围绝经期女性干眼发病相关影响因素分析

围绝经期女性是干眼的高发人群。近年来关于围绝经期妇女干眼发病的研究多从炎症等局部因素或雌激素缺乏等因素论述。然而我们认为与临床其他类型干眼相比,影响该特殊类型干眼发病的相关因素颇多。本文就泪腺和结膜异常、性激素缺乏、心理障碍、全身慢性疾病、生活环境及生活习惯等方面对围绝经期干眼发病的影响进行综述。     

干眼模型的建立方法及评价

干眼是一类非常常见的眼表疾病，理想的干眼模型对于干眼的研究具有重要的价值。目前，已有多种建立干眼动物模型的方法，如通过药物作用、改变动物性激素分泌水平、去除泪腺或眼表的神经支配、诱导泪腺产生自身免疫反应、手术摘除泪腺及手术封闭睑板腺开口等均可制作出干眼模型。这些干眼模型归纳起来主要有泪液缺乏型干眼及蒸发过强型干眼两大类型。常用于制作干眼模型的动物主要有兔、狗及鼠等，此外，还有使用猫、恒河猴、貂及马等制作干眼模型的报道。对几种常见的干眼模型的制作方法及其优缺点作一简要的综述。     

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。     

糖尿病相关干眼发病机制的研究进展

近年随着对糖尿病眼部并发症认识的不断深入, 糖尿病的眼表异常逐渐受到关注和重视。近50%糖尿病患者合并干眼。糖尿病相关干眼的主要表现为泪液分泌量异常、泪膜稳定性差、角膜知觉下降, 严重者可出现持续性角膜上皮缺损甚至角膜溃疡, 这主要与糖尿病引起的泪腺结构和功能改变、结膜杯状细胞数量减少、睑板腺功能异常及角膜神经发生退行性改变有关。本文主要就糖尿病对泪膜、角膜神经和泪腺神经的影响以及氧化应激和晚期糖基化终末代谢产物与糖尿病相关干眼的关系等方面的最新研究进展进行总结和分析, 探讨糖尿病相关干眼的发病机制, 为临床开展诊疗和研究工作提供参考。     

基于泪液功能单位的干眼治疗

干眼发病原因多,其主要特征是泪膜稳态失衡.泪膜稳态的维持得益于泪液功能单位各组成部分的正常运转.泪液功能单位由角膜、结膜、泪腺、睑板腺、泪腺以及连接它们的神经网络组成,通过调节方式控制泪液分泌.一个或多个组成部分功能失常会直接影响泪膜稳态而导致干眼.针对角膜的干眼治疗包括自体血清、神经生长因子、接触镜及抗炎治疗;针对结...     

Th细胞及其相关因子参与干眼发病机制的研究进展

干眼是眼表免疫稳态失衡所致的炎症性疾病.由泪膜、角结膜上皮、睑板腺、泪腺以及联络它们的神经通路共同组成的泪腺功能单位(lacrimal functional unit,LFU)是维持眼表生理稳态的完整系统,任何影响这一系统的因素都可以干扰眼表免疫平衡机制引发炎症反应,并最终导致干眼的发生.研究发现,Th细胞及其相关因子在干眼炎症过程中发挥了重要作用,影响Th细胞分化或Th细胞相关因子的异常表达可以控制眼表炎症反应,有助于恢复眼表免疫稳态,有效抑制干眼病理改变和缓解临床症状.     

