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糖尿病性角膜病变的研究进展

Research progress of diabetic keratopathy

来源期刊: 眼科学报 | 2022年1月 第37卷 第1期 65-71 发布时间:2021–08–02 收稿时间:2022/11/28 11:11:29 阅读量:2633
作者:
关键词:
角膜糖尿病糖尿病性角膜病变
cornea diabetes diabetic keratopathy
DOI:
10.3978/j.issn.1000-4432.2021.12.01
晚期糖尿病(diabetes mellitus,DM)患者常出现的糖尿病性视网膜病变能够被发现,而糖尿病性角膜病变(diabetic keratopathy,DK)却时常被人们忽略。近年来的许多研究表明,DK对角膜的结构、代谢、生理功能等多个方面均有重要影响。目前临床上尚无根治DK的有效疗法,现主流疗法多集中于对症治疗以维持光滑湿润的眼表,最大限度地减少视觉损失以及提高舒适度,如局部滴用人工泪液、使用角膜绷带镜及局部使用抗炎药物等,但这些现有的治疗方法对于角膜组织损伤的修复能力有限。近年来出现神经生长因子、胰岛素疗法等新兴的治疗方法,有望未来应用于临床。
The diabetic retinopathy which often occurs in patients with advanced diabetes mellitus (DM) can usually be realized, but diabetic keratopathy (DK) could sometimes be ignored. In recent years, many studies have found out that DK can cause significant abnormal changes in many ways, including structure, metabolism and physiological functions of the cornea. At present, there is no effective therapy to cure DK. The current mainstream therapy mostly focuses on symptomatic treatment to maintain a smooth and moist ocular surface, minimize visual loss and improve comfort, such as local drip of artificial tears, use of corneal bandage lens and local use of anti-inflammatory drugs. However, these existing treatment methods have limited repair ability for corneal tissue damage. In recent years, a number of new treatment methods have emerged, which are expected to be clinically used in the future, such as nerve growth factors and insulin therapy.
    糖尿病(diabetes mellitus,DM)是当前严重威胁人类健康的世界性公共卫生问题,是一种常见的代谢性疾病。由于生活方式的改变,热量摄入增加,导致肥胖的发生。DM的发病率一直呈上升趋势。目前,全世界有4.15亿成年人被诊断为DM,预计到2040年,将有超过6.4亿人将罹患DM。
    糖尿病性角膜病变(diabetic keratopathy,DK)是DM患者中常见但常被忽视的眼部并发症,是一种潜在的视力威胁性疾病。DK的临床表现取决于疾病的严重程度,包括持续性角膜上皮糜烂、浅点状角膜病变、上皮再生延迟和角膜敏感性降低,可导致视力下降或永久性视力丧失。临床上47%~64%的DM患者会出现DK,但大部分未能被及时诊断。同时,由于临床研究数量有限,很难完全了解DK的病理生物学,且目前尚无有效的治疗方法[1]。本文就DM的生物学特征、DM的病理生理学、其对角膜的影响、病理生理学以及DK的现行及未来可能用于临床的治疗策略进行综述。

1 DM的生物学特征

    DM是一种由自身免疫性胰岛素耗竭或获得性胰岛素抵抗引起的疾病,可分为T1DM和T2DM两种类型。由于持续的高血糖水平会引起广泛的血管损伤,影响心脏、眼睛、肾和神经的功能,T1DM和T2DM晚期均可导致多种并发症的发生[2]。研究[3]表明:长期高血糖症产生的晚期糖基化终末产物(advanced glycation end products,AGEs)是引起DM慢性并发症的重要因素之一,它集中存在于富含层粘连蛋白的上皮基底膜,参与DM高血糖记忆效应的发生并能改变机体的糖脂代谢情况;同时,它可与糖基化终末产物受体(receptor of advanced glycation end products,RAGE)结合,启动细胞活性氧(reactive oxygen species,ROS)生成、造成炎症反应、细胞凋亡,引起组织生物力学改变,使组织黏弹性降低、胶原纤维滑移、上皮细胞附着减少,增加基质脆性和胶原纤维敏感性,因而促进DK的发生及发展[4]

2 DM的病理生理学

    美国DM协会定义的DM诊断标准如下[5]:1)空腹血糖水平>126 mg/dL(7 mmol/L);2) 2 h血浆胰岛素激发后的血糖水平:75 g>200 mg/dL(7 mmol/L);3)葡萄糖化血红蛋白(HbA1C)>6.5% (48 mmol/L);4)随机血糖水平>200 mg/dL(11.1 mmol/L)。这些指标因种族差异而不同,在剔除年龄、性别和BMI等无关因素后,糖耐量较低的亚洲人较白种人HbA1C水平更高。
    在疾病发展方面,由于细胞从循环中摄取的葡萄糖减少,T1DM和T2DM均可导致高血糖。而T2DM导致损伤的潜在机制则归因于“慢性燃料过剩”,主要表现为高糖对细胞的毒性、脂代谢异常、胰岛素抵抗以及胰腺β细胞损伤等,引发全身性炎症反应。DM患者常表现出胰腺、肝和脂肪组织等多器官功能障碍[6]。另外,长期高血糖会促进高表达蛋白质(如胶原蛋白、层粘连蛋白和硫酸乙酰肝素蛋白多糖)生成AGEs,导致与血管阻塞和内皮损伤相关的病理学疾病。DM的发展也与可遗传因素有关,包括与β细胞功能和代谢有关的关键基因,如转录因子TCFL2以及与脂肪团和肥胖相关的蛋白(fat and obesity associated,FTO)[7]

