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。     

黏蛋白与眼表疾病相关性进展

黏蛋白是决定泪膜稳定性的关键因素,对维持眼表稳态至关重要。杯状细胞能够改变角膜和结膜上皮细胞分泌黏蛋白,促进干眼(DED)和眼表炎症的发生。本文基于对黏蛋白生物学的认识,就黏蛋白和眼表疾病之间的潜在联系进行总结,旨在更好地了解黏蛋白的重要性,基于眼表疾病有针对性地选择最为合适的治疗方案。     

黏蛋白和干眼的研究进展

干眼是由于泪液的质和量的异常引起泪膜的不稳定和眼表损害，从而导致眼部不适。黏蛋白是泪膜的重要成分，对维持眼表稳定及预防眼表病变起着重要作用。对眼表黏蛋白的功能和调节机制的研究将为干眼的治疗提供新的有效途径。[眼科新进展2007；27（3）：239-2,40]     

黏蛋白异常型干眼基础研究及中医药治疗展望

黏蛋白异常型干眼是由于各种因素造成眼表上皮细胞(尤其杯状细胞)受损而引起的眼表疾病。眼表上皮细胞及杯状细胞表达分泌的黏蛋白是泪膜的重要组成部分,在维持眼表稳态方面具有重要的作用。本文综述了近年来在眼表上皮细胞、杯状细胞及其表达分泌的黏蛋白方面的基础研究结果,阐述了它们在黏蛋白异常型干眼发病机制中的重要作用,并简要总结了中医药针对本型干眼的治疗研究进展,为对其发病机制的深入研究,以及中医药治疗提供了思路。     

眼表黏蛋白的研究进展

黏蛋白是眼表泪膜的重要组成部分，由角膜结膜上皮细胞和结膜杯状细胞分泌，具有稳定泪膜、润滑眼表、防止微生物入侵等作用。本文主要综述眼表黏蛋白的来源与分类，黏蛋白的功能，影响黏蛋白分泌的因素以及黏蛋白与眼表疾病的关系。     

黏蛋白MUC5AC与眼病的关系

眼表黏蛋白MUC5AC是由结膜杯状细胞分泌的大分子胶样分泌性黏蛋白,其溶解于泪膜的水液层,具有清理眼表碎屑、防止眼表结构受到伤害、润滑眼表、促进泪液排出、维持泪膜稳定、防止病原体侵入、对眼表止血等作用.MUC5AC黏蛋白与许多眼表疾病有密切关系.感染性疾病、免疫性疾病、准分子激光手术、配戴角膜接触镜及维生素缺乏等均可引起MUC5AC表达水平的下降或反应性升高,引起多种临床症状,并使眼表抵御外界侵袭的能力下降,发生干眼、眼表过敏性疾病、变性类疾病等.     

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。     

首诊干眼患者结膜黏蛋白表达变化及临床意义

目的了解首诊干眼患者结膜黏蛋白MUC1、MUC4、MUC5AC和MUC16表达情况及其与干眼症状体征的相关性。方法采用横断面研究方法, 于2016年12月至2018年5月在厦门大学附属厦门眼科中心、首都医科大学附属北京同仁医院、四川大学华西医院和上海市普陀区中心医院4个临床研究中心纳入首次就诊干眼患者69例69眼作为干眼组, 正常志愿者40例40眼作为正常对照组。受检者均填写中国干眼问卷、眼表疾病指数量表(OSDI)和干眼相关生活质量评分问卷(DEQS), 以评估干眼相关症状;采用泪膜破裂时间(TBUT)检查、角结膜荧光素钠染色、基础泪液分泌试验(Schirmer试验Ⅰ)以评估干眼相关体征;采用结膜印迹细胞学方法采集结膜细胞, 采用实时荧光定量PCR法检测受检者结膜中MUC1、MUC4、MUC5AC和MUC16 mRNA表达情况;采用Spearman秩相关分析探讨结膜黏蛋白表达量与干眼症状体征之间的关联。结果干眼组患者结膜黏蛋白MUC1和MUC16 mRNA相对表达量分别为3.277(0.568, 5.790)和1.815(1.048, 3.694), 均较正常对照组的1.055(0....     

