泪液渗透压在干眼发病机制中的作用及诊疗进展

干眼是一种以眼表稳态丧失,泪膜不稳定性增加为特征的多因素疾病,伴有眼干涩、异物感、灼烧感、眼红、疼痛、畏光、流泪、眼疲劳、视力下降、分泌物增多、对外界刺激敏感等眼部症状,其病理生理机制主要是泪膜不稳定、泪液渗透压(tear osmolarity, Tosm)升高、眼表炎症和损伤及神经感觉异常。Tosm是维持泪膜稳定性和眼表舒适度的重要因素。Tosm升高可造成干眼患者眼部不适、角膜上皮损伤、杯状细胞丢失及眼部炎症反应,炎症反应可进一步降低泪膜稳定性和增加Tosm,使干眼陷入恶性循环。为了更全面地了解泪液高渗(tear hyperosmolarity, THO)与干眼的关系,本文将从病理生理学方面,重点讨论THO在干眼发病机制、干眼诊断、干眼严重程度分级中的作用,及其针对性治疗。     

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。     

Keratitis in Dry Eye Disease and Topical Ciclosporin A

Tear film alterations in dry eye disease (DED) include reduced tear volume and an increase in inflammatory cytokines. Instability and reduced tear production initiate a vicious cycle where hyperosmolarity, ocular inflammation, and apoptosis may induce damage of the ocular surface including keratitis. Topical cyclosporine (CsA) has been used for the treatment of moderate-to-severe DED; however, previous studies failed to demonstrate its benefits by the European Agency standards. A new formulation of CsA 0.1% has been recently approved in the EU to treat severe keratitis in DED patients. Patients with severe keratitis showed a better improvement after 6 months of treatment with CsA compared with vehicle. HLA-DR expression was significantly reduced by CsA treatment. The clinically significant improvement in keratitis associated with the inflammatory biomarker HLA-DR confirms the efficacy of CsA to improve inflammation and its damaging effect on the ocular surface in DED patients.     

眼表病理生理改变在干眼中的研究进展

干眼的发病率逐年升高,目前已成为最常见的眼部疾病之一。干眼的症状主要为眼部的干涩感、异物感、烧灼感、痒、分泌物等,这些不适很大程度上影响了干眼患者的日常生活、工作学习、心理健康和身体功能。干眼是一种多因素眼病,其特征是泪膜稳态的丧失,泪液的高渗透压、眼表炎性反应和损伤以及神经感觉异常等参与了干眼的发生发展,同时,干眼患者眼部会出现组织结构及眼表微环境的改变。由于干眼是一种日益严重的公共卫生问题,严重影响人们的视觉质量和生活质量,因此,研究干眼的病理生理对开展高效的诊断、更具针对性的治疗及减少不良事件的发生具有重要意义。本文对近年来干眼的病理生理学的研究进展进行综述。     

A new approach for better comprehension of diseases of the ocular surface

The mechanistic view of dry eye disease aims at completing the classic etiological approach that classifies the disease as parallel ocular surface disorders leading to lacrimal film impairment and dry eye. This approach proposes two levels of ocular surface impairment (with standard etiologies, previously validated in the NEI/Industry workshop), which may not be independent diseases but rather risk factors and/or ways to enter a self-stimulated biological process involving the ocular surface. All external disorders proposed in this model, although unlikely to be fully exhaustive, are classical mechanisms considered to be causes of tear film impairment and ocular surface damage, by tear instability and evaporation, tear hyposecretion, or both. These mechanisms, sometimes alone--when severe or becoming chronic or repeatedly present on the ocular surface and when two or more are present--may cause the patient to enter the self-stimulated loop. Tear film instability/imbalance can be considered as the key point of dry eye disease. It will cause local or diffuse hyperosmolarity of the tear film and therefore of superficial epithelial cells of the cornea and/or conjunctiva, stimulating epithelial cells and resident inflammatory cells. Cell damage in the cornea and conjunctiva, by means of apoptosis and direct mechanical and/or osmotic stress, will stimulate the reflex neurosensory arc, in turn stimulating lacrimal gland and neurogenic inflammation, with inflammatory cytokine release, MMP activation, and inflammatory involvement of the conjunctival epithelium. Goblet cell loss is thus directly related to chronic inflammation and surface cell apoptosis subsequent to cell hyperosmolarity and chronic damage, resulting in further tear film instability/imbalance. On the other hand, bacterial changes and an imbalance resulting from specific diseases or from tear film abnormalities may trigger release of endotoxins, lipopolysaccharides, and/or lipase activation, causing eyelid inflammation, meibomian gland dysfunction, and lipidic changes, directly influencing tear film stability and favoring tear evaporation. The lipidic hypothesis therefore participates in the vicious circle as a parallel, independent, or complementary loop. This mechanistic approach proposes a synthetic combination of mechanisms previously validated independently, with two levels of ocular surface impairment, a first level including many possible acute or chronic causes that favor or trigger the imbalance and can be reversible if correctly and specifically managed when possible, and the further involvement of a series of biological cascades centered by tear film imbalance and inflammatory stimulation, finally acting as an independent vicious circle, however the patient entered the loop. Clinically, this approach may explain examples of dry eye syndrome occurring after ocular surgery, contact lens wear, chronic allergy or systemic or topical drugs, and the long-lasting effect even though all causal factors have been removed or have disappeared. This model should be considered as a basis for further reflection on biological mechanisms that could be even more complex but individually constitute potential leads for targeting therapeutic strategies to allow patients to leave the loop even though the triggering factors are still present or can only be attenuated, such as in Sj?gren syndrome or ocular rosacea. It also should be considered a complement to more classic etiological and severity classifications aimed at understanding and classifying the large number of diseases that may cause dry eye disease and better assessing the major impairment it causes on the patient's quality of life.     