3 DM对角膜的影响及其病理生理学

    DM对角膜的形态、生理、代谢和临床等方面都有重大影响[8]。高血糖对人体所有细胞几乎都有毒性作用,当主要胶原亚型(如I型、III型和V型胶原)或蛋白多糖(如角蛋白聚糖、基膜聚糖或核心蛋白聚糖)表达异常时,它会影响胶原蛋白纤维之间形成交联的数量,改变角膜内原纤维的直径和构造,进而影响组织的生物力学性能,造成视力障碍。而当DM患者出现角膜细胞功能障碍和修复机制紊乱时,表现为角膜组织复发性糜烂、伤口愈合延迟、溃疡和水肿。在高血糖状态下,角膜结构可能产生不同的病理改变[9],如持续性上皮缺损和干眼、复发性角膜糜烂[10]和细菌感染及基底膜退化等[11]
    首先,DM会导致角膜上皮功能障碍,如出现浅表穿刺性角膜炎和上皮糜烂,角膜上皮异常是DM最常见的并发症之一。角膜上皮基底细胞(corneal epithelial basal cells,CEBC)来源于角膜缘干细胞,在基底膜的形成中起重要作用。Chang等[12]发现,DM患者CEBC密度降低、细胞大小变异性增加和细胞内空间变宽。角膜神经纤维释放多种神经肽以维持角膜上皮的稳态,而神经营养因子作为关键的调节分子,在DK中发挥重要作用[13]。神经支配的改变可能是DM患者CEBC密度降低的主要原因。
角膜是机体神经末梢分布最广的器官之一,DM对基底下神经群的影响可能是DM对角膜组织产生病理影响的另一主要原因。角膜神经纤维的功能之一是维持健康的角膜和促进眼外伤后的伤口愈合[14],角膜神经的缺失会导致神经营养因子供应减少,愈合时间延长。因此,角膜神经支配受损的患者,例如疱疹性角膜炎、糖尿病和屈光手术后,由于营养支持减少,角膜损伤的风险增加[15]。另外,DM还能改变角膜感觉神经形态,如使三叉神经纤维密度下降,分支减少[16]。而角膜神经受损可导致角膜敏感性减弱、干眼、神经营养性角膜炎甚至失明[17]
    Taylor和Kimsey[18]报道DM患者角膜基底膜较正常更厚。这一病理变化目前可归因为基底膜代谢异常。众所周知,AGEs在DK中起重要作用。Ishida等[19]检测到DM患者与健康人相比角膜自体荧光增强。角膜自体荧光与DM角膜中AGEs的沉积相关。同时,在DM大鼠的角膜上皮和上皮基底膜部位也检测到AGEs的累积[20]。AGEs可通过激活c-Jun N末端激酶和p38丝裂原活化蛋白激酶途径以及产生ROS,诱导人角膜上皮细胞凋亡[21]。此外,DM中角膜神经的丧失导致神经营养支持减少,导致上皮细胞的加速丧失和增殖减少、异常基底膜的产生和上皮细胞与异常基底膜的黏附不足[22]
    DM也可引起角膜基质的改变,角膜基质的结构和功能改变,使角膜透明度丧失,威胁患者的视力[23]。透射电镜显示DM角膜前基质的组织结构不同:在DM角膜的中心,虽然胶原层的结构与正常角膜中相似,但基底上皮层比正常角膜更厚。在外周角膜中,前部上皮基底层中出现异常的瓷砖状胶原纤维。同时,在角膜基质中还检测到AGE免疫反应,这都有可能导致胶原交联和基质异常。AGEs的增加导致胶原分子和蛋白聚糖之间的非酶交联,使角膜基质的超微结构变化,从而导致角膜硬化和增厚[24]
    DM对角膜内皮也有影响。Liaboe等[25]发现DM患者的平均ECD显著降低,而DM角膜的细胞面积变异系数较高[26]。此外,DM患者眼睛中多形性内皮细胞数量显著增加。内皮细胞含有许多免疫和炎症因子,如血管内皮生长因子、肿瘤坏死因子-α、白细胞介素(IL)和基质金属蛋白酶。这些因素也损伤角膜内皮,导致内皮功能和形态的改变,以及分子水平的改变[27]

4 DK的现行及未来可能用于临床的治疗策略

4.1 DK的现行治疗策略

    DM现行的治疗方式主要是控制机体血糖水平,改变生活方式(如饮食和运动)及药物干预(如使用胰岛素、α-葡萄糖苷酶抑制剂和双胍类等降糖药物);而DK的治疗也同样集中于控制血糖水平的支持性疗法,主要是预防感染和提供有利于愈合的最佳环境。
    DK局部治疗的目的是维持光滑湿润的眼表、保持完整的上皮,最大限度地减少视觉损失并提高舒适度。具体的治疗方法取决于病情的严重程度及所涉及的具体结构。这些主流治疗方法主要包括局部滴用人工泪液、使用角膜绷带镜及局部使用抗炎药物,如非甾体类抗炎药、类固醇和环孢菌素A等,以减轻眼表炎症、保护角膜上皮细胞,促进角膜上皮生长。但这些现有的治疗方法对于角膜组织损伤的修复能力有限。近年来,一批新兴的治疗方法涌现,未来有望应用于临床。

