P2Y2受体激动剂用于干眼治疗的研究进展

干眼属常见的眼表疾病,是指由于泪液的量和（或）质的异常引起的泪膜不稳定和眼表面的损害,从而导致眼部不适症状的一类疾病。目前我国干眼的治疗包括病因治疗、人工泪液替代治疗、抗炎治疗、免疫抑制剂治疗、手术治疗以及中医治疗等。Ｐ２Ｙ２受体激动剂是一种治疗干眼的新型药物,它能够通过激动位于眼表的Ｐ２Ｙ２受体,促使结膜上皮细胞泪液的分泌以及结膜杯状细胞对黏蛋白的分泌,从而增强泪膜稳定性,改善干眼症状。３０ｇ·Ｌ－１地夸磷索四钠滴眼液是目前唯一上市的Ｐ２Ｙ２受体激动剂。本文就近年来地夸磷索四钠用于干眼治疗的临床疗效、安全性以及相关研究进展作一综述。     

针刺治疗干眼症的研究进展

临床上干眼症的发病率很高,治疗干眼症的方法主要是治标,被动性增加泪液分泌.祖国医学针刺具有无创伤和促进泪腺主动性分泌泪液的作用.本文就针刺治疗干眼症的临床疗效和可能机制做一综述.     

泪腺嘌呤受体研究新进展

嘌呤受体分为腺苷作用的P1受体和ATP作用的P2受体2大类。P2受体又分为P2X(离子通道受体)和P2Y(G蛋白偶联受体)。多种嘌呤受体亚型表达于泪腺,并参与调节泪腺蛋白质等的分泌。嘌呤受体和配体与干燥综合征的发病机制密切相关,并可能成为慢性炎症及免疫性疾病治疗的新靶点。本文就泪腺嘌呤受体研究的新进展作一综述。     

针刺对干眼兔泪腺形态学及泪腺上皮细胞凋亡相关基因蛋白表达的影响

目的 探讨针刺对干眼兔泪腺形态学及泪腺上皮细胞凋亡相关基因蛋白表达的影响,分析针刺对干眼的作用机制.方法 取健康新西兰白兔18只随机分为空白组、模型组、针刺组,每组6只,空白组不作任何处理;模型组皮下注射氢溴酸东莨菪碱,每天4次,每次2 mg·kg-1共24 d;针刺组在与模型组同样处理的基础上进行针刺,每天1次,共14 d.不同时段观察各组泪液分泌试验检测泪液量的结果,光镜、电镜观察泪腺形态学变化,免疫组织化学检测泪腺组织中凋亡相关基因蛋白的表达.结果 泪液分泌试验检测泪液量结果显示在针刺第4、7、14天同时段针刺组与模型组相比明显升高,差异均有统计学意义(均为P＜0.05);在针刺第14天时,针刺组与实验前相比,差异无统计学意义(P＞0.05).光镜、电镜示针刺组泪腺上皮细胞胞浆丰富,排列紧密,活动良好,与空白组接近.免疫组织化学检测显示与模型组比较,针刺组泪腺导管及腺泡上皮细胞中Bax的阳性细胞半定量评分值明显低,差异有统计学意义(P ＜0.05);Bcl-2的阳性细胞半定量评分值亦低,但差异无统计学意义(P＞0.05).与空白组相比,针刺组Bax、Bcl-2评分值差异均无统计学意义(均为P＞0.05).与模型组比较,针刺组的泪腺导管及腺泡上皮细胞中Fas、FasL的阳性细胞半定量评分值明显低,差异均有统计学意义(均为P＜0.05).与空白组相比,针刺组Fas、FasL评分值差异均无统计学意义(均为P＞0.05).结论 针刺通过抑制干眼兔泪腺组织的细胞凋亡及腺体萎缩,促进兔干眼模型的泪腺代谢,从而达到增加泪液分泌的作用.     

