[Cell technologies as a basis for the development of regenerative principles for the treatment of lacrimal gland diseases]. / Kletochnye tekhnologii kak osnova razrabotki regeneratornykh printsipov lecheniya zabolevanii sleznoi zhelezy.

The lacrimal gland (LG) is a tubuloacinar exocrine gland composed of acinar, ductal, and myoepithelial cells. Three-dimensional distribution of acinar lobules, ducts, and myoepithelial cells is necessary for the effective functioning of the organ. LG is the main organ of immune surveillance of the ocular surface system. The embryogenesis of the gland is regulated by the interaction of genetic mechanisms, internal epigenetic (enzyme systems, hormones) and exogenous factors. There is no doubt that there is a clear genetic program for the implementation of the complex process of embryonic development. The mechanisms regulating LG organogenesis initiate the work of a huge number of structural oncogenes, transcription and growth factors, etc. Studying the expression and selective activity of regulatory genes during organ development, their participation in the differentiation of different cell types is a current trend at the nexus of clinical genetics, molecular biology, embryology and immunocytochemistry. Due to its relatively simple structure and accessibility, human LG is a suitable object for potential application in regenerative medicine. Development of a universal protocol for obtaining functional differentiated secretory epithelium of LG capable of expressing tissue-specific markers is an urgent task. Determining the nature and origin of stem cells and progenitor cells will allow the isolation and multiplication of these cells in culture. After obtaining a functionally active culture of LG cells, it is possible to create a model of autoimmune diseases.

Novel findings on the anatomy of medial canthus in dogs.

PURPOSE: Severe entropion of the medial canthus results in ocular surface diseases and tear staining syndrome. However, detailed anatomical structures of the medial canthus and lacrimal ducts in dogs are poorly understood. We aimed to understand the anatomical structures of the medial canthus by analyzing the distances from the medial palpebral commissure to the superior lacrimal punctum (DSP) and to the inferior lacrimal punctum (DIP) and by histological examinations of the medial canthal anatomy. METHODS: Dogs that underwent modified medial canthoplasty (MMC) between April 2017 and March 2021 were studied. As a reference, non-brachycephalic dogs that underwent other surgeries were also examined. DSP and DIP were measured preoperatively in all dogs in both the non-everted and everted positions. Histological examinations of the medial canthal anatomy were performed in four eyes isolated from beagles. RESULTS: The ratios of DIP to DSP (mean ± SD) at the non-everted and everted positions in 242 MMC eyes of 126 dogs were 2.05 ± 0.46 and 1.05 ± 0.13, respectively (p < .01). The ratios of everted to non-everted positions for DIP and DSP were 0.98 ± 0.21 and 1.93 ± 0.49, respectively (p < .01). Histological findings indicated that the orbicularis oculi muscle (OOM) circumjacent lacrimal canaliculus transformed into collagen fibers and were attached to the lacrimal bone. CONCLUSIONS: Histological studies revealed that the OOM circumjacent lacrimal canaliculus transformed into collagen fibers and these collagen fibers may be related to the difference between DSP and DIP.

Microbial Reconstitution Improves Aging-Driven Lacrimal Gland Circadian Dysfunction.

Lacrimal glands are highly susceptible to aging and exhibit age-related structural and functional alterations. However, the mechanisms by which aging affects the lacrimal glands are not well-established. The current study explores the crosstalk between the aging process, gut microbiota, and circadian rhythm in age-associated lacrimal gland dysfunction. C57BL/6J mice were divided into young, old, and fecal microbiota transplant (FMT)-treated old groups. The gut bacterial community diversity was analyzed by 16S rRNA sequencing. Exorbital lacrimal glands (ELGs) were collected at 3-hour intervals over a 24-hour circadian cycle, and total RNA was subjected to high-throughput sequencing. Rhythmic transcriptional data were analyzed using the Jonckheere-Terpstra-Kendall algorithm and bioinformatics analysis technology. Immunostaining was used to identify lymphocytic infiltration, lipid deposition, and nerve innervation in the ELGs. Compared with young mice, old mice underwent a significant gut microbial community shift. The rhythmically transcriptomic profile was significantly reprogrammed over a 24-hour cycle in the old ELG group. Intervention with serial FMT from young donors for 1 month rejuvinated the gut microbial community of the old mice. Most alterations in rhythmic transcriptomic profiling were improved. Furthermore, chronic inflammation, lipid deposition, and aberrant neural response of the aging lacrimal glands were significantly reduced. Thus, the study shows that reconstitution of age-associated gut dysbiosis with FMTs from young donors improves aging-driven lacrimal gland circadian dysfunction.