间充质干细胞对兔自身免疫性干眼模型病理改变及细胞因子表达的影响

目的 建立兔自身免疫性干眼模型,观察间充质干细胞(mesenchymal stem cells,MSCs)治疗后兔自身免疫性干眼的组织病理学变化及泪腺组织中细胞因子表达的变化.方法 取健康成年雌性新西兰白兔24只24眼,采用随机数学表法将兔分为正常对照组、干眼模型组和MSCs治疗组,每组各8只8眼.MSCs治疗6周后,观察兔眼组织病理学改变,实时荧光定量PCR检测泪腺组织中Th1、Th17细胞分化相关细胞因子mRNA相对表达量.流式细胞仪检测干眼模型组和MSCs治疗组兔泪腺组织和脾脏组织中调节性T细胞(CD4+ Foxp3+细胞)占淋巴细胞的比例.结果 MSCs治疗6周后,取各组兔泪腺并行HE染色显示:正常对照组未见或仅见少量淋巴细胞浸润;干眼模型组泪腺内部分腺体细胞出现萎缩,腺管周围和小血管周围可见散在分布的淋巴细胞汇集区;与干眼模型组相比,MSCs治疗组泪腺内淋巴细胞浸润减轻,腺泡细胞形态较好.与干眼模型组比较,MSCs治疗组结膜组织中淋巴细胞浸润聚集显著减轻,上皮结构完整,变性和萎缩细胞较少见.MSCs治疗组泪腺组织中Th1特征性细胞因子IFN-γ以及转录因子T-bet mRNA表达水平较干眼模型组明显下降,差异均有统计学意义(均为P ＜0.05);Th17细胞分化相关细胞因子IL-17表达水平有下降趋势,但两组差异无统计学意义(P＞0.05);其转录因子RORa mRNA的表达水平较干眼模型组显著降低,差异有统计学意义(P＜0.05).MSCs治疗组泪腺组织中炎症因子TNF-α表达较干眼模型组显著降低,而抑炎因子TGF-β的表达较干眼模型组显著升高,差异均有统计学意义(均为P＜0.05).泪腺组织中干眼模型组调节性T细胞(CD4+ Foxp3+细胞)占淋巴细胞的比例为10.0％,而MSCs治疗组中调节性T细胞占淋巴细胞的比例为27.8％,MSCs治疗组调节性T细胞较干眼模型组显著升高,差异有统计学意义(P＜0.05).结论 MSCs可以减轻自身免疫性干眼的组织病理学改变,对自身免疫性干眼具有一定的免疫调节及治疗作用,其免疫调控作用可能与调节抑炎因子和促炎因子平衡有关.     

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。     

兔自身免疫性干眼模型的建立及泪腺炎症因子研究

目的　通过静脉回输自体激活的淋巴细胞建立稳定的兔自身免疫性干眼模型,并分析干眼的泪腺炎性因子,探究干眼的泪腺免疫反应。方法　通过体外分离、培养兔泪腺上皮细胞和自体外周血淋巴细胞,建立二者的共培养体系。将体外激活的自体外周血淋巴细胞通过耳缘静脉注射的方法诱发自身免疫性泪腺炎。对干眼临床指标及泪腺细胞因子表达进行检测。结果　与正常对照组相比,干眼模型组泪液分泌显著减少（ｔ＝１１５．６,Ｐ＜０．０５）,泪膜破裂时间缩短（ｔ＝９２．５,Ｐ＜０．０５）。荧光素钠染色显示角膜弥漫性点状着色,正常对照组基本无着色。泪腺组织ＨＥ染色显示淋巴细胞浸润,正常对照组很少。ＲＴ-ＰＣＲ结果显示,干眼模型组泪腺中炎性因子ＩＦＮ-γ、ＩＬ-６、ＩＬ-１７ｍＲＮＡ相对表达量显著升高（ｔ＝２６．２、１８．７、８．４;均为Ｐ＜０．０５）,抑炎因子ＩＬ-１０、ＴＧＦ-βｍＲＮＡ相对表达量显著降低（ｔ＝２２．１、１４．２;均为Ｐ＜０．０５）。结论　经兔泪腺上皮细胞激活的自体外周血淋巴细胞静脉回输后,成功诱发干燥综合征样自身免疫泪腺炎,建立了稳定的兔自身免疫性干眼模型。泪腺组织中细胞因子ＩＬ-６、ＩＬ-１７、ＩＦＮ-γ、ＴＧＦ-β、ＩＬ-１０参与泪腺内炎症反应的发生和发展。     

干眼的免疫学研究现状及进展

干眼,是指由于泪液量或质的异常引起的泪膜不稳定和眼表面损害而致眼部不适的一类疾病。依照干眼发病与泪膜的关系,干眼可分为五类[1]:水液缺乏型干眼,脂质缺乏型干眼,粘蛋白缺乏型干眼,泪液动力学异常型干眼,混合型干眼。随着近年来研究的深入,干眼发病过程中免疫机制越来越受到重视,本文拟对部分干眼的免疫发病机帛研究及干眼的免疫调控治疗作一综述。一、和泪腺的免疫环境眼表面由角膜,结膜和角结膜缘三部分组成,是经常发生炎症和免疫反应的潜在部位。睑结膜和球结膜具有独特的细胞群体,包括杯状细胞,肥大细胞和附属泪腺。出生时正常的眼…     

Tearful relationships? Sex, hormones, the lacrimal gland, and aqueous-deficient dry eye

Sex and the endocrine system exert a significant influence on the physiology and pathophysiology of the lacrimal gland. The purpose of this article is to briefly review the nature and magnitude of these interactions between sex, hormones and lacrimal tissue, and to address how they may relate to the pathogenesis of aqueous-deficient dry eye. Towards this end, this article has a 3-fold approach: first, to summarize the influence of androgens, estrogens, glucocorticoids, mineralocorticoids, retinoic acid, prolactin, alpha-melanocyte stimulating hormone, adrenocorticotropic hormone, luteinizing hormone, follicle-stimulating hormone, growth hormone, thyroid-stimulating hormone, arginine vasopressin, oxytocin, thyroxine, parathyroid hormone, insulin, glucagon, melatonin, human chorionic gonadotropin and cholecystokinin on the structure and function of the lacrimal gland; second, to discuss the mechanism of action of each hormone on lacrimal tissue; and third, to discuss the clinical relevance of the endocrine-lacrimal gland interrelationship, with a particular focus on each hormone's role (i.e. if relevant) in the development of aqueous-tear deficiency.     