TFOS DEWS II Definition and Classification Report

The goals of the TFOS DEWS II Definition and Classification Subcommittee were to create an evidence-based definition and a contemporary classification system for dry eye disease (DED). The new definition recognizes the multifactorial nature of dry eye as a disease where loss of homeostasis of the tear film is the central pathophysiological concept. Ocular symptoms, as a broader term that encompasses reports of discomfort or visual disturbance, feature in the definition and the key etiologies of tear film instability, hyperosmolarity, and ocular surface inflammation and damage were determined to be important for inclusion in the definition. In the light of new data, neurosensory abnormalities were also included in the definition for the first time. In the classification of DED, recent evidence supports a scheme based on the pathophysiology where aqueous deficient and evaporative dry eye exist as a continuum, such that elements of each are considered in diagnosis and management. Central to the scheme is a positive diagnosis of DED with signs and symptoms, and this is directed towards management to restore homeostasis. The scheme also allows consideration of various related manifestations, such as non-obvious disease involving ocular surface signs without related symptoms, including neurotrophic conditions where dysfunctional sensation exists, and cases where symptoms exist without demonstrable ocular surface signs, including neuropathic pain. This approach is not intended to override clinical assessment and judgment but should prove helpful in guiding clinical management and research.     

The correlation between the tear film lipid layer and dry eye disease

Dry eye, also known as keratoconjunctivitis sicca, can be due either to insufficient tear production or excessive tear evaporation, both resulting in tear hyperosmolarity that leads to symptoms of discomfort and ocular damage. Additionally, the severity of dry eye symptoms appears to be correlated to lipid layer thickness. It is now generally recognized that increased evaporation due to a compromised lipid layer is one of the most common etiologies for hyperosmolarity of the tear film. Thus, therapies targeted at replenishing or stabilizing the lipid layer are key to the treatment of dry eye, either as monotherapy or in conjunction with therapies designed to enhance aqueous production.     

Tear clearance implications for ocular surface health

Tear clearance/turnover provides a global assessment of the function of the lacrimal functional unit and of tear exchange on the ocular surface. It is an indirect measure of dry eye induced inflammation on the ocular surface. It shows better correlation with the severity of ocular irritation symptoms and corneal epithelial disease in dry eye than the Schirmer 1 test. Delayed tear clearance may prove to be the best measure for identifying patients with tear film disorders who may respond to anti-inflammatory therapy.     