4.2 DK未来可能用于临床的治疗策略

4.2.1 神经生长因子局部滴眼治疗
    神经生长因子(nerve growth factor,NGF)是调节发育中的神经元生长分化的分子,参与神经元的维护和生长,从而控制维持角膜上皮细胞的正常和更新[28]。胶质细胞源性神经营养因子(glial cell line-derived neurotrophic factor,GDNF)和睫状神经营养因子(ciliary neurotrophic factor,CNTF)等因子通过在角膜上皮中的受体刺激角膜上皮细胞增殖和迁移,以增强其免疫保护功能[29]。其中NGF和GDNF来源于角膜上皮细胞,存在于角膜、结膜、泪液和泪腺中[30],参与角膜神经再生,可因高血糖受损[31]。体外研究结果表明:角膜上皮细胞和神经元之间存在营养支持,如三叉神经神经元释放神经递质和神经因子,以促进角膜上皮细胞的生长、增殖、分化和VII型胶原的产生[32];基质角膜细胞也产生神经营养素,如神经营养素3和4[33]。目前的研究[34]表明:局部应用NGF可通过促进ROS的形成反转糖尿病模型中角膜的凋亡和炎症,小鼠NGF也已成功用于加速角膜伤口愈合。因此,NGF可作为促进角膜伤口愈合的有潜力的治疗剂。但是,因为与NGF临床疗效相关的大多数实验证据都是通过小鼠实验获得的,所以结论具有一定的局限性。如重组人神经生长因子(recombinant human nerve growth factor,rhNGF)在人类周围神经病变中的作用与小鼠NGF的作用并不可比[35]。同时,由于其目前的成本高昂,无法大规模用于临床治疗。
4.2.2 局部胰岛素疗法
    胰岛素较神经生长因子价格更廉价安全,又能更好地被眼组织耐受[36],是一种更经济、更成熟的替代品。对DM患者全身或局部使用胰岛素均可促进皮肤伤口愈合[37]。在眼部应用方面,胰岛素也被认为对DK有类似的积极治疗作用:在一项针对32例DM患者的小型人体临床试验中,与安慰剂治疗的对照组相比,术后1个月局部胰岛素治疗组预后良好,上皮缺损减少,角膜上皮的恢复也有显著改善[38]。类似地,胰岛素样生长因子1(insulin like growth factor-1,IGF-1)能促进细胞增殖,局部给II型DM小鼠服用后,与对照组相比角膜基底下神经密度有所改善[39]。这些研究支持了降低细胞外葡萄糖水平对促进角膜伤口修复至关重要这一假说。
    但值得注意的是,胰岛素或IGF-1治疗的疗效取决于DM的严重程度,在正常角膜中使用胰岛素并不会加速伤口愈合。虽然实验证明胰岛素能促进角膜上皮伤口愈合,但目前其具体机制尚未明确。另一方面,当胰岛素浓度>10 ng/mL时会激活低亲和力受体(如IGF-1R),因此长期局部球后注射胰岛素可能会引发严重的不良并发症[40],限制了局部胰岛素疗法在DK患者中的应用,因此,在胰岛素或IGF-1局部治疗法被广泛推广前需要进行进一步的研究以及更多的数据支持。
4.2.3 小分子疗法之纳曲酮
    靶向阿片样物质受体也能改善DM患者的伤口愈合情况,加速角膜移植。内源性阿片物质是类生长抑制因子,其通过抑制或减缓细胞DNA的合成,延缓角膜上皮的增殖和创伤愈合。靶向阿片样物质受体的作用机制是通过抑制阿片类生长因子受体,促进成纤维细胞增殖,从而抑制醛糖还原酶的产生,减少其对上皮屏障的损害[41]
    纳曲酮是一种长效阿片类拮抗剂,局部或口服给药均被证明可加速角膜伤口愈合并恢复角膜敏感性,在多种动物模型中也被证明是安全有效的[42]。同时,纳曲酮可在体外逆转人DM角膜和DM动物模型的角膜病变。以上发现均表明:局部使用纳曲酮作为DK的治疗剂没有不良反应或较大的毒性,具有很大的应用潜力。然而,为方便制备和管理,目前所有关于纳曲酮的临床研究均以溶液形式进行。此时,药物溶液的局部眼部给药会被滞留的泪液迅速稀释,并通过鼻泪管引流消除。同时,纳曲酮的味道非常苦。因此,未来的研究应侧重于延长纳曲酮在角膜前的停留时间,并尽量减少其通过鼻泪管的引流,以尽量减少苦味感,从而提高患者对该药物的接受能力。
4.2.4 小分子疗法之醛糖还原酶抑制剂
    DM的并发症还与通过山梨醇途径增加的代谢流量有关,该过程的第一步需通过醛糖还原酶介导葡萄糖转化为山梨醇。与山梨醇途径在DM导致的角膜缺损中的作用一致,抑制醛糖还原酶对伤口的愈合有积极作用。在一组实验中,与未经治疗的半乳糖喂养的对照组相比,实验组在局部和口服醛糖还原酶抑制剂(aldose reductase inhibitors,ARI)7个月后角膜敏感性仍保持不变[43]
4.2.5 抗氧化剂
    由于DM能导致炎症的增加,抗氧化剂混合物在改变或抑制DM相关的病理学方面也具有靶向作用。角膜的生理结构使其本身易受氧化损伤的影响,氧化和抗氧化剂水平失衡会导致mtDNA突变,突变随着时间的推移不断累积,一旦超过阈值,细胞将会产生能量障碍,出现疾病的临床表型[44]。基于上述机制,可以使用抗氧化剂治疗某些角膜疾病,以减少角膜损伤。在清创术后7 d,对STZ诱导的DM小鼠纳米胶束内和鼻内姜黄素给药,与未经治疗的对照组相比,实验组角膜再上皮化和敏感性有明显改善[45]。其他生长因子/抗氧化剂混合物也有过应用。例如,局部应用色素上皮衍生因子(pigment epithelium-derived factor,PEDF)和二十二碳六烯酸(docosahexaenoic acid,DHA)可改善STZ诱导的小鼠模型上皮清创术后12 d角膜的再上皮化、神经纤维的保持和敏感性[46]。这些结果表明,以参与DM的下游效应器为目标可能有助于预防或延缓DM相关的病理。
4.2.6 基因治疗
    除现有的传统方法外,新的治疗手段,如靶向份子治疗、基因和干细胞疗法都很有希望,但这些领域已发表的成果大多数仍局限于对动物模型的评估,而尚未进入临床试验阶段,尚未转化为常规疗法。
    随着基因治疗的迅速发展,目前已有很多新的方法用于修复DM角膜。当前的研究中主要应用病毒作为载体[47]。病毒可以有效地进行基因传递,效率高、效果持久,但可能诱发免疫反应、炎症或不受控制地整合到宿主基因组中。虽然新重组腺病毒、腺相关病毒和慢病毒不会引起严重的免疫反应,也不会转染非分裂细胞,但安全问题(如对干细胞的毒性)和表达载体特异性缺乏等依然存在。miRNA是重要的转录后基因表达调控因子,可调控基因沉默,用于治疗DM角膜伤口愈合延迟,但仅在器官培养中有过报道[48]。另一方面,由于大多数miRNA作用于多个靶点,并在不同的DM组织中表达的变化不同,因此,在治疗中时应先对传递途径和生物分布等进行彻底地论证。总体来说,基因治疗是用于恢复异常DM角膜的很有前途的工具,应进一步发展为未来临床所用。

