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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 April 2017) | Viewed by 90290

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Dr. Igor A. Butovich

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Department of Ophthalmology, and the Graduate School of Biomedical Sciences, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9057, USA
Interests: meibomian gland dysfunction; dry eye; lipidomics; mass spectrometry
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Dear Colleagues,

Dry eye disease (DE) is a persistent, wide-spread, multifactorial disease that severely impacts the quality of life of people by impairing their vision, progresses with aging, and disproportionately affects women. In DE patients, the tear film—a protective layer that that covers the entire ocular surface – deteriorates and becomes unstable, losing its protective properties. There is evidence that DE is related to morphological changes in Meibomian glands (MG) and the chemical composition of MG secretions. Other known, highly relevant factors are the protein content of aqueous tears and their salinity. A delicate balance of all the components of the tear film is critical for maintaining a healthy ocular surface, and is altered in DE patients. This Special Issue of IJMS is seeking articles that would provide new insights into the underlying mechanisms of the onset of DE, the biochemistry and biophysics of the normal and DE tear film, new approaches to modelling and studying the condition, and new therapies and treatments for DE that would be able to alleviate or cure the disease.

Igor A. Butovich
Guest Editor

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Keywords

Dry Eye
Meibomian Gland
Lacrimal Gland
Cornea
Conjunctiva
Lipids and Lipidomics
Proteins and Proteomics
Meibum
Tear Film

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Emerging OMICS Approaches to Studying the Eye in the Norm and Pathology in International Journal of Molecular Sciences (11 articles)

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1500 KiB

Open AccessArticle

Human Meibum Age, Lipid–Lipid Interactions and Lipid Saturation in Meibum from Infants

by Samiyyah Sledge, Collin Henry, Douglas Borchman, Marta C. Yappert, Rahul Bhola, Aparna Ramasubramanian, Ryan Blackburn, Jonathan Austin, Kayla Massey, Shanzeh Sayied, Aliza Williams, Georgi Georgiev and Kenneth N. Schikler

Int. J. Mol. Sci. 2017, 18(9), 1862; https://doi.org/10.3390/ijms18091862 - 28 Aug 2017

Cited by 35 | Viewed by 4694

Abstract

Tear stability decreases with increasing age and the same signs of instability are exacerbated with dry eye. Meibum lipid compositional changes with age provide insights into the biomolecules responsible for tear film instability. Meibum was collected from 69 normal donors ranging in age from 0.6 to 68 years of age. Infrared spectroscopy was used to measure meibum lipid phase transition parameters. Nuclear magnetic resonance spectroscopy was used to measure lipid saturation. Increasing human meibum lipid hydrocarbon chain unsaturation with age was related to a decrease in hydrocarbon chain order, cooperativity, and in the phase transition temperature. The change in these parameters was most dramatic between 1 and 20 years of age. Meibum was catalytically saturated to determine the effect of saturation on meibum lipid phase transition parameters. Hydrocarbon chain saturation was directly related to lipid order, phase transition temperature, cooperativity, changes in enthalpy and entropy, and could account for the changes in the lipid phase transition parameters observed with age. Unsaturation could contribute to decreased tear film stability with age. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders)

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4739 KiB

Open AccessArticle

Herbal Supplement in a Buffer for Dry Eye Syndrome Treatment

by Hung-Chang Chen, Zhi-Yu Chen, Tsung-Jen Wang, Victor J. Drew, Ching-Li Tseng, Hsu-Wei Fang and Feng-Huei Lin

Int. J. Mol. Sci. 2017, 18(8), 1697; https://doi.org/10.3390/ijms18081697 - 3 Aug 2017