Acute Inhibitory Effects of Antidepressants on Lacrimal Gland Secretion in the Anesthetized Rat.

Purpose: Patients that medicate with antidepressants commonly report dryness of eyes. The cause is often attributed to the anticholinergic properties of the drugs. However, regulation of tear production includes a substantial reflex-evoked component and is regulated via distinct centers in the brain. Further, the anticholinergic component varies greatly among antidepressants with different mechanisms of action. In the current study it was wondered if acute administration of antidepressants can disturb production of tears by affecting the afferent and/or central pathway. Methods: Tear production was examined in vivo in anesthetized rats in the presence or absence of the tricyclic antidepressant (TCA) clomipramine or the selective serotonin reuptake inhibitor (SSRI) escitalopram. The reflex-evoked production of tears was measured by challenging the surface of the eye with menthol (0.1 mM) and cholinergic regulation was examined by intravenous injection with the nonselective muscarinic agonist methacholine (1-5 µg/kg). Results: Acute administration of clomipramine significantly attenuated both reflex-evoked and methacholine-induced tear production. However, escitalopram only attenuated reflex-evoked tear production, while methacholine-induced production of tears remained unaffected. Conclusions: This study shows that antidepressants with different mechanisms of action can impair tear production by attenuating reflex-evoked signaling. Further, antimuscarinic actions are verified as a likely cause of lacrimal gland hyposecretion in regard to clomipramine but not escitalopram. Future studies on antidepressants with different selectivity profiles and mechanisms of action are required to further elucidate the mechanisms by which antidepressants affect tear production.

Randomized, crossover clinical efficacy trial in humans and mice on tear secretion promotion and lacrimal gland protection by molecular hydrogen.

The incidence of dry eye disease is increasing worldwide because of the aging population and increasing use of information technology. Dry eye disease manifests as tear-layer instability and inflammation caused by osmotic hypersensitization in tear fluids; however, to our knowledge, no agent that treats both pathologies simultaneously is available. Molecular hydrogen (H2) is known to be effective against various diseases; therefore, we aimed to elucidate the effects of H2 on tear dynamics and the treatment of dry eye disease. We revealed that administering a persistent H2-generating supplement increased the human exhaled H2 concentration (p < 0.01) and improved tear stability (p < 0.01) and dry eye symptoms (p < 0.05) significantly. Furthermore, H2 significantly increased tear secretion in healthy mice (p < 0.05) and significantly suppressed tear reduction in a murine dry eye model (p = 0.007). H2 significantly and safely improved tear stability and dry eye symptoms in a small exploratory group of 10 human subjects, a subset of whom reported dry eye symptoms prior to treatment. Furthermore, it increased tear secretion rapidly in normal mice. Therefore, H2 may be a safe and effective new treatment for dry eye disease and thus larger trials are warranted.

Lateral Canthal Sling Procedure for Meibomian Gland Dysfunction? Results of a Pilot Study.

