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Dry Eye and Ocular Surface Disorders 3.0

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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 March 2022) | Viewed by 28512

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Dr. Murat Dogru

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Guest Editor

Department of Ophthalmology, Keio University School of Medicine, Shi-nanomachi 35, Shinjuku-ku, Tokyo 160-8582, Japan
Interests: dry eye; oxidative stress; diagnostic imaging; biomarkers; ocular allergy; contact lens
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Dr. Takashi Kojima

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Guest Editor

Department of Ophthalmology, School of Medicine, Keio University, Tokyo 160-8582, Japan
Interests: dry eye; neuropathic pain; refractive surgery; oxidative stress; behavior science
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

In recent years, dry eye has been widely investigated in many studies including epidemiological, basic, and clinical studies, and the recent achievements are remarkable. Dry eye is a disease in which the tear film stability decreases. The mechanism is associated with inflammation, friction with the eyelids, changes in tear osmolarity, amount of tear secretion, wettability of the ocular surface, tear evaporation, etc., which are involved in a complex way to form a pathological condition. In addition, in dry eye disease, it has been pointed out that there is a difference between subjective symptoms and ocular findings. Recently, research has been conducted considering several elements, including the involvement of the nervous system, and it has become clear that dry eye also contains elements of neuropathic pain. Treatments targeting tear stability, inflammation, and friction are often performed. Moreover, in recent years, a secretagogue made up of water and mucin components has been widely used in Asian countries. However, the understanding of dry eye pathology, diagnosis, and treatment is still inadequate. New insights and breakthroughs will be needed to overcome these problems in the future. In this Special Issue, we are looking for research results including new findings in the fields of ocular surface and dry eye disease. The aim is to broaden the direction and possibilities of dry eye research. We are very much looking forward to receiving your invaluable work for this Special Issue.

This is the joint Special Issue both in IJMS and Diagnostics.

Assoc. Prof. Murat Dogru
Dr. Takashi Kojima
Guest Editors

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Keywords

Dry eye
basic research
clinical research
treatment animal
model
neuropathic pain
ocular surface
pathophysiology
diagnosis

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Dry Eye and Ocular Surface Disorders 2.0 in International Journal of Molecular Sciences (12 articles)

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11 pages, 4017 KiB

Open AccessArticle

Aqueous-Deficient Dry Eye Exacerbates Signs and Symptoms of Allergic Conjunctivitis in Mice

by Tatsuma Kishimoto, Waka Ishida, Isana Nakajima, Ken Fukuda and Kenji Yamashiro

Int. J. Mol. Sci. 2022, 23(9), 4918; https://doi.org/10.3390/ijms23094918 - 28 Apr 2022

Cited by 4 | Viewed by 2660

Abstract

Dry eye disease (DED) and allergic conjunctivitis affect a large number of patients, and many patients usually have both symptoms. We investigated the interactions between DED and allergic conjunctivitis in mice. Four experimental groups were compared: control, DED, allergy, and allergy with DED. DED was induced by removing the extraorbital lacrimal glands of the mice. Allergic conjunctivitis was induced by intraperitoneal administration of ovalbumin and antigen eye drops. The early phase reaction of the allergy was evaluated using the clinical score, scratching behavior, and vascular permeability in the conjunctiva. Epithelial barrier function was assessed by an LC-biotin assay. Tear fluid volume and corneal fluorescein staining decreased in the DED and allergy with DED groups. LC-biotin penetrated the entire epithelium of both the cornea and conjunctiva in DED mice. The clinical score of the early phase reaction was higher in allergy-induced mice than in non-allergy mice. Edema of the eyelid and conjunctiva were aggravated in mice with DED. The number of scratching episodes and leakage of Evans blue into the conjunctiva were higher in allergy-induced DED mice than in control mice. The presence of aqueous-deficient dry eye caused ocular surface epithelial damage and exacerbated allergic signs and symptoms. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders 3.0)

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21 pages, 4243 KiB

Open AccessArticle

Porcine Corneas Incubated at Low Humidity Present Characteristic Features Found in Dry Eye Disease

by Alice Rocha Teixeira Netto, José Hurst, Karl-Ulrich Bartz-Schmidt and Sven Schnichels

Int. J. Mol. Sci. 2022, 23(9), 4567; https://doi.org/10.3390/ijms23094567 - 20 Apr 2022

