Pathophysiology Of Dry Eye Disease Research Articles

The Analysis Study of Interventions of Dry Eye: A Comprehensive Systematic Review

Introduction : Dry eye disease (DED) is a common, multifactorial condition affecting the tear film and ocular surface, leading to discomfort, visual disturbances, and progressive ocular damage if untreated. DED involves a complex interplay among anatomical structures, inflammatory pathways, and environmental factors. It is classified into aqueous-deficient and evaporative types, often presenting as mixed forms. DED significantly affects quality of life, daily functionality, and psychological well-being. This systematic review synthesizes current evidence on DED pathophysiology, classification, diagnosis, and management while highlighting recent advancements in therapeutic strategies. Methods :This review adhered to PRISMA 2020 guidelines, focusing on original research published since 2018. Inclusion criteria targeted studies on DED’s inflammatory mechanisms, diagnostic tools, and treatment approaches. Databases searched included PubMed, ScienceDirect, Embase, Cochrane Library, and Web of Science. Keywords such as “dry eye disease,” “ocular surface inflammation,” and “meibomian gland dysfunction” were employed. Following a rigorous screening process, eight studies met the inclusion criteria for comprehensive analysis. Results : The analysis reaffirmed the central role of inflammation in DED pathophysiology, driven by cytokines and matrix metalloproteinases. Emerging diagnostics, such as tear osmolarity tests and meibography, enhance disease identification. Treatment advancements emphasize anti-inflammatory therapies, artificial tears, and meibomian gland support. The review highlights the burden of DED on quality of life and identifies gaps in addressing work-related and environmental stressors. Conclusion : DED is a complex disorder requiring a multidisciplinary approach. Future research should prioritize innovative therapies targeting underlying mechanisms, comprehensive patient education, and integration of mental health support. Holistic management can mitigate the burden of DED and improve patient outcomes.

Inflammation in Dry Eye Disease-Pathogenesis, Preclinical Animal Models, and Treatments.

Dry eye disease (DED) is a rapidly growing ocular surface disease with a significant socioeconomic impact that affects the patients' visual function and, thus, their quality of life. It is distinguished by a loss of tear film homeostasis, leading to tear film instability, hyperosmolarity, ocular surface inflammation, and neurosensory abnormalities, with all of these playing etiological roles in the propagation of the vicious DED circle. While current treatments primarily focus on reducing tear film instability and hyperosmolarity, increasingly more attention is being placed on tackling the underlying inflammation that propagates and potentiates these factors. As such, preclinical models are crucial to further elucidate the DED pathophysiology and develop novel therapeutic strategies. This review outlines the role of inflammation in DED, highlighting related signs and diagnostic tools before focusing on relevant preclinical animal models and potential therapeutic strategies to tackle DED-associated inflammation.

Genomics of Staphylococcus aureus and Enterococcus faecalis isolated from the ocular surface of dry eye disease sufferers

Ocular surface inflammatory disorders, such as dry eye, are becoming increasingly prevalent. Developing new treatment strategies targeting harmful bacteria could provide significant therapeutic benefits. The purpose of this study was to characterize the common ocular pathogen Staphylococcus aureus and the rarer endophthalmitis-associated species Enterococcus faecalis isolated from the ocular surface of dry eye disease patients in Norway. Together the 7 isolates (5 S. aureus and 2 E. faecalis) comprise the complete set of members of each species isolated in our previous study of the ocular microbiome of 61 dry eye sufferers. We aimed to investigate the pathogenic potential of these isolates in relation to ocular surface health. To this end, we used whole genome sequencing, multiplex PCR directed at virulence genes and antibiotic susceptibility tests encompassing clinically relevant agents. The E. faecalis isolates showed resistance to only gentamicin. S. aureus isolates displayed susceptibility to most of the tested antibiotics, except for two isolates which showed resistance to trimethoprim/sulfamethoxazole and three isolates which were resistant to ampicillin. Susceptibilities included sensitivity to several first-line antibiotics for treatment of ocular infections by these species. Thus, treatment options would be available if required. However, spontaneous resistance development to gentamicin and rifampicin occurred in some S. aureus which could be a cause for concern. Whole genome sequencing of the isolates showed genome sizes ranging from 2.74 to 2.83 Mbp for S. aureus and 2.86 Mbp for E. faecalis, which is typical for these species. Multilocus sequence typing and phylogenetic comparisons with previously published genomes, did not suggest the presence of eye-specific clusters for either species. Genomic analysis indicated a high probability of pathogenicity among all isolates included in the study. Resistome analysis revealed the presence of the beta-lactamase blaZ gene in all S. aureus isolates and the dfrG gene in two of them; while E. faecalis isolates carried the lsa(A) gene which confers intrinsic resistance to lincosamides and streptogramin A in this species. Screening for virulence factors revealed the presence of various pathogenicity associated genes in both S. aureus and E. faecalis isolates. These included genes coding for toxin production and factors associated with evading the host immune system. Some of the identified genes (tst, hylA &hylB) are suggested to be linked to the pathophysiology of dry eye disease. Lastly, the presence of specific S. aureus virulence genes was confirmed through multiplex PCR analysis.