Background: Involutional changes of lid structures often induce horizontal lid laxity; this can result in a reduction of Meibomian gland expression, potentially leading to symptoms of dry eye. The aim of this study was to evaluate the effect of tightening the lower eyelid via a lateral canthal sling (LCS) procedure on dry eye parameters.Methods: Patients with Meibomian Gland Dysfunction (MGD), lower lid laxity (positive Snap-back Test and positive Pinch Test) and no previous lid surgery were evaluated before and 3 months after LCS procedure for symptoms by OSDI. The fellow eye without surgery functioned as a control group. MGD parameters included lipid layer thickness (LLT), non-invasive breakup time (NIBUT), tear meniscus height, loss of Meibomian glands, lid margin parallel conjunctival folds (LIPCOFs), Schirmer's test, the number of expressible Meibomian glands as well as quality of Meibum.Results: Fourteen patients (8 men and 6 women; 79.2 ± 4.0 years) were enrolled in this prospective clinical study. After 3 months, the OSDI showed a significant reduction (preop 42.9 ± 24.7; postop 23.8 ± 21.6; p = .002); NIBUT (5.5 ± 2.6 s to 9.9 ± 6.8 s p = .08) and LLT (64.3 ± 30.4 to 74.1 ± 27.8; p = .025) improved, while Schirmer Test (15.3 ± 4.7 mm to 11.9 ± 2.9 mm; p = .03) and tear meniscus height were reduced (0.8 ± 0.3 to 0.6 ± 0.2; p = .05). Meibomian gland loss scored by the meiboscale slightly increased postoperatively (1.2 ± 0.9 to 1.4 ± 0.9; p = .18). The number of expressible Meibomian glands improved (4.4 ± 2.6 to 6.8 ± 2.1, p = .002) as well as the quality of Meibum (0.9 ± 1.0 to 0.5 ± 0.8, p = .04). Snap back test as well the pinch test were negative in all patients postoperatively.Conclusion: Addressing lower lid laxity with an LCS procedure simultaneously enhances tear drainage, reduces tear film volume parameters and increases tear film stability results with an improvement of dry eye symptoms. It is likely that increased lower eyelid tension and thus excretory pressure on the Meibomian glands is responsible for these alterations.

Investigation of the effect of the dual orexin receptor antagonist almorexant on ophthalmological, spermatogenic, and hormonal variables in healthy male subjects.

BACKGROUND/AIMS: The aim of this single-center, double-blind study was to investigate the effect of a 4-week once daily administration of 200 mg almorexant on tear film break-up time, spermatogenesis, hormone levels, and pancreatic elastase in stool in healthy male subjects. METHODS: Almorexant 200 mg or matching placebo was administered in the evening for 4 weeks once daily to 56 healthy male subjects. Changes in ophthalmological variables, sperm composition, hormone levels, and pancreatic elastase levels in stool were evaluated periodically up to 8 weeks after discontinuation of drug administration. Blood samples for pharmacokinetic measurements were taken after 4 weeks to confirm compliance to study drug intake. RESULTS: The results of this study revealed no treatment effects of almorexant, neither on tear film break-up time nor on other ophthalmological variables investigated during this study. Furthermore, spermatogenesis, hormones of the hypothalamic-pituitary-adrenal and -gonadal axes, and endocrine pancreatic secretion were shown to be not affected by a 4-week once daily administration of almorexant. CONCLUSION: Almorexant was well tolerated and had no effect on the spectrum of pharmacodynamic variables assessed. Ophthalmology and testicular findings detected in preclinical studies were not observed in this clinical study. Therefore, these preclinical findings appear not to be relevant for humans and do not prevent from conducting larger clinical trials with either healthy subjects or patients.

THC Regulates Tearing via Cannabinoid CB1 Receptors.

Purpose: Aqueous deficiency dry eye (ADDE) is a chronic condition affecting millions, with symptoms ranging from a dry itchiness to blurred vision and accompanied by an increased risk of eye infections. ADDE typically arises from disorders of the lacrimal gland that produces tears necessary for eye lubrication. Cannabis users frequently report dry eye, but the basis for this is unknown. If the effects occur via the endogenous cannabinoid signaling system, then this may represent a novel mechanism for the regulation of tearing. Methods: We examined expression of cannabinoid CB1 receptors in the lacrimal gland using immunohistochemistry, Western blotting, and PCR and tested tetrahydrocannabinol (THC) regulation of tearing in wild-type and CB1-null mice. Results: We now report that CB1 receptors are expressed in the axons of cholinergic neurons innervating the lacrimal gland. Little if any staining is seen in lacrimal gland epithelial cells (acinar and ductal) or myoepithelial cells (MECs). Activation of CB1 receptors by THC or the cannabinoid agonist CP55940 reduces tearing in male mice. In female mice, THC has no effect, but CP55940 increases tearing. In both sexes, the effect of CP55940 is absent in CB1 knockout mice. CB1 mRNA and protein levels are approximately four- to fivefold higher in males than females. In male knockouts, THC increases tearing, suggesting that THC also acts through different receptors. Conclusions: Our results suggest a novel, albeit sex-dependent, physiologic basis for the dry eye symptoms experienced by cannabis users: activation of neuronal CB1 receptors in the lacrimal gland reduces tearing.

