Cil, O. | Search bioRxiv

bioRxiv2025

Model of ocular surface ion and water transport predicts efficacy of dry eye therapeutics targeting epithelial transport and tear fluid dynamics

The composition and volume of tear fluid lining the ocular surface are governed by the rates of lacrimal gland secretion, tear film evaporation, nasolacrimal drainage, and epithelial ion and water transport. Tear fluid hyperosmolality and reduced volume are key drivers of dry eye disease (DED) pathogenesis. We constructed a mathematical model to compute the composition and volume of tear fluid and epithelial cell compartments, with transport parameters specified for the mouse eye from published data and in vivo measurements of ocular surface potential differences. The model accounted for transcellular and paracellular transport across the epithelia under open-circuit conditions utilizing flux equations for individual transport mechanisms, with mass balance constraints on solute and water content in cytoplasm and tear fluid. Under DED conditions established by reduced lacrimal secretion and increased evaporation, the model predicted the efficacy of currently available DED therapies including punctal plugs, humidification goggles, lacrimal gland stimulation, and artificial tears eye drops. The model also predicted the limited efficacy of anti-absorptive and pro-secretory drugs targeting epithelial ion transporters, and the high efficacy of targeting epithelial water permeability or paracellular ion permeability. The modeling herein provided quantitative predictions to prioritize novel targets for DED and drive the development of new therapies. Author SummaryDry eye disease (DED) affects billions of adults worldwide, but a full picture is lacking of how the tear film becomes abnormally thin and hyperosmolar. The computer model built here links four processes - tear production by the lacrimal gland, tear fluid evaporation, tear drainage through tear ducts, and transport of solutes and water across eye surface epithelial cells - to predict the thickness and composition of the tear film in various conditions. Model parameters were selected using published data and electrical measurements of voltage changes across the ocular surface produced by ion transport. The model predicted that existing therapies, such as punctal plugs, moisture goggles, or stimulating tear production, can substantially increase tear thickness or lower saltiness. The model also predicted limited efficacy of drug therapies in current development that target ion transport, and identified epithelial cell water transport and paracellular ion permeability as novel targets for DED treatment. By making ocular surface transport mechanisms explicit and testable, our work offers a roadmap for development of new therapies that restore a healthy tear film, a major unmet medical need.

systems biology↗

bioRxiv2024

Crypt and Villus Enterochromaffin Cells are Distinct Stress Sensors in the Gut

The crypt-villus structure of the small intestine serves as an essential protective barrier, with its integrity monitored by the guts sensory system. Enterochromaffin (EC) cells, which are rare sensory epithelial cells that release serotonin (5-HT), surveil the mucosal environment and signal both within and outside the gut. However, it remains unclear whether EC cells in intestinal crypts and villi respond to different stimuli and elicit distinct responses. In this study, we introduce a new reporter mouse model to observe the release and propagation of serotonin in live intestines. Using this system, we show that crypt EC cells exhibit two modes of serotonin release: transient receptor potential A1 (TRPA1)-dependent tonic serotonin release that controls basal ionic secretion, and irritant-evoked serotonin release that activates gut sensory neurons. Furthermore, we find that a thick protective mucus layer prevents TRPA1 receptors on crypt EC cells from responding to luminal irritants such as reactive electrophiles; if this mucus layer is compromised, then crypt EC cells become susceptible to activation by luminal irritants. On the other hand, villus EC cells detect oxidative stress through TRPM2 channels and co-release serotonin and ATP to activate nearby gut sensory fibers. Our work highlights the physiological importance of intestinal architecture and differential TRP channel expression in sensing noxious stimuli that elicit nausea and/or pain sensations in the gut.

physiology↗