High-Glucose Environment Enhanced Oxidative Stress and Increased Interleukin-8 Secretion From Keratinocytes

Abstract

Impaired wound healing frequently occurs in patients with diabetes. Interleukin (IL)-8 production by keratinocyte is responsible for recruiting neutrophils during healing. Intense inflammation is associated with diabetic wounds, while reduction of neutrophil infiltration is associated with enhanced healing. We hypothesized that increased neutrophil recruitment by keratinocytes may contribute to the delayed healing of diabetic wounds. Using cultured human keratinocytes and a diabetic rat model, the current study shows that a high-glucose environment enhanced IL-8 production via epidermal growth factor receptor (EGFR)–extracellular signal–regulated kinase (ERK) pathway in a reactive oxygen species (ROS)-dependent manner in keratinocytes. In addition, diabetic rat skin showed enhanced EGFR, ERK, and IL-8 expression compared with control rats. The dermal neutrophil infiltration of the wound, as represented by expression of myeloperoxidase level, was also significantly higher in diabetic rats. Treating diabetic rats with dapsone, an agent known to inhibit neutrophil function, was associated with improved healing. In conclusion, IL-8 production and neutrophil infiltration are increased in a high-glucose environment due to elevated ROS level and contributed to impaired wound healing in diabetic skin. Targeting these dysfunctions may present novel therapeutic approaches.

Downregulation of miRNAs during Delayed Wound Healing in Diabetes: Role of Dicer

“…Egf belongs to a family of growth factors that regulate cell proliferation and migration by binding to epidermal growth factor receptor (Egfr) on the cell surface. Increased phosphorylatedepidermal growth factor receptor (p-Egfr) has been associated with the skin during diabetes in an oxidative stressprone environment (32). In a similar first compared basal levels of these genes in the normal and diabetic rat skin (unwounded).…”

Effects of Systemic Chlorogenic Acid on Random-Pattern Dorsal Skin Flap Survival in Diabetic Rats

“…5,54,55) In the current study, the harmful effects of diabetes were also detected in our histopathological, immunohistochemical, Doppler and microangiographical assays. The semiquantitative histopathological findings of our study showed enhanced capillary density and fibroblast proliferation and decreased necrosis in peripherally CGA-treated rats compared with the PBS-treated rats.…”

“…16) Chronic hyperglycemia induces pathological changes in tissues, delays wound healing and increases the predisposition to infections. 5,54,55) CGA has been reported to modulate blood glucose levels and exhibits protective effects against tissue changes in diabetes. 41) CGA has been shown to exhibit hypoglycemic activity at a 27 mg/kg dosage in streptozotocin diabetic rats within 11 d 24) or 5 mg/kg/day orally for 45 d in streptozotocin-nicotinamide-induced diabetes.…”

Folic Acid Promotes Wound Healing in Diabetic Mice by Suppression of Oxidative Stress

“…Increased oxidative stress in diabetes is due to an imbalance between the production of ROS and the protection by cellular antioxidants (4,5,31). GSH plays important roles in antioxidant defense.…”

“…Refractory skin wound healing in diabetic patients represents a challenging medical and societal problem leading to a substantial reduction in quality of life (3). Previous studies demonstrated that sustained hyperglycemia induces excessive production of reactive oxygen species (ROS) (4). Excess ROS causes multiple cellular components damage, including excessive oxidation of lipids and proteins.…”