Comparative Analysis of Age-Related Changes in Lacrimal Glands and Meibomian Glands of a C57BL/6 Male Mouse Model.

It is not known how biological changes in the lacrimal (LGs) and meibomian (MGs) glands contribute to dry eye disease (DED) in a time-dependent manner. In this study, we investigated time-sequenced changes in the inflammation, oxidative stress, and senescence of stem cells in both glands of an aging-related DED mouse model. Eight-week (8W)-, one-year (1Y)-, and two-year (2Y)-old C57BL/6 male mice were used. MG areas of the upper and lower eyelids were analyzed by transillumination meibography imaging. The number of CD45+, 8-OHdG+, Ki-67+, and BrdU+ cells was compared in both glands. Increased corneal staining and decreased tear secretion were observed in aged mice. The MG dropout area increased with aging, and the age-adjusted MG area in lower lids was negatively correlated with the National Eye Institute (NEI) score. Increased CD4+ interferon (IFN)-γ+ cells in LGs were found in both aged mice. An increase in 8-OHdG+ cells in both glands was evident in 2Y-old mice. Reduced Ki-67+ cells, but no change in CD45+ cells, was observed in the MGs of 1Y-old mice. Increased BrdU+ cells were observed in the LGs of aged mice. This suggests that age-dependent DED in C57BL/6 mice is related to inflammation of the LGs, the development of MG atrophy, and oxidative stress in both glands.

The Human Lacrimal Gland: Historical Perspectives, Current Understanding, and Recent Advances.

PURPOSE: The lacrimal glands produce the aqueous component of the pre-ocular tear film, which is essential for ocular health and optimal vision. This review explores its history, current understanding, recent advances, and scope for future research. METHODS: The authors reviewed the major studies discussing the history of lacrimal glands and their anatomical description, including microscopic anatomy, innervation patterns, imaging, and ongoing translational research. RESULTS: The review traces the evolution of human knowledge about the source of tears across several millennia, with specific emphasis on the individuals who made seminal contributions to this field. It provides a detailed update on the morphology, microscopic structure, innervation, vascular supply, and imaging modalities of both the main and accessory lacrimal glands. The review also summarizes the recent advances in lacrimal gland regeneration and repair for the treatment of dry eye disease, particularly the role of mesenchymal stem cells. Lastly, the review gazes into the future of lacrimal gland research, which aims at translating the existing laboratory knowledge into clinical application, with the possibility of transplanting in vitro cultivated lacrimal constructs or the use of cell-based therapies for in situ repair of diseased human lacrimal glands. CONCLUSIONS: Knowledge about the lacrimal glands in health and disease has improved tremendously since its discovery in the mid-eighteenth century. Today we stand at the cusp of exploring potential regenerative approaches for the treatment of lacrimal gland damage in dry eye disease.

Deterioration of contrast sensitivity in eyes with epiphora due to lacrimal passage obstruction.

PURPOSE: Epiphora causes deterioration in contrast sensitivity in some eye diseases. This study was conducted to investigate contrast sensitivity in eyes with epiphora caused by lacrimal passage obstruction. METHODS: This single-center, prospective case series enrolled 57 patients with unilateral lacrimal passage obstruction. The best-corrected visual acuity (BCVA), contrast sensitivity function, and lower tear meniscus of the affected and contralateral unaffected eyes were compared. The area under the log contrast sensitivity function (AULCSF) was calculated. RESULTS: The BCVA did not significantly differ between the affected and contralateral eyes, while the AULCSF was significantly lower in the affected eyes than that in the contralateral eyes (median 1.35, interquartile range 1.22-1.44 vs. median 1.36, interquartile range 1.28-1.46, P = 0.032). Lower tear meniscus parameters were significantly higher in the affected eyes than those in the contralateral eyes (P < 0.005). CONCLUSIONS: The contrast sensitivity function is significantly diminished in eyes with epiphora caused by lacrimal passage obstruction.

Adding myofibroblasts to the lacrimal pump.