Quintessence of currently approved and upcoming treatments for dry eye disease.

Dry eye disease (DED), also known as dry eye syndrome, is a multifactorial ocular surface disease. The aim of this review is to present the details of currently approved and upcoming treatment options for DED in a nutshell. We conducted a thorough literature search using PubMed and searched US FDA website, clinicaltrials.gov, and data available in public domain for currently approved and upcoming treatment options for DED. Currently, the US Food and Drug Administration (FDA)-approved medical treatments for treatment of DED include cyclosporine formulations (RESTASIS® [cyclosporine 0.05% ophthalmic emulsion], VEVYE® [cyclosporine 0.1% ophthalmic solution], and CEQUA™ [cyclosporine 0.09% ophthalmic solution]), XIIDRA® (lifitegrast), a leukocyte function-associated antigen-1 (LFA-1)/intracellular adhesion molecule-1(ICAM-1) inhibitor, EYSUVIS™ (loteprednol etabonate ophthalmic suspension 0.25%), a corticosteroid, and MIEBO™ (perfluorohexyloctane ophthalmic solution), a semifluorinated alkane. TYRVAYA™ (varenicline solution nasal spray), a cholinergic agonist, is another formulation approved for the treatment of the signs and symptoms of DED. The medical devices approved for treating DED due to meibomian glands dysfunction (MGD) include Lumenis OptiLight™ (intense pulsed light [IPL] device), TearCare® system, and TearScience™ LipiFlow™ thermal pulsation system. Punctal plugs are another treatment option approved for management of DED. There are hundreds of clinical studies evaluating newer treatments for managing the signs and symptoms. Cyclosporine formulations TJO-087 (cyclosporine A nanoemulsion 0.08%), SCAI-001 eye drops (cyclosporine 0.01%, 0.02%) are being evaluated against RESTASIS® and other approved treatments. The potential treatments being assessed include IC 265, OK-101, PL9643, SYL1001 (tivanisiran), SHJ002, OXERVATE® (cenegermin-bkbj ophthalmic solution 0.002%), HBM9036 (tanfanercept ophthalmic solution), OCS-02 (licaminlimab), MIM-D3 (tavilermide ophthalmic solution 5%), AR-15,512, BRM421, reproxalap, and AZR-MD-001 (selenium sulphide ointment 0.5%). The pathophysiology of DED is complex and multifactorial; there is a need to understand it even deeper. The new treatments and different delivery systems seem promising and provide a hope of effective treatment for DED.

Pathophysiology of dry eye disease and novel therapeutic agents

Pathophysiology of dry eye disease and novel therapeutic agents

TRPV1 in Dry Eye Disease.

