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Review
. 2023 Dec 1;12(23):2755.
doi: 10.3390/cells12232755.

The Molecular Mechanisms Responsible for Tear Hyperosmolarity-Induced Pathological Changes in the Eyes of Dry Eye Disease Patients

Affiliations
Review

The Molecular Mechanisms Responsible for Tear Hyperosmolarity-Induced Pathological Changes in the Eyes of Dry Eye Disease Patients

Carl Randall Harrell et al. Cells. .

Abstract

Dry eye disease (DED) is a multifactorial disorder of the lacrimal system and ocular surface, characterized by a deficiency in the quality and/or quantity of the tear fluid. The multifactorial nature of DED encompasses a number of interconnected underlying pathologies, including loss of homeostasis, instability and hyperosmolarity of the tears, and the induction and propagation of detrimental inflammatory responses in the eyes, which finally results in the development of neurosensory dysfunction and visual disruption. Dryness, grittiness, scratchiness, discomfort, inflammation, burning, watering, ocular fatigue, pain, and decreased functional visual acuity are common symptoms of DED. Eye dysfunction drastically attenuates patients' quality of life. Accordingly, a better understanding of the pathogenic processes that regulate the development and progression of DED is crucially important for the establishment of new and more effective DED-related treatment approaches, which would significantly improve the quality of life of DED patients. Since the process of osmoregulation, which guards the ocular surface epithelia and maintains normal vision, is affected when the osmolarity of the tears is greater than that of the epithelial cells, tear hyperosmolarity (THO) is considered an initial, important step in the development, progression, and aggravation of DED. In order to delineate the role of THO in the pathogenesis of DED, in this review article, we summarize current knowledge related to the molecular mechanisms responsible for the development of THO-induced pathological changes in the eyes of DED patients, and we briefly discuss the therapeutic potential of hypo-osmotic eye drops in DED treatment.

Keywords: corneal epithelial cells; dry eye disease; eye inflammation; hypo-osmotic eye drops; tear hyperosmolarity.

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Conflict of interest statement

Author C.R.H. was employed by the company Regenerative Processing Plant. The remaining authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Crucial factors contributing to the development of THO and DED. Hormones, medicaments, environmental factors, dysfunctional neural regulation of lacrimal gland secretion, poor aqueous tear flow, and excessive tear evaporation result in the development of THO. THO induces increased activation and maturation of dendritic cells, which generates a detrimental Th1 and Th17 cell-driven immune response in the eyes of DED patients. Through the production of inflammatory cytokines, Th1 and Th17 cells induce inflammation, which causes injury to the epithelial and goblet cells in the eyes of DED patients. The loss of goblet, corneal, and conjunctival epithelial cells results in excessive tear evaporation and tear film instability, which crucially contribute to the development of THO and DED.
Figure 2
Figure 2
THO-induced changes in the phenotype and function of CECs. Apoptotic cell death is observed in THO-exposed CECs. THO induces stress in the ER and promotes mitochondrial damage by enhancing Fas- and TRAIL-dependent activation of caspase-3, capsase-8, and caspase-9, which results in apoptosis of THO-exposed CECs. Additionally, THO promotes an increased expression of E and P selectins and induces an enhanced production of inflammatory cytokines (TNF-α, IL-1β, IL-6) in CECs, which results in a massive influx of circulating immune cells in inflamed eyes of DED patients, resulting in the aggravation of ongoing inflammation.
Figure 3
Figure 3
Detrimental immune response in the eyes of DED patients. Increased expressions of MHC proteins and co-stimulatory molecules were noticed in eye-infiltrated DCs of DED patients. DCs of DED patients have increased capacities for the production of inflammatory, pro-Th1 (IL-12), and pro-Th17 cytokines (IL-1β, IL-6, IL-12, IL-23), crucially contributing to the generation of detrimental Th1 and Th17 cell-driven immune responses. Accordingly, an increased number of IFN-γ-producing Th1, NK, and NKT cells and an increased number of IL-17- and IL-22-producing Th17 cells were observed in the eyes of DED patients. Additionally, THO promotes NETosis in eye-infiltrated neutrophils, importantly contributing to the progression of DED.
Figure 4
Figure 4
Therapeutic potential of hypo-osmotic eye drops in DED treatment. THO induces dehydration and consequent injury of CECs. Hypo-osmotic eye drops contain a lower concentration of salt and other solutes compared to the tears on the ocular surface. Accordingly, hypo-osmotic eye drops restore the natural osmotic balance of the ocular surface, improve tear film function, and attenuate THO-induced damage of the corneal epithelial barrier.

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