5 结语

    角膜的生理功能正常是获取高质量视觉图像的前提。DK作为DM的慢性并发症之一常造成患者视力下降,严重者甚至失明,但在临床上,因其发生常伴有其他眼部疾病的发生而常被忽视。该领域已有大量相关研究,但目前仍缺乏有效的医疗手段,凸显了该疾病的复杂性。机体的高血糖水平与DK密不可分,近年来的临床研究主要是对DM的干预。本文综述了DM的生物学及病理生理学特征和DM对角膜的影响,总结了DK现行的治疗方式。局部滴用人工泪液、使用角膜绷带镜及局部使用抗炎药物安全有效,同时已证明可以减轻角膜病变的症状,为目前DK临床治疗的主要疗法,而涉及局部胰岛素和阿片类拮抗剂纳曲酮疗法、基因、纳米和细胞治疗等新方法仍处于实验阶段,未来需要进一步大量的临床实验来证实其疗效及安全性。由于目前还没有特效药物,进一步深入了解细胞水平上DK发展的病理生理学对开发能够促进角膜再上皮化以加速伤口愈合的潜在药剂至关重要。随着技术的融合及生物制剂作为治疗手段的迅猛发展,未来有望在DK的治疗上提供更多新的和更有效的治疗选择。此外,随着血管生成、免疫学和内分泌代谢领域的不断发现,相信在不久的将来,将出现新的潜在的治疗靶点,将会有更多新的治疗DK的方法将应用于临床。