Dry eye disease (DED) is a prevalent ophthalmic ailment with intricate pathogenesis and that occurs primarily due to various factors which affect the ocular surface. DED is characterized by the disruption of tear film homeostasis, inflammatory reaction, and neuroparesthesia. Transient receptor potential vanilloid 1 (TRPV1) is a versatile receptor that can be stimulated by heat, acid, capsaicin (CAP), hyperosmolarity, and numerous inflammatory agents. There is accumulating evidence that implicates TRPV1 in the initiation and progression of DED through its detection of hypertonic conditions and modulation of inflammatory pathways. In this article, we present a comprehensive review of the expression and function of the TRPV1 channel in tissues and cells associated with DED. In addition, we outline the potential mechanisms that implicate TRPV1 in the pathophysiology of DED. The aim of this review is to establish a theoretical basis for TRPV1 as a possible therapeutic target in DED, thereby encouraging further investigations into its role in DED.

Effects of dietary imbalances of micro- and macronutrients on the ocular microbiome and its implications in dry eye disease

Dry eye disease (DED) is a complex and multifactorial ocular surface disease affecting a large proportion of the population. There is emerging evidence of the impact of the microbiomes of the ocular surface and gut on the symptoms of DED, with many parallels being drawn to inflammatory diseases of other organ systems. A key factor involved in the promotion of healthy microbiomes, and which has been associated with ocular surface disease, is micro- and macronutrient deficiency. A comprehensive review of how these deficiencies can contribute to DED is absent from the literature. This review reports the composition of healthy ocular and gut microbiomes, and how nutrient deficiencies may impact these floral populations, with linkage to the subsequent impact on ocular health. The review highlights that vitamin B1 and iron are linked to reduced levels of butyrate, a fatty acid implicated in inflammatory conditions such as ulcerative colitis which itself is a condition known to be associated with ocular surface diseases. Vitamin B12 has been shown to have a role in maintaining gut microbial eubiosis and has been linked to the severity of dry eye symptoms. Similar beneficial effects of gut microbial eubiosis were noted with vitamin A and omega-3 polyunsaturated fatty acids. Selenium and calcium have complex interactions with the gut microbiome and have both been implicated in the development of thyroid orbitopathy. Further, diabetes mellitus is associated with ocular surface diseases and changes in the ocular microbiome. A better understanding of how changes in both the gut and eye microbiome impact DED could allow for an improved understanding of DED pathophysiology and the development of new, effective treatment strategies.

Tear and Saliva Metabolomics in Evaporative Dry Eye Disease in Females.

Accurate diagnosis of dry eye disease (DED) is challenging, and even today there is no gold standard biomarker of DED. Hypothesis-free global metabolomic studies of tears from DED patients have great potential to discover metabolites and pathways affected in the pathophysiology of DED, and to identify possible future biomarkers. These metabolites and biomarkers could be important for diagnosing and monitoring disease as well as for new therapeutic targets and strategies. As DED is associated with dry mouth, this study aimed to perform metabolomic analyses of tears and saliva from patients with decreased tear film break-up time but normal Schirmer test, and age-matched controls with both tear production and stability within physiological range. We applied strict inclusion criteria to reduce sampling bias in the metabolomic analyses and selected only age-matched females with Schirmer test values between 10-15 mm/5 min. The tear film analysis arm included 19 patients (with tear film break-up time 0-5 s) and 12 controls (with tear film break-up time 10-30 s), while the salivary analysis arm consisted of a subset which included 18 patients and six controls. Metabolomic analyses were performed using liquid chromatography and high-resolution mass spectrometry. Analyses using a global database search detected a total of 56 metabolites in tear samples that were significantly different between the groups. Of these, several have known associations with DED. These metabolites are present in meibum and have anti-oxidative characteristics or associations with the ocular microbiome, and altered concentrations suggest that they may play a significant role in DED associated with decreased tear film stability. In saliva, hypotaurine levels were lower among patients with tear film instability. In this pilot study, we found different levels of several metabolites in patients with decreased tear film break-up time that may have associations with DED. Future studies are required to replicate our findings and clarify the exact roles of these metabolites.

The impact of dry eye disease on corneal nerve parameters: A systematic review and meta-analysis.

