Abstract
Dry eye syndrome (DES) is characterized by decreased tear production and stability, leading to desiccating stress, inflammation and corneal damage. DES treatment may involve targeting the contributing inflammatory pathways mediated by polyunsaturated fatty acids and their derivatives, oxylipins. Here, using an animal model of general anesthesia-induced DES, we addressed these pathways by characterizing inflammatory changes in tear lipidome, in correlation with pathophysiological and biochemical signs of the disease. The decline in tear production was associated with the infiltration of inflammatory cells in the corneal stroma, which manifested one to three days after anesthesia, accompanied by changes in tear antioxidants and cytokines, resulting in persistent damage to the corneal epithelium. The inflammatory response manifested in the tear fluid as a short-term increase in linoleic and alpha-linolenic acid-derived oxylipins, followed by elevation in arachidonic acid and its derivatives, leukotriene B4 (5-lipoxigenase product), 12-hydroxyeicosatetraenoic acid (12-lipoxigeanse product) and prostaglandins, D2, E2 and F2α (cyclooxygenase products) that was observed for up to 7 days. Given these data, DES was treated by a novel ophthalmic formulation containing a dimethyl sulfoxide-based solution of zileuton, an inhibitor of 5-lipoxigenase and arachidonic acid release. The therapy markedly improved the corneal state in DES by attenuating cytokine- and oxylipin-mediated inflammatory responses, without affecting tear production rates. Interestingly, the high efficacy of the proposed therapy resulted from the synergetic action of its components, namely, the general healing activity of dimethyl sulfoxide, suppressing prostaglandins and the more specific effect of zileuton, downregulating leukotriene B4 (inhibition of T-cell recruitment), as well as upregulating docosahexaenoic acid (activation of resolution pathways).
Highlights
Dry eye syndrome (DES; known as dry eye, dry eye disease, or keratoconjunctivitis sicca) is a common multifactorial ocular surface disease, characterized by decreased production/increased evaporation of the tear, resulting in its hyperosmolarity and instability of the tear film [1]
To induce DES, the animals within all the experimental groups were exposed to six hours of general anesthesia in accordance with the approach developed in our previous study [6]
Cracks and folds of preparations arethat of an origin.process in our DES model involved ocular surface inflammation, We concluded theartificial pathological reaching a maximum on day one after anesthesia, which was accompanied by a decline in tear production
Summary
Dry eye syndrome (DES; known as dry eye, dry eye disease, or keratoconjunctivitis sicca) is a common multifactorial ocular surface disease, characterized by decreased production/increased evaporation of the tear, resulting in its hyperosmolarity and instability of the tear film [1]. The desiccating stress leads to compensatory reflex stimulation of the lachrymal gland, which may activate a neurogenic inflammatory cytokine response [3,8] These events induce maturation and an increase in the density of antigen-presenting dendritic cells in the cornea, subsequent activation of T-cells and their recruitment to the ocular surface (including conjunctiva and lacrimal glands) and release of additional effector cytokines in the TF, thereby causing further damage to the corneal epithelium [3,13]. UPLC-MS/MS-based approach to identify and characterize baseline patterns of lipid mediators in the TF of healthy rabbits and demonstrated that they did not differ significantly from that of human TF [29] We employed these approaches to characterize TF lipidomic changes in DES, focusing on PUFAs, oxylipins and phospholipid derivatives contributing to the regulation of inflammation, and to find correlations between these changes and the pathophysiological and biochemical signs of the disease. Biochemical and lipidomic studies, this therapy was found to markedly improve the corneal state in DES by selective suppression of its inflammatory component, without affecting tear production rates
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