Protection against corneal hyperosmolarity with soft-contact-lens wear

Hyperosmotic tear stimulates human corneal nerve endings, activates ocular immune response, and elicits dry-eye symptoms. A soft contact lens (SCL) covers the cornea preventing it from experiencing direct tear evaporation and the resulting blink-periodic salinity increases. For the cornea to experience hyperosmolarity due to tear evaporation, salt must transport across the SCL to the post-lens tear film (PoLTF) bathing the cornea. Consequently, limited salt transport across a SCL potentially protects the ocular surface from hyperosmotic tear. In addition, despite lens-wear discomfort sharing common sensations to dry eye, no correlation is available between measured tear hyperosmolarity and SCL-wear discomfort. Lack of documentation is likely because clinical measurements of tear osmolarity during lens wear do not interrogate the tear osmolarity of the PoLTF that actually overlays the cornea. Rather, tear osmolarity is clinically measured in the tear meniscus. For the first time, we mathematically quantify tear osmolarity in the PoLTF and show that it differs significantly from the clinically measured tear-meniscus osmolarity. We show further that aqueous-deficient dry eye and evaporative dry eye both exacerbate the hyperosmolarity of the PoLTF. Nevertheless, depending on lens salt-transport properties (i.e., diffusivity, partition coefficient, and thickness), a SCL can indeed protect against corneal hyperosmolarity by reducing PoLTF salinity to below that of the ocular surface during no-lens wear. Importantly, PoLTF osmolarity for dry-eye patients can be reduced to that of normal eyes with no-lens wear provided that the lens exhibits a low lens-salt diffusivity. Infrequent blinking increases PoLTF osmolarity consistent with lens-wear discomfort. Judicious design of SCL material salt-transport properties can ameliorate corneal hyperosmolarity. Our results confirm the importance of PoLTF osmolarity during SCL wear and indicate a possible relation between PoLTF osmolarity and contact-lens discomfort.     

A mass and solute balance model for tear volume and osmolarity in the normal and the dry eye

Tear hyperosmolarity is thought to play a key role in the mechanism of dry eye, a common symptomatic condition accompanied by visual disturbance, tear film instability, inflammation and damage to the ocular surface. We have constructed a model for the mass and solute balance of the tears, with parameter estimation based on extensive data from the literature which permits the influence of tear evaporation, lacrimal flux and blink rate on tear osmolarity to be explored. In particular the nature of compensatory events has been estimated in aqueous-deficient (ADDE) and evaporative (EDE) dry eye.The model reproduces observed osmolarities of the tear meniscus for the healthy eye and predicts a higher concentration in the tear film than meniscus in normal and dry eye states. The differential is small in the normal eye, but is significantly increased in dry eye, especially for the simultaneous presence of high meniscus concentration and low meniscus radius. This may influence the interpretation of osmolarity values obtained from meniscus samples since they need not fully reflect potential damage to the ocular surface caused by tear film hyperosmolarity.Interrogation of the model suggests that increases in blink rate may play a limited role in compensating for a rise in tear osmolarity in ADDE but that an increase in lacrimal flux, together with an increase in blink rate, may delay the development of hyperosmolarity in EDE. Nonetheless, it is predicted that tear osmolarity may rise to much higher levels in EDE than ADDE before the onset of tear film breakup, in the absence of events at the ocular surface which would independently compromise tear film stability. Differences in the predicted responses of the pre-ocular tears in ADDE compared to EDE or hybrid disease to defined conditions suggest that no single, empirically-accessible variable can act as a surrogate for tear film concentration and the potential for ocular surface damage. This emphasises the need to measure and integrate multiple diagnostic indicators to determine outcomes and prognosis. Modelling predictions in addition show that further studies concerning the possibility of a high lacrimal flux phenotype in EDE are likely to be profitable.     

NLRP12- and NLRC4-mediated corneal epithelial pyroptosis is driven by GSDMD cleavage accompanied by IL-33 processing in dry eye

PurposeDry eye disease (DED) is a common and multifactor-induced autoimmune ocular surface disease. Environmental factors, such as desiccating stress (DS) and hyperosmolarity, affect the corneal epithelium to induce ocular surface inflammation in DED. We aimed to explore the potential mechanisms by which innate immunity and pyroptosis are initiated in the mucosal epithelium in response to environmental stress.MethodsExperimental dry eye was established in C57BL/6 J mice and genetic mice on the background of C57BL/6 J mice by subcutaneous injection of scopolamine and exposure to a desiccating environment. SDHCEC cell line was subjected to hyperosmolarity stress (450 mOsM). The phenol red thread tear test and corneal epithelial defects evaluation were used as assessments of severity of DED. RNA-sequencing, quantitative real-time PCR, western blotting and immunofluorescence staining were performed in this study.ResultsLoss-of-function studies indicated that genetic deletion of GSDMD alleviates DS-induced corneal epithelium defects, and GSDMD is needed for IL-33 processing. We further found that NLRP12 collaborates with NLRC4 inflammasome to initiate GSDMD-dependent pyroptosis, which requires TLR4-induced caspase-8 (CASP8) activation in the mucosal corneal epithelium in response to DS.ConclusionsThese findings provide compelling evidence that GSDMD-dependent pyroptosis plays a pivotal role in DED. A novel mechanism involving NLRP12 and NLRC4 inflammasomes-induced GSDMD-dependent pyroptosis, accompanied by IL-33 processing is responsible for ocular surface epithelial defects in response to environmental stress. GSDMD is required for IL-33 processing and the subsequent amplification of inflammatory cascades. These findings reveal novel therapeutic targets for treating DED.     