Hormonal regulatory influence in tear film

Tear film quality depends on fine regulatory mechanisms affected by neuronal and hormonal influences. Indeed, receptors for androgens, estrogens, progesterone and prolactin have been identified in several ocular tissues in the rat, rabbit and in humans. The eye is thus a target organ for sex hormones, particularly the androgens. These hormones regulate the immune system, the morphology and secretory functions of lacrimal glands and the functioning of Meibomian glands. The influence of hormone replacement therapy in menopausal women remains unclear, as some authors support the idea that they improve the quality and the volume of tear film, whereas others have shown that they increase the risk of dry eye. Finally, knowledge of the interactions between the hormones that influence the lacrimal glands is essential for the understanding of the regulation of lacrimal gland function. However, the data presently available strongly suggest that optimal bioavailable androgen levels are essential for normal lacrimal gland function and that prolactin and estrogens also play important roles in providing a hormonal milieu that contributes to normal lacrimal gland function.     

The clinical and echographic features of tear in the dry eye syndrome

The paper presents the results of three-dimensional combined tear ultrasound analysis in various diseases accompanied by the dry eye syndrome. Sixty-five patients with clinical manifestations of the dry eye syndrome were examined. Of them, there were 20 patients with Sjogren's syndrome and disease, 25 with dry eye syndrome of unknown genesis, 5 with lachrymal gland tumorous lesion, 5 with cystic lacrimal gland changes (dacryops), and 10 persons above 65 years of age (a risk group). In each of the study group the study determined the mean sizes of a ultrasound section of the lacrimal gland, its mean volume, and densitometric indices, such as density and vasculogenicity index, as well as the mean values of hemodynamic parameters in the lacrimal artery. The characteristic echographic signs of lacrimal gland structural changes and vascularization are described in Sjogren's disease and syndrome, dry eye syndrome of unknown genesis, dacryops, neoplastic processes involving the lacrimal gland. The proposed algorithm of lacrimal gland ultrasound study can enhance the accuracy and validity of results of the differential diagnosis of various lacrimal gland diseases with the clinical manifestations of the dry eye syndrome. The findings may be further used for the monitoring and detection of three-dimensional and structural changes in the lacrimal gland, which result from various pathological processes with the clinical manifestations of the dry eye syndrome.     

Effect of calorie restriction on change in lacrimal gland with age

Rapid growth in the number of dry eye syndrome patients has been observed worldwide. Increased life span is considered to be at least part of the reason for this because there is a close association between aging and decreased secretory function in the lacrimal gland. Recent advances have led to a new way of thinking about intervention in the aging process. Calorie restriction (CR) is believed to retard functional decline in various organs with age. We hypothesized that CR could prevent age-related lacrimal dysfunction. In this paper, we begin by reviewing the epidemiology of dry eye syndrome and explaining how aging affects lacrimal gland function. We then introduce a possible therapeutic approach to this problem, intervention by means of CR. Finally, suggestions are made for further prospective research that would elucidate the molecular mechanisms by which CR maintains lacrimal gland function.     

Why the eye becomes dry: a cornea and lacrimal gland feedback model.

PURPOSE: Many explanations have been offered for why a large segment of the population develops dry eye. The purpose of this paper is to describe a new unifying theory of dry eye that incorporates all of these causes. METHODS: Data from the Department of Ophthalmology, University of Iowa Hospitals and Clinics was analyzed from 520 patients with dry eye, blepharitis and other conditions to assess the relationship between dry eye and blepharitis. This data was reviewed in terms of the relationship between dry eye, menopause, and aging. Also examined in detail were many of the proposed causes for dry eye in the literature. RESULTS: A close relationship between corneal damage and lacrimal gland function is hypothesized. Not only does decreased lacrimal gland output damage the ocular surface, but also damage to the corneal surface creates a negative feedback loop and damage to the lacrimal gland. There are probably several mechanisms by which this feedback occurs. One mechanism results from interruption or damage to the sensory corneal nerves. Damage to the nerves within the lacrimal gland may be another mechanism. Alteration of growth factor levels in the lacrimal gland, which occurs following corneal damage, represents another possible mechanism. Contact lenses and corneal refractive surgery are additional elements that may create negative feedback to the lacrimal gland. CONCLUSION: The ocular surface and the lacrimal gland functions as a tightly integrated unit. Dry eye conditions damage the ocular surface and this in turn leads to further damage to the lacrimal gland.     