干眼病理损害中的炎症机制

干眼是一种泪液和眼表的多因素性疾病,可引起眼部不适、视觉障碍、泪膜不稳定和眼表损害,并伴有泪膜渗透性升高和眼表炎症。目前研究表明,炎症在干眼的发病和病理损害中起着重要作用。本文从炎症与泪液渗透压、眼表黏蛋白表达、角结膜上皮结构及功能、泪腺及睑板腺结构和功能等方面对炎症造成干眼眼表和泪液功能损害的可能机制进行综述。     

针刺对兔泪液分泌的影响及其泪腺形态学变化

任何原因引起泪膜（质和量）和眼表面的异常均可引起干眼症，严重者可导致视力明显下降而影响工作和生活。目前临床治疗干眼症常用泪液替代和心量维持泪液在眼内存留时间的方法。这些属于被动性增加泪液法。环孢素A、泪点栓塞、自体颌下腺移植术等均有一定的疗效，但也存在不足。理想的治疗干眼症的方法应既无创伤又能促进泪腺主动分泌泪液。中医的针刺方法正符合前述两点。针刺治疗干眼症的相关文献报道较少，多数为临床研究，而探讨针刺治疗干眼机制的研究很少。     

免疫抑制剂在干眼治疗应用中的进展

干眼是眼科最常见的眼表疾病之一。干眼的发病机制十分复杂,目前的研究认为神经性炎症、性激素失调、病理性凋亡、泪液渗透压增高和泪腺的免疫性炎症共同参与了干眼的发病,其中泪液的高渗状态和泪腺的免疫性炎症是促使干眼持续发展的重要原因。免疫抑制剂如他克莫司、环孢霉素A等,已经广泛用于治疗眼科疾病,对治疗干眼有一定的效果。现对免疫抑制剂在干眼临床治疗应用中的进展做一简要综述。     

针刺对干眼的抗炎作用以及与JAK2/STAT3信号转导通路的关系

目的　检测干眼模型兔泪腺JAK2/STAT3信号转导通路中相关因子表达变化,探讨针刺对干眼的抗炎作用以及与JAK2/STAT3信号转导通路的关系。方法　选取42只健康新西兰兔,随机分为7组,空白组、模型组、西药组、针刺组、假针刺组、拮抗组、拮抗加针刺组,每组6只。空白组不做处理,其余各组动物每天8∶00、11∶00、14∶00和18∶00时皮下注射氢溴酸东莨菪碱,每次2.0 mg,连续21 d,制作干眼炎症模型。针刺组于造模成功后开始给予针刺治疗,穴位:睛明、攒竹、丝竹空、太阳穴、瞳子髎。其余各组在建模成功的基础上给予相应处理。采用Schirmer试纸检测各组动物不同时间段泪液分泌量,ELISA法检测干眼模型兔泪腺中乙酰胆碱（acetylcholine,ACh）及受体α7nAChR含量的变化,运用实时定量 PCR检测泪腺内STAT3、JAK2 mRNA表达情况。结果　Schirmer I实验结果说明氢溴酸东莨菪碱造模21 d有效,西药和针刺治疗可增加干眼模型兔的泪液分泌量。与空白组相比,模型组、假针刺组、拮抗组、拮抗加针刺组干眼模型兔泪腺中α7nAChR含量和ACh含量均显著降低,差异均有统计学意义（均为P<0.05）。与模型组相比,空白组、西药组、针刺组干眼模型兔泪腺中α7nAChR含量和ACh含量均显著升高,差异均有统计学意义（均为P<0.05）。与空白组相比,西药组、针刺组兔泪腺中JAK2 mRNA相对表达量显著升高,差异均有统计学意义（均为P<0.05）;拮抗组、拮抗加针刺组兔泪腺中JAK2 mRNA相对表达量显著降低,差异均有统计学意义（均为P<0.05）。与模型组相比,西药组、针刺组兔泪腺中STAT3 mRNA和JAK2 mRNA相对表达量均显著升高,差异均有统计学意义（均为P<0.05）;拮抗加针刺组兔泪腺中JAK2 mRNA相对表达量显著降低,差异有统计学意义（P<0.05）。结论　针刺能够促进干眼模型兔泪液分泌,可以增加泪腺中α7nAChR和ACh含量,同时增加泪腺内STAT3、JAK2 mRNA表达,针刺治疗干眼的抗炎作用可能与JAK2/STAT3信号通路的激活相关。     