The lacrimal sac (LS) empties in the nasolacrimal duct to drain the tears in the inferior nasal meatus. Different studies indicated the role of the lacrimal pump in the lacrimal drainage. Although controversial, the lacrimal pump mechanism is an extrinsic one, either active, or passive. An intrinsic contractile potential of the LS was not documented previously. We thus aimed a retrospective immunohistochemical study to test the alpha-smooth muscle actin (α-SMA) and h-caldesmon expression in the LS wall. We used archived paraffin-embedded samples of LS from ten adult patients. The α-SMA + phenotype was detected in basal epithelial cells, in subepithelial ribbons of stromal cells, in vascular smooth muscle cells, as well as in pericytes. H-caldesmon was exclusively expressed in pericytes, vascular smooth muscle cells and myoepithelial cells of the subepithelial glands. The most striking feature we found in all samples was a consistent stromal network of α-SMA+/h-caldesmon- myofibroblasts. This finding supports an intrinsic scaffold useful for the lacrimal pump.

Lacrimal drainage function after cheese wiring of lacrimal passage intubation.

PURPOSE: To investigate how cheese wiring affects lacrimal drainage function by quantitative assessment of tear function and punctal dimensions. METHODS: Patients who underwent lacrimal passage intubation between January 2017 and September 2018 were enrolled prospectively. Among these patients, those with postoperative cheese wiring who received lacrimal passage intubation in one eye met the criteria for further investigation. The subjective symptoms of epiphora, dimensions of puncta, lower tear meniscus, and tear clearance were assessed postoperatively in both the involved eye and untreated contralateral eye. Punctum dimensions were analysed using the digital slit-lamp image. Tear meniscus and tear clearance were assessed by anterior segment optical coherence tomography. RESULTS: Postoperative cheese wiring was observed in 68 of 314 eyes. Among these cases, 36 patients (age 70.5 ± 11.7 years) had cheese wiring only in one eye: with the involvement of both puncta in 15 patients (group A) and only the lower punctum in 21 patients (group B). There was no patient with the involvement of only the upper punctum. While tear function of the involved eyes in group B did not differ from that of the untreated eye, it was significantly decreased in group A compared with that in untreated control eyes (p < 0.05). The tear clearance rate correlated significantly with the upper punctum dimensions (p < 0.05), but not with the lower punctum. CONCLUSION: Analysis of cheese wiring after lacrimal passage intubation with tear function demonstrated that the integrity of the puncta and the canaliculus is important for lacrimal drainage.

Rebamipide promotes lacrimal duct epithelial cell survival via protecting barrier function.

Nasolacrimal duct obstruction (NLDO) is thought to be due to inflammation and fibrosis of lacrimal duct epithelial cells (LDECs). Here we investigated the effect of rebamipide, a drug that is used for the protection of the mucosa and the treatment of gastritis and gastroduodenal ulcers, on LDECs, both in vitro and in vivo. In this study, LDECs were cultured from rabbit lacrimal duct tissues, and the barrier function of LEDCs was examined in vitro via transepithelial electrical resistance (TER) measurement, with or without interleukin (IL)-6 and/or rebamipide. For the in vivo examination, benzalkonium chloride (BAC) was injected into the rabbit lacrimal ducts, followed by the application of rebamipide or a placebo vehicle alone. The results of the in vitro examination revealed a significant decrease in TER in the group treated with IL-6 alone compared with the placebo-vehicle group (p < 0.05) and the group treated with IL-6 and rebamipide (p < 0.01). The results of the in vivo examination revealed that the infiltration of neutrophils under the basement membrane and the disruption of tight junction proteins with BAC injection and rebamipide attenuates the disturbance of tissue construction. These results suggest that rebamipide protects LDECs via an anti-inflammatory effect and preserves the barrier function of those cells.

Microarray Data of Lacrimal Gland Implicates Dysregulated Protein Processing in Endoplasmic Reticulum in Graves' Ophthalmopathy.

