Effects of p38 MAPK Inhibition on Early Stages of Diabetic Retinopathy and Sensory Nerve Function
Effects of p38 MAPK Inhibition on Early Stages of Diabetic Retinopathy and Sensory Nerve Function
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DOI：
10.1167/iovs.09-3674
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发表时间：
2010-04-01
影响因子：
4.4
通讯作者：
Kern, Timothy S.
中科院分区：
文献类型：
--
作者：
Du, Yunpeng;Tang, Jie;Kern, Timothy S.
目的.已知p38丝裂原活化蛋白激酶（MAPK）在疾病的炎症过程中起调节作用。炎症也与啮齿动物中糖尿病视网膜病变的发展有关。本研究旨在评价p38 MAPK抑制剂对大鼠早期糖尿病视网膜病变的影响。将链脲佐菌素糖尿病大鼠分为两组--用p38 MAPK抑制剂PHA 666859（Pfizer，纽约，NY）处理和未处理--并与年龄匹配的非糖尿病对照动物进行比较。在糖尿病2个月时，胰岛素缺乏的糖尿病对照大鼠表现出视网膜超氧化物、一氧化氮（NO）、环氧合酶（考克斯）-2和视网膜微血管内白细胞淤滞的显著增加。所有这些异常均被p38 MAPK抑制剂（25 mg/kgBW/d）显著抑制。在糖尿病10个月时，对照糖尿病大鼠与非糖尿病对照动物相比，变性（无细胞）毛细血管和周细胞血影的数量显著增加，药物抑制p38 MAPK可显著抑制所有这些异常（均P < 0.05）。这种疗法对糖尿病患者眼外也有有益的影响，抑制糖尿病引起的外周神经对轻触的超敏反应（触觉异常性疼痛）就证明了这一点。结论。p38 MAPK在糖尿病诱导的视网膜炎症中起重要作用，并且抑制p38 MAPK提供了抑制糖尿病视网膜病变的早期阶段和糖尿病的其他并发症的发展的新的治疗方法。（Invest Ophthalmol维斯科学。2010; 51：2158-2164）DOI：10.1167/iovs.09-3674
PURPOSE. p38 mitogen-activated protein kinase (MAPK) is known to play a regulatory role in inflammatory processes in disease. Inflammation has been linked also to the development of diabetic retinopathy in rodents. This study was conducted to evaluate the effect of a p38 MAPK inhibitor on the development of early stages of diabetic retinopathy in rats.METHODS. Streptozotocin-diabetic rats were assigned to two groups-treated with the p38 MAPK inhibitor PHA666859 (Pfizer, New York, NY) and untreated-and compared with age-matched nondiabetic control animals.RESULTS. At 2 months of diabetes, insulin-deficient diabetic control rats exhibited significant increases in retinal superoxide, nitric oxide (NO), cyclooxygenase (COX)-2, and leukostasis within retinal microvessels. All these abnormalities were significantly inhibited by the p38 MAPK inhibitor (25 mg/kgBW/d). At 10 months of diabetes, significant increases in the number of degenerate (acellular) capillaries and pericyte ghosts were measured in control diabetic rats versus those in nondiabetic control animals, and pharmacologic inhibition of p38 MAPK significantly inhibited all these abnormalities (all P < 0.05). This therapy also had beneficial effects outside the eye in diabetes, as evidenced by the inhibition of a diabetes-induced hypersensitivity of peripheral nerves to light touch (tactile allodynia).CONCLUSIONS. p38 MAPK plays an important role in diabetes-induced inflammation in the retina, and inhibition of p38 MAPK offers a novel therapeutic approach to inhibiting the development of early stages of diabetic retinopathy and other complications of diabetes. (Invest Ophthalmol Vis Sci. 2010; 51: 2158-2164) DOI:10.1167/iovs.09-3674