Dry eye disease (DED) is a growing global health problem with a significant impact on the quality of life of patients. While neurosensory abnormalities have been recognised as a contributor to DED pathophysiology, the potential role of in vivo corneal confocal microscopy in detecting nerve loss or damage remains unclear. This systematic review with meta-analysis (PROSPERO registered CRD42022381861) investigated whether DED has an impact on sub-basal corneal nerve parameters. PubMed, Embase and Web of Science Core Collection databases were searched from inception to 9 December 2022. Studies using laser scanning confocal microscopy to compare corneal nerve parameters of DED with healthy eyes were included. Study selection process and data extraction were performed by two independent members of the review team. Twenty-two studies with 916 participants with DED and 491 healthy controls were included, with 21 of these studies included in subsequent meta-analyses. There was a decrease in total corneal nerve length (-3.85 mm/mm2 ; 95% CI -5.16, -2.55), corneal main nerve trunk density (-4.81 number/mm2 ; 95% CI -7.94, -1.68) and corneal nerve branch density (-15.52 number/mm2 ; 95% CI -27.20, -3.84) in DED eyes compared with healthy eyes, with subgroup analysis demonstrating that these differences were more evident in studies using NeuronJ software, a semi-automated procedure. While this review found evidence of loss of corneal nerve parameters in eyes with DED compared with healthy controls, particularly with the use of a semi-automated image analysis method, it is evident that there is substantial heterogeneity between studies in terms of corneal nerve imaging methodology. Standardisation is required in terms of terminology and analysis, with more research needed to potentially improve the clinical applicability and practicality of corneal nerve imaging. Further investigation is also required to confirm the diagnostic accuracy of this imaging modality and its potential for monitoring DED treatment efficacy.

Meibomian Gland Assessment in Routine Ophthalmology Practice.

This cross-sectional study aimed to investigate the connection between meibomian gland (MG) excreta quantity and quality after MG expression (MGX), dry eye disease (DED) symptoms, and objective DED signs and to clarify the relationship between dry eye and MG function in DED pathophysiology. The study included 200 subjects, 100 with and 100 without dry eye symptoms. Schein questionnaire was used to determine the severity of dry eye symptoms and self-reported skin type for facial skin dryness self-evaluation. Objective dry eye signs were assessed by monitoring conjunctival hyperemia, lid parallel conjunctival folds (LIPCOF), tear break-up time (TBUT), fluorescein surface staining and digital MGX. Subjects with DED symptoms had significantly lower MG quantity scores than healthy controls (p < 0.001). Meibum quality and quantity scores significantly correlated with female gender (p = 0.002), Schein questionnaire score (p < 0.001), fluorescein corneal staining score (p = 0.019), self-reported skin type (p < 0.001), TBUT (p < 0.001) and LIPCOF (p = 0.041). After adjustment for age and gender in a logistic regression analysis, dry eye was independently and significantly associated with self-reported skin type (OR 0.73, p < 0.001), LIPCOF (OR 1.04, p < 0.001), fluorescein corneal staining (OR 1.05, p = 0.019), TBUT (OR 0.77, p < 0.001) and meibum quantity score (OR 0.59, p < 0.001). Dry eye symptoms and objective signs correlated well in this study. MGX discriminated between the subjects with and without DED symptoms and was associated with other objective DED signs. Results showed a significant association between meibum quality and quantity, MG function, DED and facial skin dryness self-perception. This paper established a correlation between dry eye symptoms caused by MG dysfunction and dry skin, which can help general health practitioners consider dry eye as a cause of chronic eye complaints with patients who report dry skin.

Cornea Classic: Stern, Beuerman, Fox, Gao, Mircheff, and Pflugfelder, "The Pathology of Dry Eye: The Interaction Between the Ocular Surface and Lacrimal Glands" (1998).

In one of the most frequently cited articles from Cornea , Stern et al's "The pathology of dry eye: the interaction between the ocular surface and lacrimal glands" (1998) revolutionized our current understanding of the pathophysiology of dry eye disease.