干眼患者结膜上皮细胞及泪液中IRF4和sST2的表达情况及临床意义

目的:探讨干眼患者结膜上皮细胞及泪液中干扰素调节因子4(IRF4)、可溶性致癌抑制因子2(sST2)表达情况及其临床意义。方法:选取本院2019-01/2021-12期间收治的94例干眼患者作为干眼组,同期选取97例行眼科检查的体检者作为对照组,收集研究对象结膜上皮细胞及泪液,记录临床指标泪膜破裂时间(BUT)、角膜荧光素染色(CFS)评分、基础泪液分泌试验(SⅠt)。采用实时荧光定量PCR(qRT-PCR)法检测结膜上皮细胞IRF4、sST2水平,采用酶联免疫吸附(ELISA)法检测泪液IRF4、sST2水平,采用Pearson法分析干眼患者结膜上皮细胞及泪液中IRF4、sST2水平与临床指标的相关性。结果:干眼组治疗前结膜上皮细胞及泪液中IRF4、sST2水平均显著高于对照组(P<0.001)。干眼患者治疗4wk后结膜上皮细胞及泪液中IRF4、sST2水平均显著低于治疗前(P<0.001)。干眼患者治疗4wk后BUT、SⅠt显著增加,CFS评分显著降低(P<0.001)。干眼患者治疗前结膜上皮细胞及泪液中IRF4、sST2水平与治疗前CFS评分均呈正相关,与治疗前...     

糖尿病患者干眼与眼表异常的相关分析

目的 通过糖尿病患者干眼与眼表异常的相关分析,探讨多种眼表因素异常在糖尿病干眼发病中的作用.方法 收集106例乌鲁木齐市汉族2型糖尿病患者存在的干眼症状及有关的眼表因素（泪液基础分泌、泪膜稳定性、泪液性状、角膜上皮完整性）检查结果,量化后进行单因素及多因素的非条件Logistic回归分析.结果 泪膜稳定性下降（P=0.020,OR=12.268）、泪液基础分泌量减少（P=0.007,OR=5.398）与糖尿病人干眼发生呈显著正相关,具有统计学意义.结论 泪膜稳定性下降、泪液基础分泌量减少在汉族2型糖尿病患者干眼的发病中起一定作用.     

INS365 suppresses loss of corneal epithelial integrity by secretion of mucin-like glycoprotein in a rabbit short-term dry eye model.

P2Y2 receptor agonists, like UTP and ATP, stimulate mucin secretion from goblet cells in vitro. Therefore, mucin stimulants could be good candidates for the treatment of dry eye syndrome because mucin increases the tear film stability and protects against desiccation of ocular surface. INS365 is a more stable P2Y2 receptor agonist than UTP. In the present study, we evaluated, in normal rabbit eyes, its effectiveness to release mucin from goblet cells and to protect the corneal damage induced by desiccation. For mucin secretion, impression cytology was performed following the instillation of INS365 solution or saline into the conjunctival sac. The specimens were stained with periodic acid and Schiff (PAS) reagent, and then the staining area was calculated using computer software. INS365 dose-dependently decreased the PAS staining area of conjunctival goblet cells from 2 to 15 min post-application. Furthermore, we utilized the rabbit short-term dry eye model to evaluate if INS365 eyedrops could protect against any of the damage produced by blockage of blinking with ocular speculum. INS365 significantly suppressed corneal damage at concentrations of more than 0.1% w/v. These results suggest that this P2Y2 agonist is a good candidate for the treatment of dry eye disease.     

下泪点封闭术治疗中重度干眼症的疗效评价

探讨下泪点封闭术用于药物治疗效果不佳的重度干眼症患者的临床疗效。 方法：选择2010-01/2011-01在我院眼科门诊就诊的19例38眼使用人工泪液效果欠佳的中重度干眼症患者,采用下泪点封闭术进行治疗。分别于术前3d及术后1wk;3,6mo进行裂隙灯显微镜检查泪河高度、角膜荧光素染色、泪液膜破裂时间(BUT)、SchirmerⅠ试验(SⅠt)以观察临床疗效。 结果：术前干眼患者主诉多为干涩、异物感、视疲劳。术后患者上述症状明显减轻,甚至消失。与术前相比, 15例30眼荧光素染色角膜上皮点状着色消失,下睑缘明显有泪河线形成。与术前相比,BUT和SⅠt明显增加和延长。 结论：下泪点封闭术可明显改善干眼症患者的临床症状,增加眼表的泪液量,打破干眼症泪液分泌的恶性循环,对于药物治疗效果不佳的中重度干眼症患者是一种简便有效的方法。     