Effect of inflammation on lacrimal gland function

The lacrimal gland is the main contributor to the aqueous layer of the tear film. It secretes proteins, electrolytes and water, which helps to nourish and protect the ocular surface. Lacrimal gland secretion is primarily under neural control, which is achieved through a neural reflex arc. Stimuli to the ocular surface activate afferent sensory nerves in the cornea and conjunctiva. This in turn activates efferent parasympathetic and sympathetic nerves in the lacrimal gland to stimulate secretion. Sex steroid hormones are also important regulators of lacrimal gland functions. A decrease or lack of lacrimal gland secretion is the leading cause of aqueous tear deficient dry eye syndrome (DES). It has been suggested that DES is an inflammatory disorder that affects the ocular surface and the lacrimal gland. In several pathological instances, the lacrimal gland can become a target of the immune system and show signs of inflammation. This can result from autoimmune diseases (Sj?gren's syndrome), organ transplantation (graft versus host disease), or simply as a result of aging. The hallmarks of lacrimal gland inflammation are the presence of focal lymphocytic infiltrates and increased production of proinflammatory cytokines. The mechanisms leading to lacrimal gland dysfunction are still poorly understood. Apoptosis, production of autoantibodies, hormonal imbalance, alterations in signaling molecules, neural dysfunction, and increased levels of proinflammatory cytokines have been proposed as possible mediators of lacrimal gland insufficiency in disease states.     

Sex hormones and the dry eye

The greater prevalence of dry eye in women compared to men suggests that sex hormones may have a role in this condition. This review aims to present evidence for how sex hormones may affect the ocular structures involved in the production, regulation and maintenance of the normal tear film. It is hypothesised that hormone changes alter the homeostasis of the ocular surface and contribute to dry eye. Androgens impact on the structure and function of the meibomian and lacrimal glands and therefore androgen deficiency is, at least in part, associated with the aetiology of dry eye. In contrast, reports of the effects of oestrogen and progesterone on these ocular structures and on the conjunctiva are contradictory and the mechanisms of action of these female‐specific sex hormones in the eye are not well understood. The uncertainty of the effects of oestrogen and progesterone on dry eye symptoms is reflected in the controversial relationship between hormone replacement therapy and the signs and symptoms of dry eye. Current understanding of sex hormone influences on the immune system suggests that oestrogen may modulate a cascade of inflammatory events, which underlie dry eye.     

Dysfunctional neural regulation of lacrimal gland secretion and its role in the pathogenesis of dry eye syndromes

Tears are a complex fluid consisting of three layers, each of which is secreted by a different set of tissues or glands. The aqueous portion of the tear film is produced predominantly by the lacrimal gland. Dry eye syndromes are diseases in which the amount and composition of tears are altered, which can lead to ocular surface damage. There are many causes for dry eye syndromes. One such cause is the alteration in the functions of nerves innervating the lacrimal gland and the ocular surface. The autoimmune disease Sjogren syndrome can deleteriously affect the innervation of the lacrimal gland. Damage to the sensory nerves in the ocular surface, specifically the cornea, as a result of refractive surgery and normal aging, prevents the normal reflex arc to the lacrimal gland. Both defects can result in decreased tear secretion and dry eye syndromes. This review will discuss the current information regarding neurally-stimulated protein, water, and electrolyte secretion from the lacrimal gland and delineate how nerve dysfunction resulting from a variety of causes decreases secretion from this gland.     

Human lacrimal gland regeneration: Perspectives and review of literature

The human lacrimal gland is an essential component of the lacrimal functional unit (LFU). Any perturbation of this unit can lead to the debilitating morbid condition called the dry eye syndrome (DES). The current line of therapy available for dry eye remains supportive and palliative with the patient being dependent on life long and frequent administration of lubricating eye drops. Even advanced therapies like punctual plugs, cyclosporine B administration, and salivary gland auto-transplantation have led to a limited success. Under these scenarios, the option of cell based therapy needs to be explored to provide better and long term relief to these patients. This review gives an overview of the efforts in lacrimal gland regeneration and examines the past and ongoing research in cell based therapies in animals as well as human lacrimal gland cultures. The authors discuss their first of its kind functionally viable human lacrimal gland in vitro culture system from fresh exenteration specimens. A brief overview of research in near future and the potential implications of lacrimal gland regenerative therapies have been discussed.