Evaluation of Safety, Tolerability and Pharmacokinetic Characteristics of SA001 and Its Active Metabolite Rebamipide after Single and Multiple Oral Administration

Dry eye disease (DED) is one of the most common eye diseases caused by multiple factors. Rebamipide, which is currently used to treat peptic ulcer disease, was shown to enhance secretory function and modulate inflammation in animal disease models. Considering the pathophysiology of DED, SA001 was developed expecting enhanced systemic exposure of rebamipide. Clinical trials to evaluate the safety, tolerability and pharmacokinetic (PK) characteristics of SA001 and its active metabolite rebamipide were conducted. After oral administration of SA001, blood and urine samples were collected for PK analysis of SA001 and rebamipide. PK parameters were compared between SA001 and conventional rebamipide (Bamedin®) and also between fasted and fed. Safety and tolerability were evaluated throughout the study based on adverse events (AEs), physical examinations, vital signs, 12-lead electrocardiography and clinical laboratory tests. SA001 was rapidly absorbed and quickly converted to rebamipide. The systemic exposure of rebamipide was dose-proportional after single and multiple doses. The plasma concentration of rebamipide after administration of SA001 was higher with a dose adjusted AUClast and Cmax 2.20 and 5.45 times higher in the 240 mg dose group and 4.73 and 11.94 times higher in the 600 mg dose group compared to conventional rebamipide. The favorable PK and tolerability profiles support further clinical development.

Dry eye disease: A review of anti-inflammatory therapies.

Dry eye disease (DED) is a common chronic ocular disease. DED can have a significant impact on visual function, causing disturbances to comfort, daily activities, and general quality of life. The varied nature of DED makes it difficult to point to a specific cause of the syndrome. However, current literature agrees that the inflammation of the cornea and conjunctiva plays a major role in its pathogenesis. Therapies targeted toward inflammation have shown varied success in the treatment of DED. The purpose of this review is to provide an overview of the prevalence and inflammatory pathophysiology of DED and discussion of the available anti-inflammatory therapies including the following: Nonsteroidal anti-inflammatory drugs, corticosteroids, and other hormonal therapies, nonsteroidal immunomodulators, biological tear replacement, antibiotics, dietary supplements, tea tree oil, and intense pulsed light.

Nanoliposomes for Sensing Local Osmolarity of the Tear Film on the Corneal Surface.

Purpose: Local hotspots of elevated tear hyperosmolarity (exceeding 900 mOsM) are predicted in dry eye disease (DED) but have not been measured. This study aims to develop, characterize, and evaluate the suitability of fluorescent nanoliposomes for noninvasive sensing of the local osmolarity of the tear film. Methods: Fluorescent nanoliposomes, loaded with calcein (susceptible to self-quenching; sensor dye) and sulforhodamine 101 (SR101; reference dye), were produced by the thin-film hydration method. Results: Dynamic light scattering measurements and Cryo-TEM showed that liposomes were negatively charged (-23.7 ± 1.5 mV), spherical (diameter = 117.9 ± 6.4 nm), and uniform in size (polydispersity index = 0.15 ± 0.02). These properties were unaffected by cold storage (4°C; 14 days), but dye leakage was significant after 3 days. Swelling and shrinkage of the liposomes by exposure to hypoosmotic and hyperosmotic media led to rapid dequenching and quenching of calcein fluorescence (FGreen), with no effect on SR101 fluorescence (FRed). The ratio FGreen/FRed decreased with increasing osmolarity and vice versa, obeying the Boyle van't Hoff relationship. When liposomes were dispersed in a gelatin film with dynamic radial sucrose gradients, local FGreen/FRed decreased with increasing hyperosmolarity as predicted. When instilled on the hydrophilic surface of contact lenses or ex vivo corneas, nanoliposomes dispersed evenly as thin films. Importantly, the measured FGreen/FRed declined continuously with evaporation and consequent increase in their osmolarities. Conclusions: The study provides proof of principle for noninvasive measurement of local tear film osmolarity based on osmosensitive fluorescent nanoliposomes. The strategy can potentially advance our understanding of the pathophysiology of DED.

Review on the possible pathophysiological mechanisms underlying visual display terminal-associated dry eye disease.