干眼症眼表损害炎症机制

干眼症为一种多因素造成泪膜稳定性和眼表功能损害的疾病,易引起眼部不适、视力障碍、泪膜不稳定与眼表的潜在危害,可伴有泪液渗透压升高及眼表炎症反应。炎症是干眼发病中最关键因素,多种免疫细胞和炎症因子参与了干眼症的发生与发展过程。细胞凋亡、神经调节异常、性激素失调等也共同参与了干眼的发病过程。最近尽管在阐述干眼的病理生理和发病机制取得了一定进展,但目前还未形成统一标准。本文将对炎症造成干眼症眼表和泪液功能损害的可能机制进行综述。     

提高对睑板腺功能障碍的认识 重视睑板腺功能障碍相关性干眼的药物治疗

睑板腺功能障碍（MGD）是临床常见的眼表疾病,以睑板腺终末导管的阻塞和／或睑板腺分泌物质或量的改变为特征,导致脂质向泪膜的排出减少,引起泪液蒸发过强。睑缘和睑板腺的炎症是引起睑板腺阻塞,进而导致MGD的直接原因,可引起眼表功能的异常。MGD的诊断主要依靠临床症状与体征,其症状与干眼的症状相似,因此无诊断特异性。体征主要包括睑缘形态的变化、睑板腺分泌异常和睑板腺缺失。MGD的治疗方法包括热敷、清洁睑缘、促进睑板腺的分泌、抗菌、抗炎治疗及润滑眼表,中度、重度MGD患者可给予必要的抗炎治疗,常用的抗炎药物有糖皮质激素、非甾体类抗炎药及免疫抑制剂。临床医师在进行眼部疾病的检查时应重视睑板腺的功能状态,尤其在角膜屈光手术及内眼手术前更应重视MGD的筛查,以免术后引起严重的眼表并发症,有效规避医疗风险。     

Ageing and the natural history of dry eye disease: A prospective registry-based cross-sectional study

PurposeTo investigate the impact of ageing on ocular surface parameters, and empirically determine optimal prognostic cut-off ages for clinical markers of dry eye disease, aqueous tear deficiency, and meibomian gland dysfunction.MethodsA total of 1331 community residents (785 females, 546 males; mean ± SD age, 38 ± 19 years) were recruited in a prospective registry-based cross-sectional study. Dry eye symptomology, ocular surface characteristics, and tear film quality were evaluated for each participant within a single clinical session, in accordance with the global consensus recommendations of the TFOS DEWS II reports.ResultsMultivariate regression analysis demonstrated positive associations between ageing and clinical markers of dry eye disease (all p ≤ 0.001). The Youden-optimal prognostic cut-off ages for signs of meibomian gland dysfunction occurred during the third decade of life (24–29 years); the optimal predictive ages for lid wiper epitheliopathy, tear film instability, hyperosmolarity, and dry eye symptoms occurred during the fourth decade of life (31–38 years); while the optimal prognostic thresholds for signs of aqueous tear deficiency and ocular surface staining occurred in the fifth and sixth decades of life (46–52 years).ConclusionsAdvancing age is a significant risk factor for dry eye disease, which represents a growing public health concern with the ageing population worldwide. Signs of meibomian gland dysfunction appeared earlier in the natural history of disease progression, and the brief delay prior to the development of other clinical dry eye signs might represent a window of opportunity for preventative interventions in the young adult age group.     

Inflammation in dry eye

Dry eye is a condition of altered tear composition that results from a diseased or dysfunctional lacrimal functional unit. Evidence suggests that inflammation causes structural alterations and/or functional paralysis of the tear-secreting glands. Changes in tear composition resulting from lacrimal dysfunction, increased evaporation and/or poor clearance have pro-inflammatory effects on the ocular surface. This inflammation is responsible in part for the irritation symptoms, ocular surface epithelial disease, and altered corneal epithelial barrier function in dry eye. Anti-inflammatory therapies for dry eye target one or more of the inflammatory mediators/pathways that have been identified in dry eye.     

