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Dry Eye: Molecular Mechanisms, Inflammation Biology and Novel Molecular Targets

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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 (31 January 2023) | Viewed by 29641

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Dr. Cintia S. De Paiva

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Guest Editor

Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
Interests: Sjögren syndrome; dry eye; lacrimal gland; aging; microbiome; dendritic cells; CD4+ T cells; goblet cells
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Stephen C. Pflugfelder

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Guest Editor

Cullen Eye Institute, Houston, TX, USA
Interests: dry eye; ocular surface; autoimmunity; Sjogren syndrome; conjunctiva; goblet cells; dendritic cells
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Dry eye disease is a multifactorial disease where inflammation plays a key role. Dry eye affects millions of people worldwide, and is one of the most common reasons that people seek eye care. Clinically, patients often complain of sandy sensation, dry eye, ocular discomfort and pain, and loss of functional vision. Although our understanding of the pathological mechanisms has improved in the past 20 years, there is still much to discover about how inflammation causes/perpetuates dry eye disease.

In this Special Issue of IJMS, we are seeking articles that provide new insights into the underlying mechanisms of dry eye disease, including molecular and cellular mechanisms involved in the initiation and perpetuation of inflammation, new diagnostic tools/biomarkers, and new therapies and treatment options. We invite the submission of both clinical and pre-clinical studies with an emphasis on molecular biology; animal models of disease are encouraged.

Dr. Cintia S. De Paiva
Prof. Dr. Stephen C. Pflugfelder
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

dry eye
aging
inflammation
biomarkers
novel targets
conjunctiva
corneal
goblet cells
immune cells

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Published Papers (10 papers)

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Research

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11 pages, 1557 KiB

Open AccessArticle

Distinct Inflammatory and Oxidative Effects of Diabetes Mellitus and Hypothyroidism in the Lacrimal Functional Unit

by Jacqueline Ferreira Faustino-Barros, Ariane Mirela Saranzo Sant’Ana, Lara Cristina Dias, Adriana de Andrade Batista Murashima, Lilian Eslaine Costa Mendes da Silva, Marina Zílio Fantucci, Denny Marcos Garcia and Eduardo Melani Rocha

Int. J. Mol. Sci. 2023, 24(8), 6974; https://doi.org/10.3390/ijms24086974 - 10 Apr 2023

Viewed by 1850

Abstract

Diabetes mellitus (DM) and hypothyroidism (HT) are prevalent diseases associated with dry eye (DE). Their impact on the lacrimal functional unit (LFU) is poorly known. This work evaluates the changes in the LFU in DM and HT. Adult male Wistar rats had the disease induced as follows: (a) DM: streptozotocin and (b) HT: methimazole. The tear film (TF) and blood osmolarity were measured. Cytokine mRNA was compared in the lacrimal gland (LG), trigeminal ganglion (TG), and cornea (CO). Oxidative enzymes were evaluated in the LG. The DM group showed lower tear secretion (p = 0.02) and higher blood osmolarity (p < 0.001). The DM group presented lower mRNA expression of TRPV1 in the cornea (p = 0.03), higher Il1b mRNA expression (p = 0.03), and higher catalase activity in the LG (p < 0.001). The DM group presented higher Il6 mRNA expression in the TG (p = 0.02). The HT group showed higher TF osmolarity (p < 0.001), lower expression of Mmp9 mRNA in the CO (p < 0.001), higher catalase activity in the LG (p = 0.002), and higher expression of Il1b mRNA in the TG (p = 0.004). The findings revealed that DM and HT induce distinct compromises to the LG and the entire LFU. Full article

(This article belongs to the Special Issue Dry Eye: Molecular Mechanisms, Inflammation Biology and Novel Molecular Targets)

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10 pages, 6101 KiB

Open AccessCommunication

Comparison of Efficacy and Inflammatory Response to Thermoconjunctivoplasty Performed with Cautery or Pulsed 1460 nm Laser

by Rodrigo Guimaraes de Souza, David Huang, Scott Prahl, Lauren Nakhleh and Stephen C. Pflugfelder

Int. J. Mol. Sci. 2023, 24(6), 5740; https://doi.org/10.3390/ijms24065740 - 17 Mar 2023