不同浓度玻璃酸钠对新西兰兔干眼眼表变化的影响

目的：对比观察不同浓度的玻璃酸钠对干眼眼表变化的影响。

方法：制备新西兰兔干眼动物模型,使用1g/L玻璃酸钠和3g/L玻璃酸钠滴滴液治疗,分别作为低浓度治疗组(B组)和高浓度治疗组(C组),生理盐水治疗作为对照组(A组)。分别观察角膜荧光染色、泪液分泌试验、结膜杯状细胞及黏蛋白表达和组织学变化。

结果：治疗后D7和D14时,B组及C组角膜荧光染色评分低于A组(P<0.05),泪液分泌、杯状细胞密度及黏蛋白含量高于A组(P<0.05)。C组角膜泪液分泌和杯状细胞密度高于B组(P<0.05)。与B组和C组相比较,A组角膜及结膜上皮细胞层变薄,角膜及结膜基质未见明显异常。

结论：玻璃酸钠能够改善干眼眼表损害,且高浓度治疗效果优于低浓度。     

自体颌下腺移植术治疗重症角结膜干燥症

重症角结膜干燥症的治疗一直是眼科的难题之一.重症干眼引起角膜混浊、溃疡形成,导致视力丧失.自体颌下腺移植治疗重症角结膜干燥症能改善泪液缺乏,稳定眼表,联合眼表重建及板层角膜移植是治疗重症角结膜干燥症的有效方法.     

Orbital invasion despite topical anti-metabolite therapy for conjunctival carcinoma

Background Two cases of conjunctival carcinoma developed orbital invasion during treatment with topical medication. Methods This was a retrospective study from a tertiary ophthalmic oncology unit, performed after informed consent was obtained. The main outcome measurement was orbital invasion. Results Two patients treated with topical agents developed orbital invasion. Conclusion While topical agents are important in treatment of conjunctival neoplasia, recurrence or deep invasion require careful monitoring. Supported in part by a grant from the Tumori Foundation. The author has no financial interest in the subject matter.     

抗真菌药物联合结膜瓣覆盖治疗重度真菌性角膜溃疡

目的:观察抗真菌药物联合结膜瓣覆盖治疗重度真菌性角膜溃疡的临床效果。方法:对重症真菌性角膜溃疡患者19例19眼进行抗真菌药物联合结膜瓣覆盖治疗,其中使用的抗真菌药物包括氟康唑、大蒜素、那他霉素眼液、斯皮仁诺等,观察治疗前后角膜刺激症状、视力、角膜溃疡愈合等变化。结果:术后角膜刺激症状明显减轻,治疗1mo后17眼结膜伤口愈合,视力:光感～0.3。另2眼复发加重,其中1例放弃治疗,因穿孔发生眼内炎,选择眼球摘除1例。术后1a,6例患者打开结膜瓣,角膜上皮平复,角膜白斑4例和斑翳2例。结论:抗真菌药物联合结膜瓣覆盖是一种有效的重度真菌性角膜溃疡治疗方案。     

Glutathione and its transporters in ocular surface defense

Glutathione (GSH) is an abundant antioxidant ubiquitous in nearly all cell types. Deficiency of GSH has been linked to ocular disease and viral infection. Other established vital roles of GSH include detoxification and immunoprotection. Endogenous GSH plays a protagonist's role in safeguarding active transport processes compartmentalized at the interface between conjunctival mucosa and the tear film. Optimal electrokinetic transport across the conjunctival epithelium requires the mucosal presence of GSH. Glutathione is the most abundant known endogenous antioxidant molecule in tear fluid, mainly derived from conjunctival secretion. Conjunctival GSH transport, a major kinetic component of GSH turnover, occurs through multiple functionally distinct mechanisms. Cell membrane potential regulates conjunctival GSH efflux, while conjunctival GSH uptake requires extracellular Na(+). Significant modulation of GSH, its constituent amino acids, and functions of associated transporters occurs in the conjunctival epithelium with viral inflammatory disease. Topical conjunctival delivery of GSH, its metabolic precursors, or pharmacologic stimulation of endogenous conjunctival GSH secretion carry potential in alleviating viral-inflammatory conjunctivitis.     