我国干眼流行病学的研究进展

干眼是一种临床常见的慢性眼表疾病.它是由泪膜的质或量以及泪液动力学异常所致的泪膜不稳定和(或)眼表的损害,进而出现眼部不适及视功能障碍的一类疾病.近年来,我国开展了大量较高水平的干眼流行病学调查研究项目,在干眼的流行病学研究上取得了显著成果.本文中笔者就干眼在我国不同地域和人群中流行病学分布的特征和危险因素进行综述.     

Cicatricial Pemphigoid and Dry Eye

Cicatricial pemphigoid is the most common of the immunobullous disorders causing conjunctival cicatrization and is an autoimmune disease in which the ocular component of the immunopathology is directed at the conjunctival basement membrane. The disease is usually bilateral and more common in females, with most cases occurring between 30–90 years, and most often in the seventh decade. The disease occasionally occurs in children. Tear deficiency is a major cause of symptoms, although loss of vision is usually due to surface failure before the onset of aqueous tear deficiency, which occurs late in the progression of the disease. Management of the dry eye must be integrated with the management of the other components of both the ocular surface disease and inflammation. Management requires plastic surgery for the lid and lash malposition, tetracyclines and lid hygiene for the accompanying blepharitis. For the dry eye, the use of lubricants without preservatives is important, to avoid toxicity, and lubricant ointment is helpful for the relief of symptoms in terminally dry eyes without the capacity for surface wetting. Contact lenses, either large limbal diameter rigid gas permeable or gas permeable scleral lenses, are useful for treating dry eye and improving vision in some patients. Control of the conjunctival inflammation is mandatory to prevent disease progression and usually requires systemic immunosuppressive therapy.     

Dry eye disease: A review of diagnostic approaches and treatments

Dry eye (DE) is a common ocular disease that results in eye discomfort, visual disturbance and substantially affects the quality of life. It has a multifactorial etiology involving tear film instability, increased osmolarity of the tear film and inflammation of the ocular surface with potential damage to the ocular surface. This review discusses the classification, diagnostic approaches and treatments of DE.     

Dry eye: an update on clinical diagnosis,management and promising new treatments

Dry eye conditions are prevalent with one in four to five patients presenting to eye care practitioners having dry eye signs and/or symptoms. An intimate relationship exists between the ocular surface and the tear film. The cycle of tear film instability and ocular surface damage characteristic of dry eye conditions suggests that dry eye represents a dysfunction of an integrated ocular surface‐lacrimal gland unit. Therefore, dry eye is a multifactorial condition and an approach based on clinical subtypes is required for diagnosis and management. There is increasing evidence that inflammation is a contributing and exacerbating factor in dry eye conditions and anti‐inflammatory or immunomodulatory therapy for chronic dry eye conditions may facilitate ocular surface healing. Other promising new treatments for dry eye include new generation artificial tear polymers and preservative systems, secretagogues, topical androgen supplements and surgical techniques for ocular surface reconstruction.     

Role of Hyperosmolarity in the Pathogenesis and Management of Dry Eye Disease: Proceedings of the OCEAN Group Meeting

Dry eye disease (DED), a multifactorial disease of the tears and ocular surface, is common and has a significant impact on quality of life. Reduced aqueous tear flow and/or increased evaporation of the aqueous tear phase leads to tear hyperosmolarity, a key step in the vicious circle of DED pathology. Tear hyperosmolarity gives rise to morphological changes such as apoptosis of cells of the conjunctiva and cornea, and triggers inflammatory cascades that contribute to further cell death, including loss of mucin-producing goblet cells. This exacerbates tear film instability and drives the cycle of events that perpetuate the condition. Traditional approaches to counteracting tear hyperosmolarity in DED include use of hypotonic tear substitutes, which have relatively short persistence in the eye. More recent attempts to counteract tear hyperosmolarity in DED have included osmoprotectants, small organic molecules that are used in many cell types throughout the natural world to restore cell volume and stabilize protein function, allowing adaptation to hyperosmolarity. There is now an expanding pool of clinical data on the efficacy of DED therapies that include osmoprotectants such as erythritol, taurine, trehalose and L-carnitine. Osmoprotectants in DED may directly protect cells against hyperosmolarity and thereby promote exit from the vicious circle of DED physiopathology.