Graves' ophthalmopathy (GO) has become one of the most common orbital diseases. Although some evidences announced the potential mechanism of pathological changes in extraocular muscle and orbital adipose tissue, little is known about that in lacrimal enlargement of GO patients. Thus, gene expression profiles of lacrimal gland derived from GO patients and normal controls were investigated using the microarray datasets of GSE105149 and GSE58331. The raw data and annotation files of GSE105149 and GSE58331 were downloaded from Gene Expression Omnibus (GEO) database. Bioinformatics including differentially expressed genes (DEGs), Gene Ontology, Kyoto Encyclopedia of Gene and Genome (KEGG) pathway, protein-protein interaction (PPI) network construction, hub gene identification, and gene set variation analysis (GSVA) were successively performed. A total of 173 overlapping DEGs in GSE105149 and GSE58331 were screened out, including 20 up-regulated and 153 down-regulated genes. Gene Ontology, KEGG and GSVA analyses of these DEGs showed that the most significant mechanism was closely associated with endoplasmic reticulum (ER). Moreover, we identified 40 module genes and 13 hub genes which were also enriched in the ER-associated terms and pathways. Among the hub genes, five genes including HSP90AA1, HSP90B1, DNAJC10, HSPA5, and CANX may be involved in the dysfunction of protein processing in ER. Taken together, our observations revealed a dysregulated gene network which is essential for protein processing in ER in GO patients. These findings provided a potential mechanism in the progression of lacrimal enlargement in GO patients, as a new insight into GO pathogenesis.

Age- and sex-associated changes in prosaposin and its receptors in the lacrimal glands of rats.

Prosaposin, a saposin precursor, is a potent neurotrophic factor found in several tissues and various biological fluids. Saposin-deficient patients have different ophthalmic disorders, indicating a relationship between ocular health and prosaposin. However, there is little information about prosaposin on the ocular surface. Because ocular functions are diverse and depend on age and sex, we examined whether prosaposin and its receptors, G protein-coupled receptor 37 (GPR37) and GPR37L1, are expressed in the major ocular glands, the extra orbital lacrimal gland (ELG), and harderian gland (HG) of rats and whether sex and aging affect their expression. Immunohistochemical analyses revealed that prosaposin and its receptors were expressed in the ELGs and HGs of rats, although their expression varied based on the type of gland, age, and sex. Prosaposin, GPR37, and GPR37L1 were expressed in the basolateral membranes and cytoplasm of acinar cells of the ELGs, and their immunoreactivities were higher in female rats of menopausal age than age-matched male rats. However, such age- and sex-related differences in the immunoreactivities of prosaposin, GPR37, and GPR37L1 were not observed in the HGs. Triple immunofluorescence labelling revealed that prosaposin, GPR37, and GPR37L1 were co-localised in the acinar and ductal cells in the ELGs, although the degrees of colocalization varied according to the age and sex of the rats. Together, the present results showed that prosaposin and its receptors were expressed in the major ocular glands of rats, and their immunoreactivities to the ELGs differed considerably with age and sex.

MSC Transplantation Improves Lacrimal Gland Regeneration after Surgically Induced Dry Eye Disease in Mice.

Dry eye disease (DED) is a multifactorial disease characterized by a disrupted tear film homeostasis and inflammation leading to visual impairments and pain in patients. Aqueous-deficient dry eye (ADDE) causes the most severe progressions and depends mainly on the loss of functional lacrimal gland (LG) tissue. Despite a high prevalence, therapies remain palliative. Therefore, it is of great interest to develop new approaches to curatively treat ADDE. Mesenchymal stem/stromal cells (MSC) have been shown to induce tissue regeneration and cease inflammation. Moreover, an increasing amount of MSC was found in the regenerating LG of mice. Therefore, this study investigated the therapeutic effect of MSC transplantation on damaged LGs using duct ligation induced ADDE in mice. Due to the transplantation of sex-mismatched and eGFP-expressing MSC, MSC could be identified and detected until day 21. MSC transplantation significantly improved LG regeneration, as the amount of vital acinar structures was significantly increased above the intrinsic regeneration capacity of control. Additionally, MSC transplantation modulated the immune reaction as macrophage infiltration was delayed and TNFα expression decreased, accompanied by an increased IL-6 expression. Thus, the application of MSC appears to be a promising therapeutic approach to induce LG regeneration in patients suffering from severe DED/ADDE.

The Tear Function in Electronic Cigarette Smokers.