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1、Priyadarsini S, Whelchel A, Nicholas S, et al. Diabetic keratopathy: Insights and challenges[J]. Surv Ophthalmol, 2020, 65(5): 513-529.Priyadarsini S, Whelchel A, Nicholas S, et al. Diabetic keratopathy: Insights and challenges[J]. Surv Ophthalmol, 2020, 65(5): 513-529.
2、许文进, 李兵. II型糖尿病的发病机制与治疗[ J]. 医药卫生(文摘版), 2017, 8(1): 00106.
XU Wenjin, LI Bing. Pathogenesis and treatment of type 2 diabetes mellitus[ J]. Medicine and Health, 2017, 8(1): 00106.
许文进, 李兵. II型糖尿病的发病机制与治疗[ J]. 医药卫生(文摘版), 2017, 8(1): 00106.
XU Wenjin, LI Bing. Pathogenesis and treatment of type 2 diabetes mellitus[ J]. Medicine and Health, 2017, 8(1): 00106.
3、但婧, 周庆军, 谢立信. 晚期糖基化终末产物与糖尿病角膜病变 关系的研究进展[ J]. 中华眼科杂志, 2018, 54(6): 475-480. DAN Jing, ZHOU Qingjun, XIE Lixin. The research progress of relationship between advanced glycation end products and diabetic keratopathy[ J]. Chinese Journal of Ophthalmology, 2018, 54(6): 475-480.但婧, 周庆军, 谢立信. 晚期糖基化终末产物与糖尿病角膜病变 关系的研究进展[ J]. 中华眼科杂志, 2018, 54(6): 475-480. DAN Jing, ZHOU Qingjun, XIE Lixin. The research progress of relationship between advanced glycation end products and diabetic keratopathy[ J]. Chinese Journal of Ophthalmology, 2018, 54(6): 475-480.
4、高艳. AGEs/AGER1/Sirt1通路在糖尿病角膜病变中的作用及机 制研究[D]. 青岛: 青岛大学, 2016. GAO Yan. The role and mechanism of AGEs/AGER1/Sirt1 pathway in diabetic keratopathy[D]. Qingdao: Qingdao University, 2016.高艳. AGEs/AGER1/Sirt1通路在糖尿病角膜病变中的作用及机 制研究[D]. 青岛: 青岛大学, 2016. GAO Yan. The role and mechanism of AGEs/AGER1/Sirt1 pathway in diabetic keratopathy[D]. Qingdao: Qingdao University, 2016.
5、American Diabetes Association. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2019[J]. Diabetes Care, 2019, 42(Suppl 1): S13-S28.American Diabetes Association. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2019[J]. Diabetes Care, 2019, 42(Suppl 1): S13-S28.
6、Esser N, Legrand-Poels S, Piette J, et al. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes[J]. Diabetes Res Clin Pract, 2014, 105(2): 141-150.Esser N, Legrand-Poels S, Piette J, et al. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes[J]. Diabetes Res Clin Pract, 2014, 105(2): 141-150.
7、Basile KJ, Johnson ME, Xia Q, et al. Genetic susceptibility to type 2 diabetes and obesity: follow-up of findings from genome-wide association studies[J]. Int J Endocrinol, 2014, 2014: 769671.Basile KJ, Johnson ME, Xia Q, et al. Genetic susceptibility to type 2 diabetes and obesity: follow-up of findings from genome-wide association studies[J]. Int J Endocrinol, 2014, 2014: 769671.
8、Markoulli M, Flanagan J, Tummanapalli SS, et al. The impact of diabetes on corneal nerve morphology and ocular surface integrity[J]. Ocul Surf, 2018, 16(1): 45-57.Markoulli M, Flanagan J, Tummanapalli SS, et al. The impact of diabetes on corneal nerve morphology and ocular surface integrity[J]. Ocul Surf, 2018, 16(1): 45-57.
9、Zhao H, He Y, Ren YR, et al. Corneal alteration and pathogenesis in diabetes mellitus[J]. Int J Ophthalmol, 2019, 12(12): 1939-1950.Zhao H, He Y, Ren YR, et al. Corneal alteration and pathogenesis in diabetes mellitus[J]. Int J Ophthalmol, 2019, 12(12): 1939-1950.
10、Miller DD, Hasan SA, Simmons NL, et al. Recurrent corneal erosion: a comprehensive review[J]. Clin Ophthalmol, 2019, 13: 325-335.Miller DD, Hasan SA, Simmons NL, et al. Recurrent corneal erosion: a comprehensive review[J]. Clin Ophthalmol, 2019, 13: 325-335.
11、Ljubimov AV, Burgeson RE, Butkowski RJ, et al. Human corneal basement membrane heterogeneity: topographical differences in the expression of type IV collagen and laminin isoforms[J]. Lab Invest, 1995, 72(4): 461-473.Ljubimov AV, Burgeson RE, Butkowski RJ, et al. Human corneal basement membrane heterogeneity: topographical differences in the expression of type IV collagen and laminin isoforms[J]. Lab Invest, 1995, 72(4): 461-473.
12、Chang PY, Carrel H, Huang JS, et al. Decreased density of corneal basal epithelium and subbasal corneal nerve bundle changes in patients with diabetic retinopathy[J]. Am J Ophthalmol, 2006, 142(3): 488-490.Chang PY, Carrel H, Huang JS, et al. Decreased density of corneal basal epithelium and subbasal corneal nerve bundle changes in patients with diabetic retinopathy[J]. Am J Ophthalmol, 2006, 142(3): 488-490.
