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Blocking AGE-RAGE Signaling Improved Functional Disorders of Macrophages in Diabetic Wound 时间:2017-10-11 10:56 来源:未知作者:admin 点击: 次 Abstract:Advanced glycosylation end products (AGEs) accumulate in diabetic wounds. Interactions between AGEs and their receptor (RAGE) leads to dermatologic problems in diabetes. Macrophage, which plays important roles in wound healing, highly expresses RAGE. Therefore, we investigated whether RAGE-expressing macrophages might be responsible for impaired wound healing on diabetes. We used anti-RAGE antibody applied topically on diabetic wounds. After confirming that wound healing was improved in anti-RAGE antibody group compared with normal mice, our results showed that macrophages appeared insufficient in the early stage and fading away slowly in the later proliferative phase compared with the control group, which was ameliorated in anti-RAGE antibody-applied wounds. Blocking AGE-RAGE signaling also increased neutrophils phagocytized by macrophages and promoted the phenotypic switch of macrophages from proinflammatory to prohealing activities. In vitro, phagocytosis of THP-1 (M0) and lipopolysaccharide- (LPS-) induced (M1) macrophages was impaired by treatment with AGEs, while IL-4- and IL-13-induced (M2) macrophages was not. Finally, AGEs increased the proinflammatory response of M1 macrophages, while inhibiting the polarization and anti-inflammatory functions of M2 macrophages. In conclusion, inhibition of AGE-RAGE signaling improved functional disorders of macrophages in the early inflammatory phase, which promoted the healing of wounds in diabetic mice.
1. Introduction
Morbidity resulting from diabetes mellitus is rapidly increasing worldwide and constitutes a burden to our global society [1]. Impaired wound healing is a serious complication of this disease, and it results in severe pain and reduced quality of life. There is compelling evidence that AGEs accumulate in these wounds because of certain biochemical features associated with diabetes. They are thought to contribute significantly to the pathology associated with impaired wound healing [2–4].
RAGE is a receptor for AGEs, and it is expressed in a variety of cells. It is particularly enriched in macrophages. Recent clinical and experimental research has shown that blocking the AGE-RAGE signaling interaction enhances angiogenesis, increases granulation of tissues, and promotes faster re-epithelialization in wounds. This helps to promote diabetic wound healing [5].
Macrophages play a vital role in wound healing [6–8]. Although their exact roles remain incompletely understood, [9–12] macrophage-based therapies are beneficial for some patients, including the elderly and those with hard-to-heal wounds [13–18]. This offers a cellular target for improving wound-healing therapies. However, before macrophage-based therapies can be developed, a more complete understanding of macrophage dysfunction during wound healing is required.
AGEs accumulate in the diabetic derma and contribute to impaired wound healing, together with macrophages, which express high levels of the receptor RAGE, suggests that AGE-RAGE signaling might underlie the macrophage dysfunction that is a hallmark of impaired wound healing in diabetics. Here, we studied the functional changes of macrophages during wound healing in a diabetic mouse model. We also explored the influence of AGEs on THP-1 macrophages and their relationship with AGE-RAGE signaling. These results improve our understanding of the association between AGE-RAGE signaling and the functional dysregulation of macrophages in impaired wound healing. These findings may aid the development of macrophage-based therapies for this diabetic complication in the future.
2. Materials and Methods
2.1. Induction of Diabetes in Mice and Wounding
Male C57BL/6 mice (8–10 weeks old, 20–25 g) were obtained from the Experimental Animal Center of Rui Jin Hospital in Shanghai, China. All experimental procedures were in compliance with laboratory institutional guidelines and the National Institutes of Health Guide for the Care and Use of Laboratory Animals.
To induce diabetes, a daily intraperitoneal injection of STZ (Sigma-Aldrich, St. Louis, MO, USA) at a dose of 65 mg/kg body weight was administered for 5 consecutive days. Blood glucose measurements were performed for 8 weeks after the injections. When polyuria, polydipsia, polyphagia, weight loss, and elevated blood glucose (16.7 mmol/L) were observed, mice were deemed to be in a diabetic state.