Xu Ke-Ping, Li Yanfeng, Ljubimov Alexander V, Yu Fu-Shin X
Kresge Eye Institute, Department of Ophthalmology, Wayne State University School of Medicine, Detroit, Michigan, USA.
Diabetes. 2009 May;58(5):1077-85. doi: 10.2337/db08-0997. Epub 2009 Feb 2.
Patients with diabetes are at an increased risk for developing corneal complications and delayed wound healing. This study investigated the effects of high glucose on epidermal growth factor receptor (EGFR) signaling and on epithelial wound healing in the cornea.
Effects of high glucose on wound healing and on EGFR signaling were investigated in cultured porcine corneas, human corneal epithelial cells, and human corneas using Western blotting and immunofluorescence. Effects of high glucose on reactive oxygen species (ROS) and glutathione levels and on EGFR pathways were assessed in porcine and primary human corneal epithelial cells, respectively. The effects of EGFR ligands and antioxidants on high glucose-delayed epithelial wound healing were assessed in cultured porcine corneas.
High glucose impaired ex vivo epithelial wound healing and disturbed cell responses and EGFR signaling to wounding. High glucose suppressed Akt phosphorylation in an ROS-sensitive manner and decreased intracellular glutathione in cultured porcine corneas. Exposure to high glucose for 24 h resulted in an increase in ROS-positive cells in primary human corneal epithelial cells. Whereas heparin-binding EGF-like growth factor and antioxidant N-acetylcysteine had beneficial effects on epithelial wound closure, their combination significantly accelerated high glucose-delayed wound healing to a level similar to that seen in control subjects. Finally, Akt signaling pathway was perturbed in the epithelia of human diabetic corneas, but not in the corneas of nondiabetic, age-matched donors.
High glucose, likely through ROS, impairs the EGFR-phosphatidylinositol 3-kinase/Akt pathway, resulting in delayed corneal epithelial wound healing. Antioxidants in combination with EGFR ligands may be promising potential therapeutics for diabetic keratopathy.
糖尿病患者发生角膜并发症及伤口愈合延迟的风险增加。本研究调查了高糖对角膜表皮生长因子受体（EGFR）信号传导及上皮伤口愈合的影响。
使用蛋白质免疫印迹法和免疫荧光法，在培养的猪角膜、人角膜上皮细胞及人角膜中研究高糖对伤口愈合及EGFR信号传导的影响。分别在猪和原代人角膜上皮细胞中评估高糖对活性氧（ROS）和谷胱甘肽水平以及对EGFR通路的影响。在培养的猪角膜中评估EGFR配体和抗氧化剂对高糖延迟上皮伤口愈合的影响。
高糖损害离体上皮伤口愈合，扰乱细胞对伤口的反应及EGFR信号传导。高糖以ROS敏感的方式抑制Akt磷酸化，并降低培养的猪角膜中的细胞内谷胱甘肽水平。原代人角膜上皮细胞暴露于高糖24小时导致ROS阳性细胞增加。尽管肝素结合表皮生长因子样生长因子和抗氧化剂N - 乙酰半胱氨酸对上皮伤口闭合有有益作用，但它们的联合使用显著加速了高糖延迟的伤口愈合，使其达到与对照组相似的水平。最后，Akt信号通路在人类糖尿病角膜上皮中受到干扰，但在年龄匹配的非糖尿病供体角膜中未受干扰。
高糖可能通过ROS损害EGFR - 磷脂酰肌醇3 - 激酶/Akt通路，导致角膜上皮伤口愈合延迟。抗氧化剂与EGFR配体联合使用可能是治疗糖尿病角膜病变的有前景的潜在疗法。
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