Cited by 4 | Viewed by 2709

Abstract

Dry eye is a multifactorial disease that affects the ocular surface and tear fluid. Current treatment options include lubricant eye drop application several times a day. However, these eye drops often cause local side effects like ocular allergies or blurred vision after the application. To test new treatment options, a robust dry eye model is needed. Here, a porcine ex vivo model was established by means of incubation of porcine corneas in low humidity (LH) and characterized by histological damage evaluation, epithelial thickness and by relevant dry eye markers, such as interleukin 1 beta (IL-1β), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), occludin and galectin-3. In the dry eye model proposed, an increased secretion of IL-1β was observed, as well as an upregulation of NF-κB, occludin and galectin-3 mRNA expression. Moreover, the model presented a higher rate of cell death in comparison to the controls. These effects could be reversed with successful treatment of dexamethasone (dexa) and partially reversed with hyaluronic acid (HA) containing eye drops. Furthermore, medium-molecular-weight HA stimulated an increase in IL-1β in the model proposed. In conclusion, this dry eye model mimics the in vivo condition and hence allows for animal-free testing of novel dry eye treatments. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders 3.0)

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10 pages, 5253 KiB

Open AccessArticle

Salivary and Lacrimal Gland Alterations of the Epidermal Fatty Acid-Binding Protein (E-FABP) in Non-Obese Diabetic Mice

by Murat Dogru, Takashi Kojima, Cem Simsek, Taeko Nagata and Kazuo Tsubota

Int. J. Mol. Sci. 2022, 23(7), 3491; https://doi.org/10.3390/ijms23073491 - 23 Mar 2022

Cited by 1 | Viewed by 1991

Abstract

The purpose of this study was to investigate the changes in E-FABP in the salivary and lacrimal glands of the Sjögren syndrome (SS) model non-obese diabetic mice (NOD). Cotton thread and ocular vital staining tests were performed on 10-week NOD male mice (n = 24) and age- and sex-matched wild-type (WT) mice (n = 25). Tear and saliva samples were collected at sacrifice for E-FABP ELISA assays. Salivary and lacrimal gland specimens underwent immunohistochemistry stainings for E-FABP. Real-time RT-PCR was also performed for the quantification of mRNA expression levels in the salivary and lacrimal glands. Corneal vital staining scores in the NOD mice were significantly higher compared with those for the wild-type mice (p = 0.0001). The mean tear E-FABP level showed a significantly lower concentration in the NOD mice (p = 0.001). The mean saliva E-FABP level also showed a significantly lower concentration in the NOD mice (p = 0.04). Immunohistochemistry revealed intense E-FABP staining in the LG acinar epithelium and less intense staining in the acinar epitheliae of the SGs in the NOD mice compared to the WT mice. Real-time RT-PCR for the mRNA expression of E-FABP showed a significantly decreased expression in the SG and a significant increase in the LG of the NOD mice compared to the WT mice. In conclusion, the E-FABP showed marked alterations in the tear film, saliva, lacrimal, and salivary glands of the NOD mouse, which may help explain the ocular surface changes in relation to the dry eye disease in this SS model mouse and keratoconjunctivitis sicca in SS patients. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders 3.0)

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18 pages, 1983 KiB

Open AccessArticle

Lactoferrin Ameliorates Dry Eye Disease Potentially through Enhancement of Short-Chain Fatty Acid Production by Gut Microbiota in Mice

by Samuel Connell, Motoko Kawashima, Shigeru Nakamura, Toshihiro Imada, Hiromitsu Yamamoto, Kazuo Tsubota and Shinji Fukuda

Int. J. Mol. Sci. 2021, 22(22), 12384; https://doi.org/10.3390/ijms222212384 - 17 Nov 2021

Cited by 13 | Viewed by 4014

Abstract

Lactoferrin is a glycoprotein found at high concentrations within exocrine secretions, including tears. Low levels of lactoferrin have been implicated in the loss of tear secretion and ageing. Furthermore, lactoferrin possesses a range of functionalities, including anti-inflammatory properties and the ability to modulate the gut microbiota. Expanding evidence demonstrates a crucial role of the gut microbiota in immune regulation and development. The specific composition of bacterial species of the gut has a profound influence on local and systemic inflammation, leading to a protective capacity against a number of inflammatory diseases, potentially by the induction of regulatory immune cells. In this study, we demonstrated that oral administration of lactoferrin maintains tear secretion in a restraint and desiccating stress induced mouse model of dry eye disease. Furthermore, we revealed that lactoferrin induces the reduction of inflammatory cytokines, modulates gut microbiota, and induces short-chain fatty acid production. Whereas, the antibiotic vancomycin abrogates the effects of lactoferrin on dry eye disease and significantly reduces short-chain fatty acid concentrations. Therefore, this protective effect of LF against a mice model of DED may be explained by our observations of an altered gut microbiota and an enhanced production of immunomodulatory short-chain fatty acids. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders 3.0)