Roles of cytokines in the development of severe allergic conjunctival diseases: analyses using animal models

Conjunctival papillary formation and corneal damage, which are seen in severe types of allergic conjunctival diseases, are mediated by eosinophils. Eosinophils themselves are not able to recognize a specific antigen (Ag) and thus, Ag-specific T cells are thought to be important for eosinophilic infiltration into the conjunctiva. Cytokines, which are produced by Ag-specific T cells followed by Ag recognition, are considered to be involved in eosinophilic infiltration. Therefore, we investigated the involvement of cytokines, which are produced by immunocompetent cells and conjunctival cells, in the infiltration of inflammatory cells into the conjunctiva, using an animal model for allergic conjunctival diseases (experimental immune-mediated blepharoconjunctivitis, EC). The peak of expression of Th 2 cytokines such as interleukin (IL)-4 in the rat conjunctiva was 6 and 12 hours after Ag challenge. In contrast, expression of Th1 cytokines such as interferon (IFN)-gamma persisted up to 48 hours after Ag challenge. The kinetic change of IL-4 was concordant with eosinophilic infiltration into the conjunctiva and that of IFN-gamma was in accord with infiltration of macrophages. To investigate the roles of these cytokines, we induced conjunctivitis in cytokine knockout mice. The infiltration of inflammatory cells was attenuated in IL-4 knockout mice, whereas it was augmented in IFN-gamma knockout mice. To further elucidate the roles of these cytokines, we induced and analyzed EC in Brown Norway rats. Eosinophilic infiltration was increased in EC induced by the transfer of T cells, which were stimulated by IL-4. In addition, systemic treatment with IFN-gamma inhibited eosinophilic infiltration in EC induced by active immunization, but did not affect infiltration of inflammatory cells in EC induced by passive immunization. These results demonstrate that IL-4 and IFN-gamma are involved in the infiltration of eosinophils and macrophages, respectively. In addition, IFN-gamma exerts its suppressive effects on the development of EC only during the induction phase of EC. Further detailed studies investigating the roles of cytokines in the conjunctiva will elucidate the developing mechanism of allergic conjunctival diseases. These studies will provide important clues for a therapeutic approach in targeting cytokines.     

Importance of diagnosis and preoperative care of the conjunctiva

The conjunctival smear is an important part of preoperative diagnosis. Although the method is very easy there are many possible sources of error. The validity of smear results was studied; the sources of error are discussed in the present paper. The different bacterial flora of the conjunctival sac and the lid margin were investigated. It was shown that eye drop dispensers become contaminated during use. The use of single-dose Ophtiolen has the advantage--in addition to improved hygiene, that no stabilizing agents are used. Preoperative efforts to achieve asepsis have to be continued during the operation. A new adhesive tape specially developed for ophthalmic surgery has been found very effective. This new tape is described.     

HLA class II antigen expression in conjunctival precancerous lesions and squamous cell carcinomas

PURPOSE: The expression of human leukocyte antigen (HLA) class II molecules on the cell surface is necessary for the presentation of peptide antigens to helper CD4 T lymphocytes of the immune system. We studied the immunoexpression of HLA class II antigen in conjunctival precursor lesions and conjunctival squamous cell carcinomas. METHODS: HLA class II antigen expression was analyzed in 8 conjunctival dysplasias, 6 carcinomas in situ and in 7 conjunctival squamous cell carcinomas, by immunoperoxidase staining with monoclonal antibody to HLA class II antigen on the archival clinical samples. Immunoanalysis was done by a semi quantitative method based on the intensity of staining and the percentage of stained cells. RESULTS: HLA class II antigen immunoexpression was heterogeneous in 8 conjunctival dysplasias and in 6 carcinoma in situ and negative in 7 conjunctival squamous cell carcinomas. CONCLUSIONS: Human leukocyte class II antigen immunoexpression is decreased in conjunctival precancerous and squamous cell carcinomas.     