Antiinflammatory therapy for dry eye

PURPOSE: To present evidence establishing the relationship between inflammation and dry eye and supporting the use of antiinflammatory therapy for dry eye. DESIGN: Analysis of literature. METHODS: Research studies that evaluated inflammation in dry eye pathogenesis and clinical trials of antiinflammatory therapies for dry eye were reviewed. RESULTS: There is increasing evidence that decreased tear secretion, decreased tear turnover, and desiccation promote inflammation on the ocular surface. An increase in soluble mediators (cytokines and proteases) in the tear fluid, adhesion molecule expression by the conjunctival epithelium, and T-cell infiltration of the conjunctiva have been observed in dry eye patients. This inflammation appears to have a role in the pathogenesis of the ocular surface epithelial disease, termed keratoconjunctivitis sicca (KCS), that develops in dry eye. Clinical improvement of KCS has been observed after therapy with antiinflammatory agents including corticosteroids, cyclosporin and doxycycline. Cyclosporin A emulsion was approved by the Food and Drug Administration as therapy for dry eye. Randomized placebo-controlled FDA clinical trials showed that cyclosporine A was superior to vehicle in stimulating aqueous tear production, decreasing corneal punctuate fluorescein staining, reducing symptoms of blurred vision, and decreasing artificial tear use in patients with KCS. No ocular or systemic toxicity was observed from this medication. CONCLUSIONS: Ocular surface and lacrimal gland inflammation has been identified in dry eye that plays a role in the pathogenesis of KCS. Antiinflammatory therapy has efficacy for treating KCS. Cyclosporin A is the first FDA approved therapy for this indication. It improved signs and symptoms of KCS, and it is safe for long-term use.     

硅胶泪点或泪管栓塞术治疗干眼症

目的 评价硅胶泪点或泪管栓塞术治疗干眼症的临床效果。方法 确诊为干眼症并用其他方法治疗无效１６例,先行自溶型胶原泪管栓塞术,以确定该方法的初步效果,然后行水久型硅胶泪点（顶盖式）或泪管（喇叭式）栓塞术,利用主觉和客观临床检测方法评价其效果。结果 泪点或泪管栓塞术后,泪液量明显增加,泪膜稳定性有所改善,干眼症状明显缓解;若下眼睑张力较大时,使用顶盖式泪点栓时有可能产生异物感。结论 泪点或泪管栓塞中有     

Effect of overexpression of constitutively active PKCalpha on rat lacrimal gland protein secretion

PURPOSE: The lacrimal gland secretes water, electrolytes, and protein into the tear film. Decreased secretion from the lacrimal gland can lead to dry eye syndromes with deleterious effects on vision. Protein kinase C (PKC)-alpha plays a major role in cholinergic- and alpha1-adrenergic-induced protein secretion from the lacrimal gland. This study was undertaken to determine whether activation of PKCalpha alone would induce lacrimal gland protein secretion by examining the effects of overexpression of constitutively active PKCalpha. METHODS: Rat lacrimal gland acini were transduced with an adenovirus containing a gene for constitutively active PKCalpha. Protein secretion was measured in response to cholinergic and alpha1-adrenergic agonist stimulation. RESULTS: More than 84% of acinar cells were transduced, and PKCalpha expression was increased 176-fold. Western blot analysis using an antibody to phosphorylated (activated) PKCalpha indicated that the overexpressed PKCalpha was active, and basal secretion was increased. Cholinergic agonist-stimulated protein secretion was not stimulated above basal secretion, whereas alpha1-adrenergic-agonist-stimulated protein secretion was increased in transduced acini. CONCLUSIONS: Basal lacrimal gland protein secretion can be stimulated by bypassing the release of neurotransmitters and activating PKCalpha, possibly leading to the development of new treatments for dry eye syndromes.     