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20 pages, 2237 KiB

Open AccessArticle

Comparison of Two Experimental Mouse Dry Eye Models through Inflammatory Gene Set Enrichment Analysis Based on a Multiplexed Transcriptomic Approach

by Karima Kessal, Philippe Daull, Nicolas Cimbolini, Laurence Feraille, Sophie Grillo, Mylène Docquier, Christophe Baudouin, Françoise Brignole-Baudouin and Jean-Sébastien Garrigue

Int. J. Mol. Sci. 2021, 22(19), 10770; https://doi.org/10.3390/ijms221910770 - 5 Oct 2021

Cited by 6 | Viewed by 2985

Abstract

The goal of this study was to explore the specific signaling pathways related to inflammation in two experimental mouse dry eye (EDE) models. Female C57BL/6 mice housed for 10 days in a controlled desiccative environment were either treated with scopolamine (EDE-1; n = 18) or subjected to extraorbital lacrimal gland excision bilaterally (EDE-2; n = 10). Non-induced mice (n = 20) served as healthy controls. A corneal fluorescein staining (CFS) scoring was used at baseline through to day (D) 10 to evaluate epitheliopathy. At D10, corneas and conjunctivas were collected for multiplexed transcriptomic analysis with the NanoString^® mouse inflammatory CodeSet. Both EDE-1 and EDE-2 mice presented a change in corneal integrity, with a significant increase in CFS scores at D10. More gene transcripts were identified in EDE-2 compared with EDE-1 (116 vs. 96, respectively), and only a few were common to both models, 13 for the cornea and 6 for the conjunctiva. The gene functional annotation analysis revealed that the same inflammatory pathways were involved in both models. Comparative profiling of gene expression in the two EDE models leads to the identification of various targets and signaling pathways, which can be extrapolated to and confirmed in human disease. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders 3.0)

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17 pages, 4261 KiB

Open AccessArticle

Characterisation of Gel-Forming Mucins Produced In Vivo and In Ex Vivo Conjunctival Explant Cultures

by Sara I. Van Acker, Bert Van den Bogerd, Zoë P. Van Acker, Agnė Vailionytė, Michel Haagdorens, Carina Koppen, Sorcha Ní Dhubhghaill, Darlene A. Dartt and Isabel Pintelon

Int. J. Mol. Sci. 2021, 22(19), 10528; https://doi.org/10.3390/ijms221910528 - 29 Sep 2021

Cited by 3 | Viewed by 2645

Abstract

One key element to the health of the ocular surface encompasses the presence of gel-forming mucins in the pre-ocular tear film. Conjunctival goblet cells are specialized epithelial cells that secrete mucins necessary for tear film stability and general homeostasis. Their dysfunction can be linked to a range of ocular surface inflammation disorders and chronic injuries. To obtain new perspectives and angles to tackle mucin deficiency, the need for an accurate evaluation of their presence and corresponding mucin secretion in ex vivo conjunctival cultures has become a requisite. In vitro, goblet cells show a significant decrease in the production and secretion of gel-forming mucins, accompanied by signs of dedifferentiation or transdifferentiation. Explant cultures on laminin-treated CLP-PEG hydrogels can, however, support the production of gel-forming mucins. Together, we challenge the current paradigm to evaluate the presence of cultured goblet cells solely based on their general mucin (MUC) content through imaging analyses, showing the need for additional techniques to assess the functionality of goblet cells. In addition, we broadened the gel-forming mucin profile of in vivo goblet cells with MUC5B and MUC6, while MUC2 and MUC6 is added to the profile of cultured goblet cells. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders 3.0)

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13 pages, 9345 KiB

Open AccessArticle

Aged Mice Devoid of the M₃ Muscarinic Acetylcholine Receptor Develop Mild Dry Eye Disease

by Aytan Musayeva, Subao Jiang, Yue Ruan, Jenia Kouchek Zadeh, Panagiotis Chronopoulos, Norbert Pfeiffer, Werner E.G. Müller, Maximilian Ackermann, Ning Xia, Huige Li and Adrian Gericke

Int. J. Mol. Sci. 2021, 22(11), 6133; https://doi.org/10.3390/ijms22116133 - 7 Jun 2021

