Molecular nature of ocular surface barrier function, diseases that affect it, and its relevance for ocular drug delivery

Abstract

The structural and functional integrity of the ocular surface, a continuous epithelial structure comprised of the cornea, the conjunctiva, and the ductal surface of the lacrimal as well as meibomian glands, is crucial for proper vision. The ocular surface barrier function (OSBF), sum of the different types of protective mechanisms that exist at the ocular surface, is essential to protect the rest of the eye from vision-threatening physical, chemical, and biological insults. OSBF helps maintain the immune privileged nature of the cornea and the aqueous humor by preventing entry of infectious agents, allergens, and noxious chemicals. Disruption of OSBF exposes the dense nerve endings of the cornea to these stimuli, resulting in discomfort and pain. This review summarizes the status of our knowledge related to the molecular nature of OSBF, describes the effect of different ocular surface disorders on OSBF, and examines the relevance of this knowledge for ocular drug delivery.

Keywords: Adherens junction; Barrier function; Cornea; Ocular surface; Tight junction.

Figure 1.. Corneal and conjunctival components of OSBF.

The cornea is protected by a biphasic tear fluid comprised of the superficial lipid layer and muco-aqueous layer overlying the glycocalyx comprised of transmembrane mucins on apical epithelial cell surface and carbohydrate-binding proteins such as galectin-3. The corneal epithelium is a stratified squamous tissue that is held together by different cell junctional complexes including the hemidesmosomes that stabilize it on the basement membrane, gap junctions that allow intercellular communication, adherens junctions that link the neighboring cells together, desmosomes that stabilize the cytoskeletal structure in adjoining cells, and tight junctions that seal the intercellular gaps between adjacent cells. The corneal epithelial basement membrane and the underlying Bowman’s layer also contribute to the OSBF by restricting the free movement of solutes, peptides and other macromolecules between the corneal stroma and the epithelium. The vascular conjunctiva that surrounds the cornea lacks a well-defined Bowman’s layer, is more porous with relatively larger paracellular space, and contains fewer cell layers. It is populated with stratified squamous epithelial cells and scattered goblet cells that secrete mucins, and act as antigen importers as well as regulators of innate immune function.

Figure 2.. Molecular underpinnings of defects in ocular surface barrier function.

Well-known components of different cell junctional complexes that enable tissue integrity and promote apicobasal polarity are shown on the left. Any condition that causes elevated cytokine accumulation, matrix metalloproteinase activity, and/or accumulation of reactive oxygen species disrupts these cell junctional complexes, causing the breakdown of OSBF. These conditions not only destabilize the cell-junctional complexes, but also disrupt the barrier functionality of the tear fluid components aqueous and glycocalyx, as well as the epithelial basement membrane. Resulting loss of apical-basal polarity and detachment of cells from the neighboring cells and the basement membrane is a characteristic feature of epithelial-mesenchymal transition that is observed in many diseases of the ocular surface.

Figure 3.. The vicious self-perpetuating cycle of ocular surface inflammation.

Disruption of the OSBF initiates a disruptive and self-perpetuating cycle of events (shown within the yellow ovoid shape) in ocular surface epithelial cells involving inflammatory mediators and proteases, that presents with overlapping outcomes regardless of the initiating insult (shown on the perimeter). Dry eye disease is a common condition that can drive the ocular surface into this vicious cycle at multiple entry points. Similarly, infectious keratitis initiates this cycle via elevated cytokine production, while exposure to noxious chemicals, allergens, extended wear or misuse of contact lens, or physical insults such as UV exposure can initiate this cycle via elevated production of reactive oxygen species (ROS). Contact lens misuse can also promote bacterial biofilm formation and associated keratitis. Loss or destabilization of cell junctions due to genetic disorders or upregulation of MMPs by other insults can also trigger this cycle. Thus, regardless of the insult, ocular surface inflammation has the potential to exacerbate and amplify this vicious cycle of events that culminate in disruption of OSBF and ocular surface damage.