13、Müller LJ, Marfurt CF, Kruse F, et al. Corneal nerves: structure, contents and function[J]. Exp Eye Res, 2003, 76(5): 521-542.Müller LJ, Marfurt CF, Kruse F, et al. Corneal nerves: structure, contents and function[J]. Exp Eye Res, 2003, 76(5): 521-542.
14、Byun YS, Kang B, Yoo YS, et al. Poly(ADP-Ribose) polymerase inhibition improves corneal epithelial innervation and wound healing in diabetic rats[J]. Invest Ophthalmol Vis Sci, 2015, 56(3): 1948-1955.Byun YS, Kang B, Yoo YS, et al. Poly(ADP-Ribose) polymerase inhibition improves corneal epithelial innervation and wound healing in diabetic rats[J]. Invest Ophthalmol Vis Sci, 2015, 56(3): 1948-1955.
15、陈奔, 李雅嘉, 王华, 等. 生长因子在糖尿病角膜病变的作用[ J]. 临床与病理杂志, 2016, 36(9): 1457-1462. CHEN Ben, LI Yajia, WANG Hua, et al. Role of growth factor in diabetic keratopathy[ J]. Journal of Clinical and Pathology Research, 2016, 36(9): 1457-1462.陈奔, 李雅嘉, 王华, 等. 生长因子在糖尿病角膜病变的作用[ J]. 临床与病理杂志, 2016, 36(9): 1457-1462. CHEN Ben, LI Yajia, WANG Hua, et al. Role of growth factor in diabetic keratopathy[ J]. Journal of Clinical and Pathology Research, 2016, 36(9): 1457-1462.
16、Al-Aqaba MA, Dhillon VK, Mohammed I, et al. Corneal nerves in health and disease[J]. Prog Retin Eye Res, 2019, 73: 100762.Al-Aqaba MA, Dhillon VK, Mohammed I, et al. Corneal nerves in health and disease[J]. Prog Retin Eye Res, 2019, 73: 100762.
17、Taylor HR, Kimsey RA. Corneal epithelial basement membrane changes in diabetes[J]. Invest Ophthalmol Vis Sci, 1981, 20(4): 548-553.Taylor HR, Kimsey RA. Corneal epithelial basement membrane changes in diabetes[J]. Invest Ophthalmol Vis Sci, 1981, 20(4): 548-553.
18、Ishida M, Yokoi N, Okuzawa J, et al. Corneal autofluorescence in patients with diabetic retinopathy[J]. Nippon Ganka Gakkai Zasshi, 1995, 99(3): 308-311.Ishida M, Yokoi N, Okuzawa J, et al. Corneal autofluorescence in patients with diabetic retinopathy[J]. Nippon Ganka Gakkai Zasshi, 1995, 99(3): 308-311.
19、Mishima S. Clinical investigations on the corneal endothelium[J]. Ophthalmology, 1982, 89(6): 525-530.Mishima S. Clinical investigations on the corneal endothelium[J]. Ophthalmology, 1982, 89(6): 525-530.
20、Shi L, Yu X, Yang H, et al. Advanced glycation end products induce human corneal epithelial cells apoptosis through generation of reactive oxygen species and activation of JNK and p38 MAPK pathways[J]. PLoS One, 2013, 8(6): e66781.Shi L, Yu X, Yang H, et al. Advanced glycation end products induce human corneal epithelial cells apoptosis through generation of reactive oxygen species and activation of JNK and p38 MAPK pathways[J]. PLoS One, 2013, 8(6): e66781.
21、Vieira-Potter VJ, Karamichos D, Lee DJ. Ocular complications of diabetes and therapeutic approaches[J]. Biomed Res Int, 2016, 2016: 3801570.Vieira-Potter VJ, Karamichos D, Lee DJ. Ocular complications of diabetes and therapeutic approaches[J]. Biomed Res Int, 2016, 2016: 3801570.
22、Torricelli AA, Wilson SE. Cellular and extracellular matrix modulation of corneal stromal opacity[J]. Exp Eye Res, 2014, 129: 151-160.Torricelli AA, Wilson SE. Cellular and extracellular matrix modulation of corneal stromal opacity[J]. Exp Eye Res, 2014, 129: 151-160.
23、Zou C, Wang S, Huang F, et al. Advanced glycation end products and ultrastructural changes in corneas of long-term streptozotocin-induced diabetic monkeys[J]. Cornea, 2012, 31(12): 1455-1459.Zou C, Wang S, Huang F, et al. Advanced glycation end products and ultrastructural changes in corneas of long-term streptozotocin-induced diabetic monkeys[J]. Cornea, 2012, 31(12): 1455-1459.
24、Liaboe CA, Aldrich BT, Carter PC, et al. Assessing the impact of diabetes mellitus on donor corneal endothelial cell density[J]. Cornea, 2017, 36(5): 561-566.Liaboe CA, Aldrich BT, Carter PC, et al. Assessing the impact of diabetes mellitus on donor corneal endothelial cell density[J]. Cornea, 2017, 36(5): 561-566.
25、El-Agamy A, Alsubaie S. Corneal endothelium and central corneal thickness changes in type 2 diabetes mellitus[J]. Clin Ophthalmol, 2017, 11: 481-486.El-Agamy A, Alsubaie S. Corneal endothelium and central corneal thickness changes in type 2 diabetes mellitus[J]. Clin Ophthalmol, 2017, 11: 481-486.