Visual display terminal (VDT) use is a key risk factor for dry eye disease (DED). Visual display terminal (VDT) use reduces the blink rate and increases the number of incomplete blinks. However, the exact mechanisms causing DED development from VDT use have yet to be clearly described. The purpose of the study was to conduct a review on pathophysiological mechanisms promoting VDT-associated DED. A PubMed search of the literature investigating the relationship between dry eye and VDT was performed, and relevance to pathophysiology of DED was evaluated. Fifty-five articles met the inclusion criteria. Several pathophysiological mechanisms were examined, and multiple hypotheses were extracted from the articles. Visual display terminal (VDT) use causes DED mainly through impaired blinking patterns. Changes in parasympathetic signalling and increased exposure to blue light, which could disrupt ocular homeostasis, were proposed in some studies but lack sufficient scientific support. Together, these changes may lead to a reduced function of the tear film, lacrimal gland, goblet cells and meibomian glands, all contributing to DED development. Visual display terminal (VDT) use appears to induce DED through both direct and indirect routes. Decreased blink rates and increased incomplete blinks increase the exposed ocular evaporative area and inhibit lipid distribution from meibomian glands. Although not adequately investigated, changes in parasympathetic signalling may impair lacrimal gland and goblet cell function, promoting tear film instability. More studies are needed to better target and improve the treatment and prevention of VDT-associated DED.

A Tear Inflammatory Biomarker in Dry Eye Disease

Background: Dry eye disease is a chronic ocular condition and significantly impacts visual function with multifactorial origin. It is characterized by tear instability and inflammation on the ocular surface. The inflammatory response initiates by synthesis and release of cytokines, Recently, there has been increasing scientific interest using tear film biomarkers that play a role in pathophysiology of dry eye disease. The objective of this study to explain relationship of tear film biomarker in dry eye.Methods: The research design of this study used literature review. The data was collected from electronic database in PubMed, Google Scholar, and website of science and predominantly published in the last 10 years.Result: The defect on the tear film component due to oxidative stress lead to ocular surface epithelial exposure, and intracellular signaling pathways are triggered, involving an inflammatory mediator which plays a role in the pathophysiology of dry eye. Using biomarker lead to better diagnosis, drug development, and effective management for dry eye disease.Conclusion: In conclusion, TNF-a, IL-6, IL-8, IL-1 by number studies to consistently reflect disease severity and strong correlation with schirmer tear test and another test for the ocular surface in dry eye disease.

An Improved Ocular Impression Cytology Method: Quantitative Cell Transfer to Microscope Slides Using a Novel Polymer

ABSTRACT Purpose To develop a more efficient impression cytology (IC) method for the transfer of ocular surface cells onto glass microscope slides for cytochemical, immunocytochemical, and immunofluorescence studies. Methods Cells are lifted off the ocular surface with a mixed cellulose ester membrane and then firmly attached to a glass slide using a novel triblock copolymer comprised of collagen type I, polyethylenimine and poly-L-lysine (CPP), and crosslinking cells and glass slide by heating and cooling. The membrane is removed intact after softening it with a butanol/ethanol solution. Transfer of cells is complete in about 10–15 minutes and is ready for staining. The efficiency of our cell transfer method was compared to current methods based on poly-L-lysine and albumin paste. Results Our method ensured almost complete transfer of cells. In contrast, the transfer of rabbit conjunctiva cells onto poly-L-lysine-covered slides was 37.5 ± 6.3% lower, and onto albumin-paste covered slides 62.5 ± 5.6% lower (mean ± SD); the transfer of rabbit goblet cells was even less efficient. The new method was also more efficient for transfer of cells from human oral mucosa obtained by IC. Transferred cells were successfully stained with H&E, chemiluminescence, and immunofluorescence agents. Using our method, we stained ocular surface cells for S100A4 and ATF4, both of which play a role in the pathophysiology of dry eye disease. We obtained similar results with oral mucosal cells, suggesting the generalizability of our approach. We propose an explanation for the strong adhesion of cells to the glass slide, which is based on their interactions with the triblock copolymer. Conclusions We developed a novel approach for the efficient and rapid transfer of cells obtained by IC onto glass microscope slides using a novel copolymer. Compared to available methods, our improved approach makes IC robust and simple, and should increase its diagnostic yield and clinical applicability.

The Correlation Between Non-Invasive Ventilation Use and the Development of Dry Eye Disease.