Cited by 18 | Viewed by 7136

Abstract

Dry eye syndrome (DES) is one of the most common types of ocular diseases. There is a major need to treat DES in a simple yet efficient way. Artificial tears (AT) are the most commonly used agents for treating DES, but are not very effective. Herbal extractions of ferulic acid (FA), an anti-oxidant agent, and kaempferol (KM), an anti-inflammatory reagent, were added to buffer solution (BS) to replace ATs for DES treatment. The cytotoxicity and anti-inflammatory effects were examined in vitro by co-culture with human corneal epithelial cells (HCECs) to obtain the optimal concentration of KM and FA for treating HCECs. Physical properties of BS, such as pH value, osmolality, and refractive index were also examined. Then, rabbits with DES were used for therapeutic evaluation. Tear production, corneal damage, and ocular irritation in rabbits’ eyes were examined. The non-toxic concentrations of KM and FA for HCEC cultivation over 3 days were 1 µM and 100 µM, respectively. Live/dead stain results also show non-toxicity of KM and FA for treating HCECs. Lipopolysaccharide-stimulated HCECs in inflammatory conditions treated with 100 µM FA and 1 µM KM (FA100/KM1) showed lower IL-1B, IL-6, IL-8, and TNFα expression when examined by real-time PCR. The BS with FA100/KM1 had neutral pH, and a similar osmolality and refractive index to human tears. Topical delivery of BS + FA100/KM1 showed no irritation to rabbit eyes. The corneal thickness in the BS + FA100/KM1 treated group was comparable to normal eyes. Results of DES rabbits treated with BS + FA100/KM1 showed less corneal epithelial damage and higher tear volume than the normal group. In conclusion, we showed that the combination of FA (100 µM) and KM (1 µM) towards treating inflamed HCECs had an anti-inflammatory effect, and it is effective in treating DES rabbits when BS is added in combination with these two herbal supplements and used as a topical eye drop. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders)

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4613 KiB

Open AccessArticle

Surface Chemistry Interactions of Cationorm with Films by Human Meibum and Tear Film Compounds

by Georgi As. Georgiev, Norihiko Yokoi, Yana Nencheva, Nikola Peev and Philippe Daull

Int. J. Mol. Sci. 2017, 18(7), 1558; https://doi.org/10.3390/ijms18071558 - 18 Jul 2017

Cited by 28 | Viewed by 8790

Abstract

Cationorm^® (CN) cationic nanoemulsion was demonstrated to enhance tear film (TF) stability in vivo possibly via effects on tear film lipid layer (TFLL). Therefore the interactions of CN with human meibum (MGS) and TFLL in vitro and in vivo deserve special study. MGS and CN were spread at the air/water interface of a Langmuir surface balance to ensure a range of MGS/CN oil phase ratios: 20/1, 10/1, 5/1, 3/1, 2/1 and 1/1. The films capability to reorganize during dynamic area changes was evaluated via the surface pressure-area compression isotherms and step/relaxation dilatational rheology studies. Films structure was monitored with Brewster angle microscopy. CN/TFLL interactions at the ocular surface were monitored with non-contact specular microscopy. The in vitro studies of MGS/CN layers showed that (i) CN inclusion (at fixed MGS content) increased film elasticity and thickness and that (ii) CN can compensate for moderate meibum deficiency in MGS/CN films. In vivo CN mixed with TFLL in a manner similar to CN/MGS interactions in vitro, and resulted in enhanced thickness of TFLL. In vitro and in vivo data complement each other and facilitated the study of the composition-structure-function relationship that determines the impact of cationic nanoemulsions on TF. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders)

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984 KiB

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Tear Film Steroid Profiling in Dry Eye Disease by Liquid Chromatography Tandem Mass Spectrometry

by Damiana Pieragostino, Luca Agnifili, Ilaria Cicalini, Roberta Calienno, Mirco Zucchelli, Leonardo Mastropasqua, Paolo Sacchetta, Piero Del Boccio and Claudia Rossi

Int. J. Mol. Sci. 2017, 18(7), 1349; https://doi.org/10.3390/ijms18071349 - 24 Jun 2017

Cited by 42 | Viewed by 6522

Abstract

Dry eye disease (DED) is a multifactorial disorder of the ocular surface unit resulting in eye discomfort, visual disturbance, and ocular surface damage; the risk of DED increases with age in both sexes, while its incidence is higher among females caused by an overall hormonal imbalance. The role of androgens has recently investigated and these hormones were considered to have a protective function on the ocular surface. In order to correlate DED to tear steroid levels, a robust, specific, and selective method for the simultaneous quantification of cortisol (CORT), corticosterone (CCONE), 11-deoxycortisol (11-DECOL), 4-androstene-3,17-dione (ADIONE), testosterone (TESTO), 17α-hydroxyprogesterone (17-OHP), and progesterone (PROG) was developed and applied for the analysis of tear samples. The method involves a simple extraction procedure of steroids from tears collected on Schirmer strips, followed by a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis. In total, tear samples from 14 DED female patients and 13 healthy female controls were analysed and, CORT, ADIONE, and 17-OHP response levels resulted significantly decreased in dry eye patients respect to controls. The receiver operating characteristic (ROC) curve obtained by the combination of these three steroids (AUC = 0.964) demonstrated the good diagnostic power of the differential tear steroids in identifying DED. In conclusion, the present method made it possible, for the first time, to study steroid profiling directly in tear fluid. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders)