26、Chen H, Zhang X, Liao N, et al. Assessment of biomarkers using multiplex assays in aqueous humor of patients with diabetic retinopathy[J]. BMC Ophthalmol, 2017, 17(1): 176.Chen H, Zhang X, Liao N, et al. Assessment of biomarkers using multiplex assays in aqueous humor of patients with diabetic retinopathy[J]. BMC Ophthalmol, 2017, 17(1): 176.
27、Emoto I, Beuerman RW. Stimulation of neurite growth by epithelial implants into corneal stroma[J]. Neurosci Lett, 1987, 82(2): 140-144.Emoto I, Beuerman RW. Stimulation of neurite growth by epithelial implants into corneal stroma[J]. Neurosci Lett, 1987, 82(2): 140-144.
28、Chen J, Chen P, Backman LJ, et al. Ciliary neurotrophic factor promotes the migration of corneal epithelial stem/progenitor cells by up-regulation of MMPs through the phosphorylation of Akt[J]. Sci Rep, 2016, 6: 25870.Chen J, Chen P, Backman LJ, et al. Ciliary neurotrophic factor promotes the migration of corneal epithelial stem/progenitor cells by up-regulation of MMPs through the phosphorylation of Akt[J]. Sci Rep, 2016, 6: 25870.
29、Ríos JD, Ghinelli E, Gu J, et al. Role of neurotrophins and neurotrophin receptors in rat conjunctival goblet cell secretion and proliferation[J]. Invest Ophthalmol Vis Sci, 2007, 48(4): 1543-1551.Ríos JD, Ghinelli E, Gu J, et al. Role of neurotrophins and neurotrophin receptors in rat conjunctival goblet cell secretion and proliferation[J]. Invest Ophthalmol Vis Sci, 2007, 48(4): 1543-1551.
30、Di G, Qi X, Zhao X, et al. Corneal epithelium-derived neurotrophic factors promote nerve regeneration[J]. Invest Ophthalmol Vis Sci, 2017, 58(11): 4695-4702.Di G, Qi X, Zhao X, et al. Corneal epithelium-derived neurotrophic factors promote nerve regeneration[J]. Invest Ophthalmol Vis Sci, 2017, 58(11): 4695-4702.
31、Garcia-Hirschfeld J, Lopez-Briones LG, Belmonte C. Neurotrophic influences on corneal epithelial cells[J]. Exp Eye Res, 1994, 59(5): 597-605.Garcia-Hirschfeld J, Lopez-Briones LG, Belmonte C. Neurotrophic influences on corneal epithelial cells[J]. Exp Eye Res, 1994, 59(5): 597-605.
32、You L, Kruse FE, V?lcker HE. Neurotrophic factors in the human cornea[J]. Invest Ophthalmol Vis Sci, 2000, 41(3): 692-702.You L, Kruse FE, V?lcker HE. Neurotrophic factors in the human cornea[J]. Invest Ophthalmol Vis Sci, 2000, 41(3): 692-702.
33、Park JH, Kang SS, Kim JY, et al. Nerve growth factor attenuates apoptosis and inflammation in the diabetic cornea[J]. Invest Ophthalmol Vis Sci, 2016, 57(15): 6767-6775.Park JH, Kang SS, Kim JY, et al. Nerve growth factor attenuates apoptosis and inflammation in the diabetic cornea[J]. Invest Ophthalmol Vis Sci, 2016, 57(15): 6767-6775.
34、Apfel SC. Nerve growth factor for the treatment of diabetic neuropathy: what went wrong, what went right, and what does the future hold?[J]. Int Rev Neurobiol, 2002, 50: 393-413.Apfel SC. Nerve growth factor for the treatment of diabetic neuropathy: what went wrong, what went right, and what does the future hold?[J]. Int Rev Neurobiol, 2002, 50: 393-413.
35、Zagon IS, Klocek MS, Sassani JW, et al. Use of topical insulin to normalize corneal epithelial healing in diabetes mellitus[J]. Arch Ophthalmol, 2007, 125(8): 1082-1088.Zagon IS, Klocek MS, Sassani JW, et al. Use of topical insulin to normalize corneal epithelial healing in diabetes mellitus[J]. Arch Ophthalmol, 2007, 125(8): 1082-1088.
36、Vatankhah N, Jahangiri Y, Landry GJ, et al. Effect of systemic insulin treatment on diabetic wound healing[J]. Wound Repair Regen, 2017, 25(2): 288-291.Vatankhah N, Jahangiri Y, Landry GJ, et al. Effect of systemic insulin treatment on diabetic wound healing[J]. Wound Repair Regen, 2017, 25(2): 288-291.
37、Fai S, Ahem A, Mustapha M, et al. Randomized controlled trial of topical insulin for healing corneal epithelial defects induced during vitreoretinal surgery in diabetics[J]. Asia Pac J Ophthalmol (Phila), 2017, 6(5): 418-424.Fai S, Ahem A, Mustapha M, et al. Randomized controlled trial of topical insulin for healing corneal epithelial defects induced during vitreoretinal surgery in diabetics[J]. Asia Pac J Ophthalmol (Phila), 2017, 6(5): 418-424.
