Histological and Transcriptional Expression differences between Diabetic Foot and Pressure Ulcers (original) (raw)
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Glucose Toxic Effects on Granulation Tissue Productive Cells: The Diabetics’ Impaired Healing
BioMed Research International, 2013
Type 2 diabetes mellitus is a metabolic noncommunicable disease with an expanding pandemic magnitude. Diabetes predisposes to lower extremities ulceration and impairs the healing process leading to wound chroni�cation. Diabetes also dismantles innate immunity favoring wound infection. Amputation is therefore acknowledged as one of the disease's complications. Hyperglycemia is the proximal detonator of systemic and local toxic e�ectors including proin�ammation, acute-phase proteins elevation, and spillover of reactive oxygen and nitrogen species. Insulin axis de�ciency weakens wounds' anabolism and predisposes to in�ammation. e systemic accumulation of advanced glycation end-products irreversibly impairs the entire physiology from cells-to-organs. ese factors in concert hamper �broblasts and endothelial cells proliferation, migration, homing, secretion, and organization of a productive granulation tissue. Diabetic wound bed may turn chronically in�ammed, procatabolic, and an additional source of circulating pro-in�ammatory cytokines, establishing a self-perpetuating loop. Diabetic �broblasts and endothelial cells may bear mitochondrial damages becoming prone to apoptosis, which impairs granulation tissue cellularity and perfusion. Endothelial progenitor cells recruitment and tubulogenesis are also impaired. Failure of wound reepithelialization remains a clinical challenge while it appears to be biologically multifactorial. Ulcer prevention by primary care surveillance, education, and attention programs is of outmost importance to reduce worldwide amputation �gures.
Differential Regulation of Angiogenic Genes in Diabetic Wound Healing
Journal of Investigative Dermatology, 2006
Wound healing is a complicated biological process that involves interactions of multiple cell types, various growth factors, their mediators, and the extracellular matrix proteins. In this study, we have studied the differential regulation of angiogenic genes during wound healing in transgenic (Lepr À/À) diabetic mice and non-diabetic mice. Under aseptic conditions, 8 mm full thickness cutaneous wounds were created on either side of the mid-dorsal. Wound tissues were studied at 4, 7, and 11 days post-wounding and healing was assessed by histology. The pathway-specific gene array data demonstrated differential regulation of growth factors, transcription factors, and other related genes, such as fibroblast growth factors and their receptors. The extracellular matrix protein osteopontin (OPN), an important component of cellular immunity and inflammation, showed higher expression in non-diabetic wounds after 4 days post-wounding, whereas its expression was at basal level in diabetic wounds. OPN expression remained upregulated in non-diabetic wounds at day 7 post-wounding and was downregulated to basal level at day 11 post-wounding. However, expression of OPN was upregulated in diabetic wounds at day 7 post-wounding and remained constitutively higher at day 11 post-wounding. OPN expression was concomitant with the extent of healing as assessed by histology at the corresponding sampling point. This finding suggests that OPN might be playing a crucial role in the early events of the wound healing and its delayed expression may be in part responsible for the delayed healing of wounds in diabetic mice.
Cellular and molecular insights into the wound healing mechanism in diabetes
Impaired healing in diabetes affects the resolution of both acute and chronic wounds. The vicious circle between wound chronicity and a deficient control of local infection is the cause that diabetic patients constitute 85% of all non-traumatic lower extremity amputations. From an etiological viewpoint, hyperglycemia is what triggers the onset and progression of biochemical disturbances that lead to systemic complications. In contrast to normal wound healing, physiological apoptotic clearance of inflammatory cells is prevented and the inflammatory phase is abnormally prolonged in diabetic wounds. Pro-inflammatory cytokines as tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β) are increased in diabetic wounds with negative local and remote consequences. The etiopathogenic network consisting of inflammatory cytokines, local proteases, reactive oxygen and nitrogen species produces a cytotoxic and pro-degradation environment within the wound bed that impairs granulation and re-epithelialization. The nonenzymatic glycation of proteins, generating advanced glycation end-products (AGE), acts as an active pathogenic stream affecting healing. The accumulation of AGE interferes with DNA replication, cell anchoring, migration and proliferation. The binding of AGE to a receptor model (RAGE) may completely hamper the healing process. Diabetes impairs the recruitment and differentiation of bone marrow-derived stem cells, thereby limiting the availability of tissue repair cells. Re-epithelialization is also hindered by incomplete activation and/or differentiation of keratinocytes that impair migration. Novel and revolutionary pharmacological interventions are urgently needed to reduce diabetes complications, such as amputations of the lower extremities.
International Wound Journal, 2008
How differential gene expression affects wound healing is not well understood. In this study, Zucker diabetic fatty (fa/fa) male inbred rats were used to investigate gene expression during wound healing in an impaired wound‐healing model. Whole genome microarray surveys were used to gain insight into the biological pathways and healing processes in acute excisional wounds treated with vacuum‐assisted closure (V.A.C.®) Therapy, moist wound healing (MWH) or gauze under suction (GUS). Global gene expression analyses after 2 days of healing indicated major differences with respect to both number of genes showing fold changes and pathway regulation between the three different wound treatments. Statistical analysis of expression profiles indicated that 5072 genes showed a >1·6‐fold change with V.A.C. Therapy compared with 3601 genes with MWH and 3952 genes with GUS. Pathways and related genes associated with the early phases of wound healing diverged between treatment groups. For examp...
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.
Journal of Investigative Dermatology, 1998
In diabetic patients, wound healing is impaired. We studied the pathogenesis behind this clinical observation by characterizing the pattern of deposition of extracellular matrix (ECM) molecules and the cellular infiltrate in chronic (>8 wk) diabetic wounds, compared with chronic venous ulcers and an acute wound healing model. Punch biopsies were obtained from the chronic ulcer margins and control samples were collected from upper leg skin 5, 19, 28 d and 12 and 18 mo postwounding (p.w.). T . Abundant staining was seen 3 mo p.w., returning to prewounding levels after 12-18 mo p.w. In the dermis of chronic diabetic and venous