Viewed by 1554

Abstract

Conjunctivochalasis is a degenerative condition of the conjunctiva that disrupts tear distribution and causes irritation. Thermoreduction of the redundant conjunctiva is required if symptoms are not relieved with medical therapy. Near-infrared laser treatment is a more controlled method to shrink the conjunctiva than thermocautery. This study compared tissue shrinkage, histology, and postoperative inflammation in thermoconjunctivoplasty performed on the mouse conjunctiva using either thermocautery or pulsed 1460 nm near-infrared laser irradiation. Three sets of experiments were performed on female C57BL/6J mice (n = 72, 26 per treatment group and 20 control) to assess conjunctival shrinkage, wound histology, and inflammation 3 and 10 days after treatment. Both treatments effectively shrunk the conjunctiva, but thermocautery caused greater epithelial damage. Thermocautery caused greater infiltration of neutrophils on day 3 and neutrophils and CD11b⁺ myeloid cells on day 10. The thermocautery group had significantly higher conjunctival expression of IL-1β on day 3. Expression of chemokine CCL2 was higher in the conjunctiva on day 3 and tear concentrations were higher on day 7 in the laser group. These results suggest that pulsed laser treatment causes less tissue damage and postoperative inflammation than thermocautery while effectively addressing conjunctivochalasis. Full article

(This article belongs to the Special Issue Dry Eye: Molecular Mechanisms, Inflammation Biology and Novel Molecular Targets)

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19 pages, 5777 KiB

Open AccessArticle

Heterochronic Parabiosis Causes Dacryoadenitis in Young Lacrimal Glands

by Kaitlin K. Scholand, Alexis F. Mack, Gary U. Guzman, Michael E. Maniskas, Ritu Sampige, Gowthaman Govindarajan, Louise D. McCullough and Cintia S. de Paiva

Int. J. Mol. Sci. 2023, 24(5), 4897; https://doi.org/10.3390/ijms24054897 - 3 Mar 2023

Cited by 4 | Viewed by 3495

Abstract

Aging is associated with inflammation and oxidative stress in the lacrimal gland (LG). We investigated if heterochronic parabiosis of mice could modulate age-related LG alterations. In both males and females, there were significant increases in total immune infiltration in isochronic aged LGs compared to that in isochronic young LGs. Male heterochronic young LGs were significantly more infiltrated compared to male isochronic young LGs. While both females and males had significant increases in inflammatory and B-cell-related transcripts in isochronic and heterochronic aged LGs compared to levels isochronic and heterochronic young LGs, females had a greater fold expression of some of these transcripts than males. Through flow cytometry, specific subsets of B cells were increased in the male heterochronic aged LGs compared to those in male isochronic aged LGs. Our results indicate that serum soluble factors from young mice were not enough to reverse inflammation and infiltrating immune cells in aged tissues and that there were specific sex-related differences in parabiosis treatment. This suggests that age-related changes in the LG microenvironment/architecture participate in perpetuating inflammation, which is not reversible by exposure to youthful systemic factors. In contrast, male young heterochronic LGs were significantly worse than their isochronic counterparts, suggesting that aged soluble factors can enhance inflammation in the young host. Therapies that aim at improving cellular health may have a stronger impact on improving inflammation and cellular inflammation in LGs than parabiosis. Full article

(This article belongs to the Special Issue Dry Eye: Molecular Mechanisms, Inflammation Biology and Novel Molecular Targets)

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17 pages, 2371 KiB

Open AccessArticle

Airborne Exposure of the Cornea to PM₁₀ Induces Oxidative Stress and Disrupts Nrf2 Mediated Anti-Oxidant Defenses

by Mallika Somayajulu, Sharon A. McClellan, Robert Wright, Ahalya Pitchaikannu, Bridget Croniger, Kezhong Zhang and Linda D. Hazlett

Int. J. Mol. Sci. 2023, 24(4), 3911; https://doi.org/10.3390/ijms24043911 - 15 Feb 2023

Cited by 7 | Viewed by 2079

Abstract

The purpose of this study is to test the effects of whole-body animal exposure to airborne particulate matter (PM) with an aerodynamic diameter of <10 μm (PM₁₀) in the mouse cornea and in vitro. C57BL/6 mice were exposed to control or 500 µg/m³ PM₁₀ for 2 weeks. In vivo, reduced glutathione (GSH) and malondialdehyde (MDA) were analyzed. RT-PCR and ELISA evaluated levels of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling and inflammatory markers. SKQ1, a novel mitochondrial antioxidant, was applied topically and GSH, MDA and Nrf2 levels were tested. In vitro, cells were treated with PM₁₀ ± SKQ1 and cell viability, MDA, mitochondrial ROS, ATP and Nrf2 protein were tested. In vivo, PM₁₀ vs. control exposure significantly reduced GSH, corneal thickness and increased MDA levels. PM₁₀-exposed corneas showed significantly higher mRNA levels for downstream targets, pro-inflammatory molecules and reduced Nrf2 protein. In PM₁₀-exposed corneas, SKQ1 restored GSH and Nrf2 levels and lowered MDA. In vitro, PM₁₀ reduced cell viability, Nrf2 protein, and ATP, and increased MDA, and mitochondrial ROS; while SKQ1 reversed these effects. Whole-body PM₁₀ exposure triggers oxidative stress, disrupting the Nrf2 pathway. SKQ1 reverses these deleterious effects in vivo and in vitro, suggesting applicability to humans. Full article