The use of non-invasive ventilation (NIV) devices such as continuous positive airway pressure and bi-level positive airway pressure machines have been associated with an increased incidence of dry eye disease (DED). To understand how the use of these ventilation masks impacts the eyes, a review of the pathophysiology of DED and an evaluation of recent studies investigating the effects of NIV use on the severity and incidence of this condition were performed. It was found that the use of face masks associated with the ventilation devices exhibited a positive correlation to the incidence and severity of numerous ocular pathologies. However, the benefits of non-invasive mechanical ventilation are undeniable in treating conditions such as obstructive sleep apnea, chronic obstructive pulmonary disease, and respiratory failure; therefore, proper education, behavioral modifications, and treatment can help reduce or prevent the adverse effects that NIV have on the eyes.

Alterations in corneal nerves in different subtypes of dry eye disease: An in vivo confocal microscopy study

PurposeTo evaluate corneal subbasal nerve alterations in evaporative and aqueous-deficient dry eye disease (DED) as compared to controls. MethodsIn this retrospective, cross-sectional, controlled study, eyes with a tear break-up time of less than 10 s were classified as DED. Those with an anesthetized Schirmer's strip of less than 5 mm were classified as aqueous-deficient DED. Three representative in vivo confocal microscopy images were graded for each subject for total, main, and branch nerve density and numbers. ResultsCompared to 42 healthy subjects (42 eyes), the 70 patients with DED (139 eyes) showed lower total (18,579.0 ± 687.7 μm/mm2 vs. 21,014.7 ± 706.5, p = 0.026) and main (7,718.9 ± 273.9 vs. 9,561.4 ± 369.8, p < 0.001) nerve density, as well as lower total (15.5 ± 0.7/frame vs. 20.5 ± 1.3, p = 0.001), main (3.0 ± 0.1 vs. 3.8 ± 0.2, p = 0.001) and branch (12.5 ± 0.7 vs. 16.5 ± 1.2, p = 0.004) nerve numbers. Compared to the evaporative DED group, the aqueous-deficient DED group showed reduced total nerve density (19,969.9 ± 830.7 vs. 15,942.2 ± 1,135.7, p = 0.006), branch nerve density (11,964.9 ± 749.8 vs. 8,765.9 ± 798.5, p = 0.006), total nerves number (16.9 ± 0.8/frame vs. 13.0 ± 1.2, p = 0.002), and branch nerve number (13.8 ± 0.8 vs. 10.2 ± 1.1, p = 0.002). ConclusionsPatients with DED demonstrate compromised corneal subbasal nerves, which is more pronounced in aqueous-deficient DED. This suggests a role for neurosensory abnormalities in the pathophysiology of DED.

The transcriptome of rabbit conjunctiva in dry eye disease: Large-scale changes and similarity to the human dry eye.

The pathophysiology of dry eye disease (DED) remains largely unknown, accounting in part for the lack of successful treatments. We explored the pathophysiology of DED using a rabbit model of chronic DED induced with 3 weekly injections of Concanavalin A into the periorbital lacrimal glands. The transcriptome of full-thickness’s conjunctival tissue from rabbits with DED and from normal controls was determined using microarrays and, as needed, confirmatory real-time polymerase chain reactions. Results were subjected to bioinformatic analysis. DED induced large-scale changes in gene transcription involving 5,184 genes (22% of the total). Differentially expressed genes could be segregated into: functional modules and clusters; altered pathways; functionally linked genes; and groups of individual genes of known or suspected pathophysiological relevance to DED. A common feature of these subgroups is the breadth and magnitude of the changes that encompass ocular immunology and essentially all aspects of cell biology. Prominent changes concerned innate and adaptive immune responses; ocular surface inflammation; at least 25 significantly altered signaling pathways; a large number of chemokines; cell cycle; and apoptosis. Comparison of our findings to the limited extant transcriptomic data from DED patients associated with either Sjogren’s syndrome or non-Sjogren’s etiologies revealed a significant correlation between human and rabbit DED transcriptomes. Our data, establishing the large-scale transcriptomic changes of DED and their potential similarity to the human, underscore the enormous complexity of DED; establish a robust animal model of DED; will help expand our understanding of its pathophysiology; and could guide the development of successful therapeutic strategies.