SIGNIFICANCE: Prominent ocular surface dryness and poor tear film quality among electronic cigarette (e-cigarette) smokers (or vapers) indicate potential harm to the eyes from vaping. These findings may serve as precautionary signs for e-cigarette users and exposed bystanders. PURPOSE: Little is known about the effect of e-cigarettes on the eyes except for reported eye irritation among individuals who were exposed to e-cigarette vapors and e-liquids. This study aims to investigate the effect of vaping on ocular surface health of long-term vapers. METHODS: Twenty-one vapers and 21 healthy nonsmokers who are all male underwent measurements of the Ocular Surface Disease Index, noninvasive tear breakup time, fluorescein breakup time, ocular surface staining, tear meniscus height, and the Schirmer test. The effect of voltage used during vaping was also evaluated against the measurements. RESULTS: Vapers experienced moderate-to-severe eye dryness (25.0 [interquartile range, 14.6 to 43.7]) as indicated by the Ocular Surface Disease Index. Significant reductions of noninvasive tear breakup time (3.13 ± 0.97 vs. 6.57 ± 2.31 seconds; P < .0001), fluorescein breakup time (2.68 [interquartile range, 2.33 to 3.18] vs. 4.12 [3.56 to 5.07] seconds; P < .0001), and tear meniscus height (203.0 [193.0 to 225.5] vs. 235.0 [210.0 to 253.50] µm; P = .002) were noted in vapers, but the Schirmer test showed higher results (14.5 [12.0 to 17.0] vs. 8.0 [7.0 to 11.0] mm; P = .001) compared with nonsmokers. Increase in vaping voltage aggravated the dry eye symptoms and tear instability (P < .05). Higher Schirmer test result was also noted as voltage increases. CONCLUSIONS: Vapers showed moderate-to-severe symptomatic dry eye and poorer tear film quality compared with nonsmokers. High vaping voltage may have aggravated the dry eye syndrome because of hazardous by-products from pyrolysis of the e-liquid constituents. Investigation of the ocular surface health at cellular and molecular levels is warranted to gain a deeper understanding on the effect of e-cigarette to the eyes.

Effect of Melatonin and Its Analogs on Tear Secretion.

Melatonin has been shown to enhance tear secretion associated with dinucleotide diadenosine tetraphosphate. This study investigated the isolated action of melatonin and its analogs, agomelatine, N-butanoyl-2-(2-methoxy-6H-isoindolo[2,1-a]indol-11-yl) ethanamine (IIK7), and 5-methoxycarbonylamino-N-cetyltryptamine (5-MCA-NAT) (10 µl at 100 µM), on tear secretion when applied topically in the rabbit cornea and its relationship with the melatonin MT1, MT2, and MT3/quinone reductase QR2 receptors. The results showed a significant increase in tear secretion, with a maximal effect at 60 minutes for the agonists (138.9% ± 6.5%, 128.9% ± 6.4%, and 120.0% ± 5.2%, respectively; P < 0.05; 100% control) but not for melatonin (101.6% ± 7.9%; P > 0.05). Agonist action was tested combined with the antagonists DH97 (MT2 selective), prazosin (MT3/QR2 inhibitor), and luzindole (nonselective MT membrane receptor) (10 µl at 100 µM). DH97 reversed the effect of agomelatine, IIK7, and 5-MCA-NAT up to 30.85% ± 7.6%,108% ± 7.2%, and 87.01% ± 7.6%, respectively (P < 0.05; 100% control). Luzindole antagonized agomelatine and 5-MCA-NAT up to 67.35% ± 7.6% and 92.12% ± 8%, respectively (P < 0.05). Prazosin only reversed 5-MCA-NAT action up to 84.2% ± 7.7% (P < 0.05). These results suggest different pathways for the agonists to act through MT membrane receptors. Therefore, agomelatine, IIK7, and 5-MCA-NAT act through MT membrane receptors as secretagogues of tear secretion, and these analogs could be considered excellent therapeutic candidates for dry eye treatment. SIGNIFICANCE STATEMENT: Currently, dry eye with aqueous deficit is treated by adding artificial tears palliatively. This study shows that topical installation of three melatonin analogs (agomelatine, IIK7, and 5-MCA-NAT), but not melatonin, in therapeutic doses in the rabbit cornea significantly increases tear production, acting through different melatonin membrane receptor subtypes. Therefore, this study suggests that melatoninergic compounds could be considered excellent therapeutic candidates for dry eye treatment and ocular surface diseases occurring with a reduction in tear production.