonal antibodies against tumor necrosis factor (TNF)a (V1q) or monocyte/macrophage-expressed EGF-like modulecontaining mucin-like hormone receptor-like (Emr)-1 (F4/80) into wounded ob/ob mice at the end of acute wound inflammation initiated a rapid and complete neo-epidermal coverage of impaired wound tissue in the presence of a persisting diabetic phenotype. Wound closure in antibody-treated mice was paralleled by a marked attenuation of wound inflammation. Remarkably, anti-TNFaand anti-F4/80-treated mice exhibited a strong reduction in circulating monocytic cells and reduced numbers of viable macrophages at the wound site. Our data provide strong evidence that anti-TNFa therapy, widely used in chronic inflammatory diseases in humans, might also exert effects by targeting ''activated'' TNFa-expressing macrophage subsets, and that inactivation or depletion of misbehaving macrophages from impaired wounds might be a novel therapeutic clue to improve healing of skin ulcers.
Substance P Promotes Wound Healing in Diabetes by Modulating Inflammation and Macrophage Phenotype
The American Journal of Pathology, 2015
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, -: 1e11; http:// dx.
Macrophage dysfunction impairs resolution of inflammation in the wounds of diabetic mice
PloS one, 2010
Chronic inflammation is a characteristic feature of diabetic cutaneous wounds. We sought to delineate novel mechanisms involved in the impairment of resolution of inflammation in diabetic cutaneous wounds. At the wound-site, efficient dead cell clearance (efferocytosis) is a pre-requisite for the timely resolution of inflammation and successful healing. Macrophages isolated from wounds of diabetic mice showed significant impairment in efferocytosis. Impaired efferocytosis was associated with significantly higher burden of apoptotic cells in wound tissue as well as higher expression of pro-inflammatory and lower expression of anti-inflammatory cytokines. Observations related to apoptotic cell load at the wound site in mice were validated in the wound tissue of diabetic and non-diabetic patients. Forced Fas ligand driven elevation of apoptotic cell burden at the wound site augmented pro-inflammatory and attenuated anti-inflammatory cytokine response. Furthermore, successful efferocyto...
Diabetes
Patients with diabetes present a persistent inflammatory process, leading to impaired wound healing. Since nonhealing diabetic wound management shows limited results, the introduction of advanced therapies targeting and correcting the inflammatory status of macrophages in chronic wounds could be an effective therapeutic strategy to stop the sustained inflammation and to return to a healing state. In an excisional skin injury in a diet-induced diabetic murine model, we demonstrate that topical administration of low-dose aspirin (36 μg/wound/day) improves cutaneous wound healing by increasing wound closure through the promotion of the inflammation resolution program of macrophages. This treatment increased efferocytosis of wound macrophages from aspirin-treated diabetic mice compared with untreated diabetic mice. We also show that aspirin treatment of high-fat–fed mice oriented the phenotype of wound macrophages toward an anti-inflammatory and proresolutive profile characterized by a ...
Wound healing from a cellular stress response perspective
Cell Stress and Chaperones, 2008
This meeting review highlights areas of mutual interest to investigators in the cellular stress response field and to those carrying out wound-healing research. Inflammation, perhaps the major unifying theme of this meeting, is an essential component of the adult wound response and understanding the control of inflammation is a common interest shared with researchers of the cellular stress response. The particular interest of the authors of this review is in chronic non-healing wounds that frequently occur in patients with major illnesses such as diabetes and diseases of the blood vessels. This orientation has undoubtedly influenced the selection of topics. It is fair to say that the authors were often surprised and certainly impressed with the overlapping interests and possibilities for collaboration among investigators of these two research areas.
The American Journal of Pathology, 2001
Receptor for advanced glycation end-products (RAGE), and two of its ligands, AGE and EN-RAGEs (members of the S100/calgranulin family of pro-inflammatory cytokines), display enhanced expression in slowly resolving full-thickness excisional wounds developed in genetically diabetic db؉/db؉ mice. We tested the concept that blockade of RAGE, using soluble(s) RAGE, the extracellular ligand-binding domain of the receptor, would enhance wound closure in these animals. Administration of sRAGE accelerated the development of appropriately limited inflammatory cell infiltration and activation in wound foci. In parallel with accelerated wound closure at later times, blockade of RAGE suppressed levels of cytokines; tumor necrosis factor-␣; interleukin-6; and matrix metalloproteinases-2,-3, and-9. In addition, generation of thick, well-vascularized granulation tissue was enhanced, in parallel with increased levels of platelet-derived growth factor-B and vascular endothelial growth factor. These findings identify a central role for RAGE in disordered wound healing associated with diabetes, and suggest that blockade of this receptor might represent a targeted strategy to restore effective wound repair in this disorder.
Modulation of Inflammatory Dynamics by Insulin to Promote Wound Recovery of Diabetic Ulcers
Wound Healing [Working Title]
About 5% of the world population is diabetic and are at a risk of slow nonrecoverable wound formation. Estimated 15-25% of diabetic patients develop foot ulcers, 6% among them needing clinical attention among which 15-20% will need an amputation. This counts for around 50% of all traumatic amputation. Wound leads to activation of dynamic inflammatory cascade responsible for the healing process. But in diabetes, a persistent rise of pro-inflammatory cytokines and low anti-inflammatory cytokines blocks the dynamic cascade. Wounding induces various pro-inflammatory cytokines such as IL-1, IL-6, IL-12, IL-18, IFN-γ, and TNFs causing accumulation of free radicals leading to inflammation which become persistent in diabetes. Inhibition of proinflammatory cytokines drives the equilibrium towards the expression of anti-inflammatory cytokines such as IL4, IL-10, IL-11, IL-13, IFN-α, and TGF-β, which is necessary for the wound recovery process. Here in this chapter, the inflammatory modulatory roles of different drugs/formulations have been discussed to unravel their significance to promote wound recovery.
Diabetes impairs numerous components of wound healing, including inflammation, matrix deposition, and angiogenesis. The locally acting isoform of IGF-1 (mIGF-1) was shown to enhance wound healing. In this study, we tested the therapeutic potential of mIGF-1 in the skin regeneration of diabetic mice. To establish the mechanism of mIGF-1 transgene action on the diabetic wound healing the effect of mIGF-1 transgene on angiogenesis and its interrelation with the inflammatory process in the wound was verified. Also, the total IGF-1 gene expression damage in the uninjured skin of diabetic mice, and elevated level in the skin of K14/mIGF-1 transgenic mice were established.