38、Ueno H, Hattori T, Kumagai Y, et al. Alterations in the corneal nerve and stem/progenitor cells in diabetes: preventive effects of insulin-like growth factor-1 treatment[J]. Int J Endocrinol, 2014, 2014: 312401.Ueno H, Hattori T, Kumagai Y, et al. Alterations in the corneal nerve and stem/progenitor cells in diabetes: preventive effects of insulin-like growth factor-1 treatment[J]. Int J Endocrinol, 2014, 2014: 312401.
39、Wu YC, Buckner BR, Zhu M, et al. Elevated IGFBP3 levels in diabetic tears: a negative regulator of IGF-1 signaling in the corneal epithelium[J]. Ocul Surf, 2012, 10(2): 100-107.Wu YC, Buckner BR, Zhu M, et al. Elevated IGFBP3 levels in diabetic tears: a negative regulator of IGF-1 signaling in the corneal epithelium[J]. Ocul Surf, 2012, 10(2): 100-107.
40、Kubo E, Mori K, Kobayashi T, et al. Effect of aldose reductase inhibitor on corneal epithelial barrier function in galactose-fed dogs[J]. J Ocul Pharmacol Ther, 1998, 14(2): 181-190.Kubo E, Mori K, Kobayashi T, et al. Effect of aldose reductase inhibitor on corneal epithelial barrier function in galactose-fed dogs[J]. J Ocul Pharmacol Ther, 1998, 14(2): 181-190.
41、Zagon IS, Klocek MS, Sassani JW, et al. Corneal safety of topically applied naltrexone[J]. J Ocul Pharmacol Ther, 2006, 22(5): 377-387.Zagon IS, Klocek MS, Sassani JW, et al. Corneal safety of topically applied naltrexone[J]. J Ocul Pharmacol Ther, 2006, 22(5): 377-387.
42、Jacot JL, Hosotani H, Glover JP, et al. Diabetic-like corneal sensitivity loss in galactose-fed rats ameliorated with aldose reductase inhibitors[J]. J Ocul Pharmacol Ther, 1998, 14(2): 169-180.Jacot JL, Hosotani H, Glover JP, et al. Diabetic-like corneal sensitivity loss in galactose-fed rats ameliorated with aldose reductase inhibitors[J]. J Ocul Pharmacol Ther, 1998, 14(2): 169-180.
43、刘文凤, 朱佩文, 邵毅. 线粒体功能障碍与角膜疾病研究进展[J]. 眼科新进展, 2019, 39(2): 197-200.刘文凤, 朱佩文, 邵毅. 线粒体功能障碍与角膜疾病研究进展[J]. 眼科新进展, 2019, 39(2): 197-200.
44、Recent advance of mitochondrial dysfunction and corneal diseases[J]. Recent Advances in Ophthalmology, 2019, 39(2): 197-200.Recent advance of mitochondrial dysfunction and corneal diseases[J]. Recent Advances in Ophthalmology, 2019, 39(2): 197-200.
45、Guo C, Li M, Qi X, et al. Intranasal delivery of nanomicelle curcumin promotes corneal epithelial wound healing in streptozotocin-induced diabetic mice[J]. Sci Rep, 2016, 6: 29753.Guo C, Li M, Qi X, et al. Intranasal delivery of nanomicelle curcumin promotes corneal epithelial wound healing in streptozotocin-induced diabetic mice[J]. Sci Rep, 2016, 6: 29753.
46、He J, Pham TL, Kakazu A, et al. Recovery of corneal sensitivity and increase in nerve density and wound healing in diabetic mice after PEDF plus DHA treatment[J]. Diabetes, 2017, 66(9): 2511-2520.He J, Pham TL, Kakazu A, et al. Recovery of corneal sensitivity and increase in nerve density and wound healing in diabetic mice after PEDF plus DHA treatment[J]. Diabetes, 2017, 66(9): 2511-2520.
47、Ljubimov AV, Saghizadeh M. Progress in corneal wound healing[J]. Prog Retin Eye Res, 2015, 49: 17-45.Ljubimov AV, Saghizadeh M. Progress in corneal wound healing[J]. Prog Retin Eye Res, 2015, 49: 17-45.
48、Winkler MA, Dib C, Ljubimov AV, et al. Targeting miR-146a to treat delayed wound healing in human diabetic organ-cultured corneas[J]. PLoS One, 2014, 9(12): e114692.Winkler MA, Dib C, Ljubimov AV, et al. Targeting miR-146a to treat delayed wound healing in human diabetic organ-cultured corneas[J]. PLoS One, 2014, 9(12): e114692.
1、赵启霞. 润睛明目方雾化熏蒸治疗阴虚燥热型糖尿病干眼症的临床疗效观察[D].新疆医科大学,2023.ZHAO Qixia. Clinical observation on the treatment of Yin deficiency desiccant heat type diabetic dry eye syndrome by aerosol fumigation with RunJing Mingmu Decoction[D]. Urumqi: Xinjiang Medical University, 2023.
1、国家自然科学基金(81660158)()
2、江西省自然科学基金重大项目(2016ACB21017)()
3、江西省青年科学基金(20151BAB215016,20161BAB215198)()
4、江西省重点研发项目(20151BBG70223,20181BBG70004)()
5、江西省杰出青年人才计划(S2019RCQNB0259)。This work was supported by the National Natural Science Foundation of China (81660158)()
6、 Natural Science Key Project of Jiangxi Province (20161ACB21017)()
7、 Youth Science Foundation of Jiangxi Province (20151BAB215016, 20161BAB215198)()
8、 Key Research Foundation of Jiangxi Province (20151BBG70223, 20181BBG70004)()
9、 Excellent Talents Development Project of Jiangxi Province (S2019RCQNB0259), China.()
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