Cited by 12 | Viewed by 2639

Abstract

The parasympathetic nervous system is critically involved in the regulation of tear secretion by activating muscarinic acetylcholine receptors. Hence, various animal models targeting parasympathetic signaling have been developed to induce dry eye disease (DED). However, the muscarinic receptor subtype (M₁–M₅) mediating tear secretion remains to be determined. This study was conducted to test the hypothesis that the M₃ receptor subtype regulates tear secretion and to evaluate the ocular surface phenotype of mice with targeted disruption of the M₃ receptor (M3R^−/−). The experimental techniques included quantification of tear production, fluorescein staining of the ocular surface, environmental scanning electron microscopy, assessment of proliferating cells in the corneal epithelium and of goblet cells in the conjunctiva, quantification of mRNA for inflammatory cytokines and prooxidant redox enzymes and quantification of reactive oxygen species. Tear volume was reduced in M3R^−/− mice compared to age-matched controls at the age of 3 months and 15 months, respectively. This was associated with mild corneal epitheliopathy in the 15-month-old but not in the 3-month-old M3R^−/− mice. M3R^−/− mice at the age of 15 months also displayed changes in corneal epithelial cell texture, reduced conjunctival goblet cell density, oxidative stress and elevated mRNA expression levels for inflammatory cytokines and prooxidant redox enzymes. The findings suggest that the M₃ receptor plays a pivotal role in tear production and its absence leads to ocular surface changes typical for DED at advanced age. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders 3.0)

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15 pages, 3275 KiB

Open AccessArticle

Interactions of Meibum and Tears with Mucomimetic Polymers: A Hint towards the Interplay between the Layers of the Tear Film

by Petar Eftimov, Norihiko Yokoi, Ana M. Melo, Philippe Daull and Georgi As. Georgiev

Int. J. Mol. Sci. 2021, 22(5), 2747; https://doi.org/10.3390/ijms22052747 - 9 Mar 2021

Cited by 8 | Viewed by 2864

Abstract

Recent clinical findings suggest that mucomimetic polymers (MMP) can alter not only the texture of the aqueous tear but also the spreading and structure of the tear film (TF) lipid layer, thereby allowing for their synchronized performance in vivo. Thus, we aimed to evaluate in vitro (i) the capability of pharmaceutically applicable MMP to ensure the formation of post-evaporative ferning patterns (a characteristic feature of the “healthy” tear colloid) and (ii) the MMP interactions with human meibum films accessed in the course of blink-like deformations via Langmuir surface balance and Brewster angle microscopy (BAM). Four MMP were used- hyaluronic acid (HA), cross-linked hyaluronic acid (CHA), carboxymethyl cellulose (CMC) and gellan gum (GG)- at the concentrations of 0.0001%, 0.001%, 0.01%, 0.05% and 0.1%. Significant differences were observed in the MMP fern formation capability: CHA (≥0.001%) > HA (≥0.01%) = CMC (≥0.01%) > GG (≥0.05%). All MMP affected the spreading of meibum, with BAM micrographs revealing thickening of the films. CHA was particularly efficient, showing concentration-dependent enhancement of tear ferning and of meibomian layer structure, surfactant properties and viscoelasticity. Thus, endogenous and exogenous MMP may play key roles for the concerted action of the TF layers at the ocular surface, revealing novel routes for TF-oriented therapeutic applications. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders 3.0)

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17 pages, 2674 KiB

Open AccessReview

Impact of Attrition, Intercellular Shear in Dry Eye Disease: When Cells are Challenged and Neurons are Triggered

by Gysbert-Botho van Setten

Int. J. Mol. Sci. 2020, 21(12), 4333; https://doi.org/10.3390/ijms21124333 - 18 Jun 2020

Cited by 29 | Viewed by 4295

Abstract

The mechanical component in the pathophysiology of dry eye disease (DED) deserves attention as an important factor. The lubrication deficit induced impaired mechano-transduction of lid pressure to the ocular surfaces may lead to the dysregulation of homeostasis in the epithelium, with sensations of pain and secondary inflammation. Ocular pain is possibly the first sign of attrition and may occur in the absence of visible epithelial damage. Attrition is a process which involves the constant or repeated challenge of ocular surface tissues by mechanical shear forces; it is enhanced by the thinning of corneal epithelium in severe DED. As a highly dynamic process leading to pain and neurogenic inflammation, the identification of the impact of attrition and its potential pathogenic role could add a new perspective to the current more tear film-oriented models of ocular surface disease. Treatment of DED addressing lubrication deficiencies and inflammation should also consider the decrease of attrition in order to stimulate epithelial recovery and neural regeneration. The importance of hyaluronic acid, its molecular characteristics, the extracellular matrix and autoregulative mechanisms in this process is outlined. The identification of the attrition and recognition of its impact in dry eye pathophysiology could contribute to a better understanding of the disease and optimized treatment regimens. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders 3.0)

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