Differences in Cellular Infiltrate and Extracellular Matrix of Chronic Diabetic and Venous Ulcers Versus Acute Wounds

Abstract

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 cells, B cells, plasma cells, granulocytes and macrophages, and the ECM molecules fibronectin (FN), chondroitin sulfate (CS), and tenascin (TN) were visualized using immunohistochemical techniques. Expression of FN, CS, and TN was detected in dermal tissue early in normal wound healing (5-19 d p.w.). 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 ulcers with a duration of 12 mo or more, a prolonged presence of these ECM molecules was noted. Compared with normal wound healing: (i) the CD4/CD8 ratio in chronic wounds was significantly lower (p < 0.0027) due to a relatively lower number of CD4+ T cells; (ii) a significantly higher number of macrophages was present in the edge of both type of chronic ulcers (p < 0.001 versus day 29 p.w.); and (iii) more B cells and plasma cells were detected in both type of chronic wounds compared with any day in the acute wound healing model (p < 0.04 for CD20+ and p < 0.01 for CD79a+ cells). These data indicate that important differences exist in the cellular infiltrate and ECM expression patterns of acute, healing versus chronic wounds, which may be related to the nonhealing status of chronic wounds.

A novel primate model of delayed wound healing in diabetes: dysregulation of connective tissue growth factor

“…The diabetic animals also showed an increase in epidermal thickness at 2 weeks, although the lack of reduction in thickness at 4 weeks suggests that epidermal wound healing is delayed in diabetic animals. The wound microenvironment in diabetes is altered in many ways, including abnormal cellular infiltration and impaired vascular formation [35]. There is delayed and prolonged inflammation with impaired angiogenesis [36], as well as defective macrophage function and decreased collagen synthesis [35].…”

“…The wound microenvironment in diabetes is altered in many ways, including abnormal cellular infiltration and impaired vascular formation [35]. There is delayed and prolonged inflammation with impaired angiogenesis [36], as well as defective macrophage function and decreased collagen synthesis [35]. Neutrophil infiltration appears to be delayed and protracted in diabetes, while the role of the macrophage in the transition from the inflammatory to the proliferating phase of a healing wound is impaired [5].…”

Electroporative transfection with KGF-1 DNA improves wound healing in a diabetic mouse model

“…18,19 Wound healing impairment in the genetically diabetic mouse reflects similar problems such as prolonged inflammation, impaired neovascularization and decreased synthesis of collagen. 20 Expression profiles of various growth factors are also aberrant in the diabetic mouse with KGF-1 and FGF induction being premature, delayed or absent as compared to a healthy mouse. 18 The failure of diabetic mice to produce timely increases of FGF and KGF-1 levels led us and others to attempt to remedy the situation by applying growth factors or using gene therapy.…”

Differential Roles of Macrophages in Diverse Phases of Skin Repair

“…However, due to the release of proinflammatory and cytotoxic mediators, uncontrolled activity of macrophages may also be detrimental to tissue repair. Indeed, imbalanced inflammation characterized by increased numbers of macrophages is a hallmark of an attenuated repair response in human diseases encompassing diabetes mellitus, vascular disease, and aging (7,8). Currently, it is not completely understood how macrophages exactly impact the physiology of the repair response and how they may contribute to the pathology of the repair response in diseased conditions.…”