Osmotic stress caused by an increased extracellular osmolarity is a common feature of dry eye conditions and is the consequence of an increase in tear film evaporation or a decrease in tear secretion.
38 Several investigators have attempted to determine whether elevated tear film osmolarity could be correlated with ocular surface disease.
38 39 Gilbard and Farris reported a significant positive correlation between tear film osmolarity and rose bengal staining in a group of patients with dry eye disease before and after treatment with isotonic and one-half isotonic saline.
40 A recent report has shown in human corneal epithelial cells that hyperosmotic stress stimulates the production of matrix metalloproteinases, which may promote inflammation by cleavage of precursors of proinflammatory factors into their active forms, suggesting that hyperosmotic stress may cause inflammation.
41 However, the mechanism(s) by which hyperosmolarity affect surface integrity in ocular surface epithelial cells remains unclear. Compared with Na
+ (133.2 ± 0.2 mM), the concentration of Ca
+2 (0.80 ± 0.04 mM) and Mg
+2 (0.61 ± 0.03 mM) in normal tears is relatively small.
38 We hypothesize that an alteration in the balance of Ca
+2 and Mg
+2 ions in tears produces damage to the ocular surface epithelia as a result of the ions’ specific interactions with the HCLE glycocalyx components, independently of the effect of hyperosmolarity itself. As shown by Gilbard and Rossi,
38 lacrimal gland disease results in a 3.5% increase in tear electrolytes, including Ca
+2 and Mg
+2. The data in the present study show that increased Ca
+2 and Mg
+2 concentration has an adverse effect on the protection of HCLE cells, perhaps altering the distribution of cell surface components, including the protective membrane-associated mucin MUC16. Several studies have shown that divalent cations interact noncovalently with secreted mucins and that this interaction can alter the structure of mucins.
42 43 44 45 Using light-scattering analysis, Varma et al.
46 have shown that calcium ions affect the conformation of porcine submaxillary mucin, resulting in a more contracted gel. These calcium-dependent interactions with mucins can also alter the diffusion of molecules through mucus networks, as shown with saliva and respiratory mucin.
47 48 At the ocular surface, interaction of cations with membrane-associated mucins may alter the glycocalyx architecture, resulting in damage and reduced tear film stability.