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5183 KiB

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Pathological Analysis of Ocular Lesions in a Murine Model of Sjögren’s Syndrome

by Aya Ushio, Rieko Arakaki, Hiroshi Eguchi, Fumika Hotta, Akiko Yamada, Yasusei Kudo and Naozumi Ishimaru

Int. J. Mol. Sci. 2017, 18(6), 1209; https://doi.org/10.3390/ijms18061209 - 6 Jun 2017

Cited by 16 | Viewed by 6227

Abstract

Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by severe inflammation of exocrine glands such as the salivary and lacrimal glands. When it affects the lacrimal glands, many patients experience keratoconjunctivitis due to severely dry eyes. This study investigated the pathological and immunological characteristics of ocular lesions in a mouse model of SS. Corneal epithelial injury and hyperplasia were confirmed pathologically. The number of conjunctival mucin-producing goblet cells was significantly decreased in the SS model mice compared with control mice. Expression levels of transforming growth factor (TGF)-β, interleukin (IL)-6, tumor necrosis factor (TNF)-α, and C-X-C motif chemokine (CXCL) 12 were significantly higher in the corneal epithelium of the SS model mice than in control mice. Inflammatory lesions were observed in the Harderian, intraorbital, and extraorbital lacrimal glands in the SS model mice, suggesting that the ocular glands were targeted by an autoimmune response. The lacrimal glands of the SS model mice were infiltrated by cluster of differentiation (CD)4⁺ T cells. Real-time reverse transcription-polymerase chain reaction (RT-PCR) revealed significantly increased mRNA expression of TNF-α, TGF-β, CXCL9, and lysozyme in the extraorbital lacrimal glands of the SS model mice compared with control mice. These results add to the understanding of the complex pathogenesis of SS and may facilitate development of new therapeutic strategies. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders)

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4292 KiB

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Goblet Cells Contribute to Ocular Surface Immune Tolerance—Implications for Dry Eye Disease

by Flavia L. Barbosa, Yangyan Xiao, Fang Bian, Terry G. Coursey, Byung Yi Ko, Hans Clevers, Cintia S. De Paiva and Stephen C. Pflugfelder

Int. J. Mol. Sci. 2017, 18(5), 978; https://doi.org/10.3390/ijms18050978 - 5 May 2017

Cited by 75 | Viewed by 7446

Abstract

Conjunctival goblet cell (GC) loss in dry eye is associated with ocular surface inflammation. This study investigated if conjunctival GCs contribute to ocular surface immune tolerance. Antigens applied to the ocular surface, imaged by confocal microscopy, passed into the conjunctival stroma through goblet cell associated passages (GAPs) in wild type C57BL/6 (WT), while ovalbumin (OVA) was retained in the epithelium of SAM pointed domain containing ETS transcription factor (Spdef) knockout mice (Spdef⁻/⁻) that lack GCs and are a novel model of dry eye. Stimulated GC degranulation increased antigen binding to GC mucins. Induction of tolerance to topically applied OVA measured by cutaneous delayed type hypersensitivity (DTH) was observed in WT, but not Spdef⁻/⁻. OTII CD4⁺ T cells primed by dendritic cells (DCs) from the conjunctival draining lymph nodes of Spdef⁻/⁻ had greater IFN-γ production and lower Foxp3 positivity than those primed by WT DCs. These findings indicate that conjunctival GCs contribute to ocular surface immune tolerance by modulating antigen distribution and antigen specific immune response. GC loss may contribute to the abrogation of ocular surface immune tolerance that is observed in dry eye. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders)

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A Comparison of the Effects of Benzalkonium Chloride on Ocular Surfaces between C57BL/6 and BALB/c Mice

by Qian Yang, Yafang Zhang, Xiuping Liu, Nan Wang, Zhenyu Song and Kaili Wu

Int. J. Mol. Sci. 2017, 18(3), 509; https://doi.org/10.3390/ijms18030509 - 26 Feb 2017

Cited by 39 | Viewed by 9363

Abstract

Models of benzalkonium chloride (BAC)-induced ocular disruption have been created and are widely used in various animals. This study aimed to compare the effects of BAC on the ocular surfaces of C57BL/6 and BALB/c mice. C57BL/6 and BALB/c mice were treated separately with BAC eye-drops at different concentrations. Eyes were evaluated by scoring epithelial disruption, corneal opacity and neovascularization in vivo, and by histological assays with hematoxylin/eosin (H/E) and periodic acid-Schiff stainings and by determining the expression of inflammatory factors in vitro on Days 7 and 14. The in vivo corneal epithelial disruption, corneal edema/opacity and neovascularization, which were in accordance with the results of the H/E staining and peaked at Day 7, were observed in a dose-dependent manner in the BAC-treated mice, with more severe signs in the C57BL/6 mice than the BALB/c mice. The loss of conjunctival goblet cells in the conjunctivas and the increasing expression of monocyte chemoattractant protein 1 (MCP-1), growth-regulated protein alpha (GROa) and macrophage inflammatory protein-1 alpha (MIP-1a) in the corneas were found in a dose-dependent manner in both strains of mice. Topical application of BAC can dramatically disrupt the ocular surfaces of C57BL/6 and BALB/c mice, and the disruptions were much more severe in the C57BL/6 mice that received high doses of BAC. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders)