The immunomodulatory role of human conjunctival epithelial cells

PURPOSE: To characterize phenotypically the primary epithelial cells obtained from normal bulbar conjunctival biopsy specimens and a human conjunctival epithelial cell line (Wong-Kilbourne derivative of Chang conjunctiva; ChWK) with regard to their immunostimulatory function. METHODS: The effects on expression of HLA-DR and costimulatory molecules (CD80, CD86, ICAM-1, and CD40) on normal conjunctival epithelial cells and ChWK treated with various cytokines (IFN-gamma, TNF-alpha, IL-4, and IL-13) were determined using flow cytometry and confocal microscopy. RESULTS: Epithelial cells were successfully grown from conjunctival explants and cultures passaged three times, while retaining their cell surface markers. At least 97% of primary epithelial cells (n = 10) and more than 96% of ChWK cells (n = 10) were cytokeratin positive by flow cytometry and immunocytochemistry and demonstrated epithelial cell morphology. Both primary conjunctival epithelial cells and ChWK had a low basal expression of HLA-DR and ICAM-1, and both were upregulated by IFN-gamma. For ChWK cells, CD80 and CD86 were constitutively expressed at low levels. CD80 was significantly upregulated after IFN-gamma treatment (P = 0.043), whereas IL-4 induced a significant upregulation of CD86 (P = 0.039). Treatment with IL-13 and TNF-alpha did not induce significant effects. CONCLUSIONS: The ability of conjunctival epithelial cells to express costimulatory molecules suggests a proinflammatory role for conjunctival epithelial cells.     

Ways of increasing effectiveness of eye prostheses

The study of reasons of unsatisfactory eye prosthesis has shown that after insertion of cosmetic eye prosthesis into the conjunctival cavity in the majority of patients an inflammatory process develops which often goes on for several years. Discomfort and inflammation are mainly caused by a shift in acid-alkali balance in the conjunctival cavity, protein, fat and calcium deposits on the surface of prosthesis. The available agents of caring conjunctival cavity and prosthesis do not permit to fully clean prosthesis and to restore acid-alkali balance in cavity being equipped with prosthetic appliance. The authors offer new methods of taking care of prosthesis and conjunctival cavity making it possible to improve convenience of wearing eye prostheses, to disinfect them efficiently, clean them and prolong their service life.     

Effects of IL-4 on conjunctival fibroblasts: possible role in ocular cicatricial pemphigoid

PURPOSE: Increased stromal accumulation of macrophages and submucosal fibrosis due to excessive accumulation of collagens are central histologic features in ocular cicatricial pemphigoid (OCP). Interleukin (IL)-4 plays an important role in both the inflammatory and fibrotic events in several human and experimental diseases. In the present study, the possible role of IL-4 in the pathogenesis of OCP was investigated. METHODS: Biopsy specimens from the conjunctivae of 10 patients with OCP and 5 normal subjects were studied for the expression of IL-4 by immunohistochemistry. The expression level of IL-4 was also examined in conjunctival fibroblasts of normal control subjects and patients with OCP. The effects of IL-4 in the induction of inflammatory and fibrogenic molecules was studied in IL-4-treated conjunctival fibroblasts, and the expression levels of macrophage colony-stimulating factor (m-CSF), heat shock protein (HSP)-47 and type I collagen was determined by quantitative real-time PCR. The level of IL-4 was also measured by enzyme-linked immunosorbent assay (ELISA) in serum samples obtained from patients with OCP during active stage and remission and were compared with the levels in control sera. RESULTS: Compared with the weak expression of IL-4 in the normal conjunctival sections, an increased expression of IL-4 was noted in conjunctival sections of patients with OCP. A similar increase in the expression of IL-4 was also detected in fibroblasts isolated from conjunctiva of patients with OCP, compared with control fibroblasts. Real-time PCR and ELISA detected a significantly increased level of m-CSF, at both the mRNA and protein levels in IL-4-stimulated cells. Similarly, IL-4 treatment resulted in the induction of type I collagen and collagen-binding HSP47 by conjunctival fibroblasts, as detected by real-time PCR. However, no apparent changes in the levels of IL-4 were detected by ELISA in serum samples of patients with OCP and control subjects. CONCLUSIONS: Increased conjunctival expression of IL-4 may play an important role in the regulation of local accumulation of macrophages (by inducing m-CSF), and matrix accumulation (by inducing HSP47 and collagen) during conjunctival scarring in patients with OCP. IL-4, therefore, may augment or enhance both conjunctival inflammatory and subsequent fibrotic responses in patients with OCP.