Therapeutic effect of cevimeline on dry eye in patients with Sjögren's syndrome: a randomized, double-blind clinical study

PURPOSE: Sj?gren's syndrome (SS) is a systemic autoimmune disease characterized by salivary and lacrimal glandular destruction leading to symptoms of dry mouth and dry eye. Dryness can also occur in the absence of glandular destruction. Patients with SS have autoantibodies that bind to muscarinic acetylcholine receptors in the exocrine glands. Recently, a muscarinic acetylcholine receptor agonist, cevimeline, has been approved for use against symptoms of dry mouth in patients with SS. In this study, the efficacy of cevimeline in improving symptoms of dry eye was examined. DESIGN: Prospective, randomized, double-blind, multi-center clinical study. METHODS: Sixty patients were randomly assigned to three groups-placebo; cevimeline, 20 mg three times daily; or cevimeline, 30 mg three times daily-and received treatment for 4 weeks. Patients were evaluated before treatment, at week 2, at the end of treatment, and at the end of a 2- to 4-week follow-up period. RESULTS: Compared with the placebo, statistically significant differences were seen with cevimeline, 20 mg three times daily, in subjective symptoms, tear dynamics, condition of the corneoconjunctival epithelium, and global improvement rating. No difference was found among the three groups regarding the safe use of the drug. CONCLUSIONS: These results indicate that cevimeline, 20 mg three times daily, is safe and effective in improving symptoms of dry eye in patients with SS. Additional studies, with larger patient populations, are needed to further assess the effectiveness of cevimeline for dry eye.     

The evolving treatment of dry eye

Palliative treatments that historically have been the mainstay of therapy for dry eye continue to improve and are still appropriate therapy while we await new advances to control the underlying cause of dry eye disease. The approach of tear supplementation and tear preservation continues to be useful. The goal of tear stimulation or enhancement is elusive, but it may be nearer with the advent of P2Y2 agonists. The recognized importance of inflammation in producing dry eye through lacrimal gland and ocular surface damage is leading us to novel strategies to immunomodulate the disease and to restore hormonal balance to the ocular surface-lacrimal gland homeostatic cycle. It has taken 20 years of investigation to reach this threshold. The next 3 years should see promising treatments approved for dry eye disease.     

泪道激光联合引流管植入对泪道阻塞患者的影响

目的：探究泪道激光联合引流管植入对泪道阻塞患者泪膜破裂时间及角膜荧光素钠染色的影响,以便提高泪道激光联合引流管植入术对患者的治疗效果。

方法：选取2013-01/2015-12在我院进行泪道激光联合泪道引流管植入术治疗的泪道阻塞患者200例200眼,分别在治疗前、术后1mo、拔管后进行眼表评估。检测内容包括患者泪膜破裂时间、泪液分泌量、角膜荧光素钠染色情况及干眼症状问卷等。

结果：患者治疗前、术后1mo、拔管后泪膜破裂时间,三者间比较差异无统计学意义(P>0.05)。患者术后1mo泪液分泌量增加,拔管后泪液分泌量减少,差异有统计学意义(P<0.05)。患者治疗前、术后1mo、拔管后角膜荧光素钠染色评分无明显变化,三者间比较差异无统计学意义(P>0.05)。进行干眼症状问卷显示行泪道激光联合引流管植入术后流泪症状明显改善。

结论：泪道激光联合引流管植入对患者泪膜破裂时间及角膜荧光素钠染色无明显影响,此种手术方式可以使患者术后流泪症状明显改善,在治疗泪道阻塞方面具有重大意义。     

粘蛋白与干眼症

眼表粘蛋白由角膜、结膜、泪器产生,是泪膜的重要成分,具有稳定泪膜、保护眼表、参与信号转导等功能.干眼症中粘蛋白的量和结构均发生改变,是干眼症发病机制的中间环节,同时也是结果 之一.干眼症中眼表粘蛋白的检测可能具有潜在的诊断价值.促进粘蛋白分泌或表达的药物将成为治疗干眼症的重要手段.就眼表粘蛋白及其在干眼症中的表达变化做一综述.