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Review

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1535 KiB

Open AccessReview

Regenerative Therapies in Dry Eye Disease: From Growth Factors to Cell Therapy

by Antonio J. Villatoro, Viviana Fernández, Silvia Claros, Cristina Alcoholado, Manuel Cifuentes, Jesús Merayo-Lloves, José A. Andrades and José Becerra

Int. J. Mol. Sci. 2017, 18(11), 2264; https://doi.org/10.3390/ijms18112264 - 28 Oct 2017

Cited by 37 | Viewed by 10221

Abstract

Dry eye syndrome is a complex and insidious pathology with a high level of prevalence among the human population and with a consequently high impact on quality of life and economic cost. Currently, its treatment is symptomatic, mainly based on the control of lubrication and inflammation, with significant limitations. Therefore, the latest research is focused on the development of new biological strategies, with the aim of regenerating affected tissues, or at least restricting the progression of the disease, reducing scar tissue, and maintaining corneal transparency. Therapies range from growth factors and cytokines to the use of different cell sources, in particular mesenchymal stem cells, due to their multipotentiality, trophic, and immunomodulatory properties. We will review the state of the art and the latest advances and results of these promising treatments in this pathology. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders)

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1262 KiB

Open AccessReview

Analysis of the Pathogenic Factors and Management of Dry Eye in Ocular Surface Disorders

by Marcella Nebbioso, Paola Del Regno, Magda Gharbiya, Marta Sacchetti, Rocco Plateroti and Alessandro Lambiase

Int. J. Mol. Sci. 2017, 18(8), 1764; https://doi.org/10.3390/ijms18081764 - 13 Aug 2017

Cited by 38 | Viewed by 10995

Abstract

The tear film represents the interface between the eye and the environment. The alteration of the delicate balance that regulates the secretion and distribution of the tear film determines the dry eye (DE) syndrome. Despite having a multifactorial origin, the main risk factors are female gender and advanced age. Likewise, morphological changes in several glands and in the chemical composition of their secretions, such as proteins, mucins, lipidics, aqueous tears, and salinity, are highly relevant factors that maintain a steady ocular surface. Another key factor of recurrence and onset of the disease is the presence of local and/or systemic inflammation that involves the ocular surface. DE syndrome is one of the most commonly encountered diseases in clinical practice, and many other causes related to daily life and the increase in average life expectancy will contribute to its onset. This review will consider the disorders of the ocular surface that give rise to such a widespread pathology. At the end, the most recent therapeutic options for the management of DE will be briefly discussed according to the specific underlying pathology. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders)

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3301 KiB

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Dry Eye Management: Targeting the Ocular Surface Microenvironment

by Xiaobo Zhang, Vimalin Jeyalatha M, Yangluowa Qu, Xin He, Shangkun Ou, Jinghua Bu, Changkai Jia, Junqi Wang, Han Wu, Zuguo Liu and Wei Li

Int. J. Mol. Sci. 2017, 18(7), 1398; https://doi.org/10.3390/ijms18071398 - 29 Jun 2017

Cited by 175 | Viewed by 17624

Abstract

Dry eye can damage the ocular surface and result in mild corneal epithelial defect to blinding corneal pannus formation and squamous metaplasia. Significant progress in the treatment of dry eye has been made in the last two decades; progressing from lubricating and hydrating the ocular surface with artificial tear to stimulating tear secretion; anti-inflammation and immune regulation. With the increase in knowledge regarding the pathophysiology of dry eye, we propose in this review the concept of ocular surface microenvironment. Various components of the microenvironment contribute to the homeostasis of ocular surface. Compromise in one or more components can result in homeostasis disruption of ocular surface leading to dry eye disease. Complete evaluation of the microenvironment component changes in dry eye patients will not only lead to appropriate diagnosis, but also guide in timely and effective clinical management. Successful treatment of dry eye should be aimed to restore the homeostasis of the ocular surface microenvironment. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders)

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