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Abstract
Dry eye disease can be a consequence of lacrimal gland insufficiency in Sjögren’s Syndrome or increased tear film evaporation despite normal lacrimal gland function. To determine if there is a correlation between severity effects in these models and underlying pathophysiological responses, we compared the time dependent changes in each of these parameters that occur during a 6 week period. Dry eye was induced in 6-week-old female C57BL/6 mice by exposing them to an Intelligently Controlled Environmental System (ICES). Sixty mice were housed in ICES for 1, 2, 4 and 6 weeks respectively. Twelve were raised in normal environment and received subcutaneous injections of scopolamine hydrobromide (SCOP) 3 times daily for 5 days. Another sixty mice were housed in a normal environment and received no treatment. Corneal fluorescein staining along with corneal MMP-9 and caspase-3 level measurements were performed in parallel with the TUNEL assay. Interleukin-17(IL-17), IL-23, IL-6, IL-1, TNF-α, IFN-γ and TGF-β2 levels were estimated by real-time PCR measurements of conjunctival and lacrimal gland samples (LGs). Immunohistochemistry of excised LGs along with flow cytometry in cervical lymph nodes evaluated immune cell infiltration. Light and transmission electron microscopy studies evaluated LGs cytoarchitectural changes. ICES induced corneal epithelial destruction and apoptosis peaked at 2 weeks and kept stable in the following 4 weeks. In the ICES group, lacrimal gland proinflammatory cytokine level increases were much lower than those in the SCOP group. In accord with the lower proinflammatory cytokine levels, in the ICES group, lacrimal gland cytosolic vesicular density and size exceeded that in the SCOP group. ICES and SCOP induced murine dry eye effects became progressively more severe over a two week period. Subsequently, the disease process stabilized for the next four weeks. ICES induced local effects in the ocular surface, but failed to elicit lacrimal gland inflammation and cytoarchitectural changes, which accounts for less dry eye severity in the ICES model than that in the SCOP model.
Highlights
Dry eye (DE) disease therapeutic management can be limited to providing palliative relief since its underlying mechanisms are not fully understood [1,2,3]
aqueous-deficient dry eye (ADDE) is characterized by a lack of tear production and secretion by the lacrimal glands [6], while evaporative dry eye (EDE) is caused by excessive tear evaporation, which leads to tear film instability with normal tear production
The Intelligently Controlled Environmental System (ICES) model is believed to model evaporative dry eye disease whereas the scopolamine model mimics Sjögren’s syndrome mediated lacrimal gland fibrosis and autoimmune rejection resulting in aqueous deficiency [8, 9, 17]
Summary
Dry eye (DE) disease therapeutic management can be limited to providing palliative relief since its underlying mechanisms are not fully understood [1,2,3]. There are two major types of dry eye: aqueous-deficient dry eye (ADDE) and evaporative dry eye (EDE) models used for this purpose [5]. Conditions that underlie the development of the EDE model are becoming more prevalent in the human environment. They include increased exposure to environmental stresses such as excessive air conditioner mediated temperature lowering and emerging dependence on visual display terminal (VDT) usage for work and recreation [7]. More individuals are seeking symptomatic relief from this syndrome because they are becoming more aware of the potential hazards to ocular health maintenance by leaving this disease untreated
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