(This article belongs to the Special Issue Dry Eye: Molecular Mechanisms, Inflammation Biology and Novel Molecular Targets)

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7 pages, 2421 KiB

Open AccessArticle

Non-Invasive Tear Break-Up Detection with the Kowa DR-1α and Its Relationship to Dry Eye Clinical Severity

by Stephen Pflugfelder, Lauren Nakhleh, Yasushi Kikukawa, Shin Tanaka and Takuya Kosugi

Int. J. Mol. Sci. 2022, 23(23), 14774; https://doi.org/10.3390/ijms232314774 - 25 Nov 2022

Cited by 3 | Viewed by 1907

Abstract

The purpose of this study is to compare visual versus software detection of non-invasive tear break-up with the KOWA DR-1α tear interferometer and investigate the relationship between non-invasive tear break-up time (NIBUT) and dry eye clinical severity. Tear interferometry with the KOWA DR-1α, together with a standardized comprehensive ocular surface/tear evaluation, was performed on 348 consecutive eyes. Investigator visually detected or software detected non-invasive tear break-up and NIBUT were measured and compared on a subset of these examinations. The relationship between software-detected NIBUT and categorical dry eye severity based on irritation symptoms and corneal and conjunctival dye staining scores was determined. The sensitivity of visual (frame-by-frame) or software detected non-invasive tear break-up in eyes with tear instability (FBUT < 10) was similar (range 63–69%). NIBUT, measured visually or by software, had a correlation coefficient of 0.87. NIBUT was significantly lower in severity levels 2 and 3 compared to levels 0 + 1, and level 3 was significantly lower than level 2. In conclusion, there is a good correlation between investigator visually detected and software-detected tear break-up and tear break-up time in the KOWA DR-1α interferometric fringe images. Software-detected NIBUT is a clinically relevant measure of dry eye clinical severity. Full article

(This article belongs to the Special Issue Dry Eye: Molecular Mechanisms, Inflammation Biology and Novel Molecular Targets)

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13 pages, 3411 KiB

Open AccessArticle

Conjunctival Fluid Secretion Impairment via CaCC-CFTR Dysfunction Is the Key Mechanism in Environmental Dry Eye

by Jinyu Zhang, Limian Lin, Xiaomin Chen, Shuyi Wang, Yuan Wei, Wenliang Zhou, Shuangjian Yang and Shiyou Zhou

Int. J. Mol. Sci. 2022, 23(22), 14399; https://doi.org/10.3390/ijms232214399 - 19 Nov 2022

Cited by 1 | Viewed by 2080

Abstract

Dry eye disease (DED) is a multifactorial disease with an incidence of approximately 50% worldwide. DED seriously affects quality of life and work. The prevalence of environmental DED (eDED) ranges from 35 to 48%. Conjunctival fluid secretion dysfunction may be one of the major causes of DED. Notably, the Cl^– flux corresponds to the conjunctival fluid secretion and could be affected by ATP. Both the cystic fibrosis transmembrane conductance regulator (CFTR) and the Ca²⁺-activated Cl^– channel (CaCC) are Cl^– channels involved in epithelial fluid secretion. Conjunctival fluid secretion could be increased by activating P2Y₂R (an ATP receptor) in DED. However, the role of the CaCC and CFTR channels regulated by P2Y₂R in eDED remains unclear. In this study, we established a rabbit eDED model using a controlled drying system. A Ussing chamber was used to perform a conjunctival short-circuit current induced by ATP to evaluate the reactivity of the ion channels to the ATP. Our results revealed that eDED accompanied by conjunctival fluid secretion impairment was caused by a P2Y₂R dysfunction, which is related to CaCC-CFTR signaling in the conjunctiva epithelium. Notably, the coupling effect of the ATP-induced CaCC-CFTR activation and intracellular Ca²⁺ may represent a promising therapeutic target for treating eDED. Full article

(This article belongs to the Special Issue Dry Eye: Molecular Mechanisms, Inflammation Biology and Novel Molecular Targets)

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Review

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12 pages, 298 KiB

Open AccessReview

A Critical Appraisal of the Physicochemical Properties and Biological Effects of Artificial Tear Ingredients and Formulations

by Judy Weng, Michael K. Fink and Ajay Sharma

Int. J. Mol. Sci. 2023, 24(3), 2758; https://doi.org/10.3390/ijms24032758 - 1 Feb 2023

