The cornea in keratoconjunctivitis sicca

Abstract

The lacrimal functional unit (LFU) regulates tear production, composition, distribution and clearance to maintain a stable protective tear layer that is essential for maintaining corneal epithelial health. Dysfunction of the LFU, commonly referred to as dry eye, leads to increased tear osmolarity and levels of inflammatory mediators in tears that cause ocular surface epithelial disease, termed keratoconjunctivitis sicca (KCS). Corneal changes in KCS include glycocalyx loss, barrier disruption, surface irregularity inflammatory cytokine/chemokine production, cornification and apoptosis. These can reduce visual function and the increased shear force on the corneal epithelium can stimulate nociceptors sensitized by inflammation causing irritation and pain that may precede frank clinical signs. Therapy of keratoconjunctivitis sicca should be tailored to improve tear stability, normalize tear composition, improve barrier function and minimize shear forces and damaging inflammation to improve corneal epithelial health.

Keywords: Barrier function; Cornea epithelium; Dry eye; Dry eye disease; Hyperosmolarity; Nociceptor; Pain; Tear stability.

Figure 1A.

In normal eyes with a stable tear film, paracellular corneal epithelial barrier is maintained by tight junctions between the apical epithelial cells. Transcellular barrier is provided by the tear film and glycocalyx composed of membrane associated mucins (MAM), particularly MUC16. 1B. In keratoconjunctivitis sicca, osmotic stress from increased sodium (Na+) ions in the tears is a danger signal that activates the JNK and NFκB stress signaling pathways, leading to increased expression of inflammatory cytokines, chemokines and matrix metalloproteinases, in particular MMP-9 that can lyse the tight junction protein, occludin. Epithelial barrier is compromised by loss of glycocalyx and tight junction disruption. Additionally, JNK2 activation stimulates expression of cornified envelope precursors (CEP) that are found in the cornified envelope of the epidermis and may promote apoptosis. Osmotic stress and the reactive oxygen species (ROS) it induces promote NLRP3 inflammasome activation leading to caspase 1 activation and conversion of pro-IL-1β and pro-IL-18 to their active forms.