Cited by 7 | Viewed by 4521

Abstract

Dry eye disease is among the most prevalent diseases affecting the ocular surface. Artificial tears remain the cornerstone therapy for its management. There are currently a wide variety of marketed artificial tears available to choose from. These artificial tears differ significantly in their composition and formulation. This article reviews the physicochemical and biological properties of artificial tear components and how these characteristics determine their use and efficacy in the management of dry eye. Furthermore, this article also discusses the various formulations of artificial tears such as macro and nanoemulsion and the type of preservatives present in them. Full article

(This article belongs to the Special Issue Dry Eye: Molecular Mechanisms, Inflammation Biology and Novel Molecular Targets)

21 pages, 2531 KiB

Open AccessReview

The Potential Role of Regulated Cell Death in Dry Eye Diseases and Ocular Surface Dysfunction

by Camilla Scarpellini, Alba Ramos Llorca, Caroline Lanthier, Greta Klejborowska and Koen Augustyns

Int. J. Mol. Sci. 2023, 24(1), 731; https://doi.org/10.3390/ijms24010731 - 1 Jan 2023

Cited by 14 | Viewed by 4927

Abstract

The research on new treatments for dry eye diseases (DED) has exponentially grown over the past decades. The increased prevalence of dry eye conditions, particularly in the younger population, has received much attention. Therefore, it is of utmost importance to identify novel therapeutical targets. Regulated cell death (RCD) is an essential process to control the biological homeostasis of tissues and organisms. The identification of different mechanisms of RCD stimulated the research on their involvement in different human pathologies. Whereas apoptosis has been widely studied in DED and included in the DED vicious cycle, the role of RCD still needs to be completely elucidated. In this review, we will explore the potential roles of different types of RCD in DED and ocular surface dysfunction. Starting from the evidence of oxidative stress and inflammation in dry eye pathology, we will analyse the potential therapeutic applications of the following principal RCD mechanisms: ferroptosis, necroptosis, and pyroptosis. Full article

(This article belongs to the Special Issue Dry Eye: Molecular Mechanisms, Inflammation Biology and Novel Molecular Targets)

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12 pages, 1408 KiB

Open AccessReview

A, B, C’s of Trk Receptors and Their Ligands in Ocular Repair

by Akash Gupta, Jeremias G. Galletti, Zhiyuan Yu, Kevin Burgess and Cintia S. de Paiva

Int. J. Mol. Sci. 2022, 23(22), 14069; https://doi.org/10.3390/ijms232214069 - 15 Nov 2022

Cited by 4 | Viewed by 2798

Abstract

Neurotrophins are a family of closely related secreted proteins that promote differentiation, development, and survival of neurons, which include nerve growth factor (NGF), brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4. All neurotrophins signal through tropomyosin receptor kinases (TrkA, TrkB, and TrkC) which are more selective to NGF, brain-derived neurotrophic factor, and neurotrophin-3, respectively. NGF is the most studied neurotrophin in the ocular surface and a human recombinant NGF has reached clinics, having been approved to treat neurotrophic keratitis. Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 are less studied neurotrophins in the ocular surface, even though brain-derived neurotrophic factor is well characterized in glaucoma, retina, and neuroscience. Recently, neurotrophin analogs with panTrk activity and TrkC selectivity have shown promise as novel drugs for treating dry eye disease. In this review, we discuss the biology of the neurotrophin family, its role in corneal homeostasis, and its use in treating ocular surface diseases. There is an unmet need to investigate parenteral neurotrophins and its analogs that activate TrkB and TrkC selectively. Full article

(This article belongs to the Special Issue Dry Eye: Molecular Mechanisms, Inflammation Biology and Novel Molecular Targets)

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14 pages, 1486 KiB

Open AccessReview

Proteases and Their Potential Role as Biomarkers and Drug Targets in Dry Eye Disease and Ocular Surface Dysfunction

by Alba Ramos-Llorca, Camilla Scarpellini and Koen Augustyns

Int. J. Mol. Sci. 2022, 23(17), 9795; https://doi.org/10.3390/ijms23179795 - 29 Aug 2022

Cited by 7 | Viewed by 3368

Abstract

Dry eye disease (DED) is a multifactorial disorder that leads to ocular discomfort, visual disturbance, and tear film instability. DED is accompanied by an increase in tear osmolarity and ocular surface inflammation. The diagnosis and treatment of DED still present significant challenges. Therefore, novel biomarkers and treatments are of great interest. Proteases are present in different tissues on the ocular surface. In a healthy eye, proteases are highly regulated. However, dysregulation occurs in various pathologies, including DED. With this review, we provide an overview of the implications of different families of proteases in the development and severity of DED, along with studies involving protease inhibitors as potential therapeutic tools. Even though further research is needed, this review aims to give suggestions for identifying novel biomarkers and developing new protease inhibitors. Full article

(This article belongs to the Special Issue Dry Eye: Molecular Mechanisms, Inflammation Biology and Novel Molecular Targets)

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