Tear dysfunction and the cornea: LXVIII Edward Jackson Memorial Lecture

Abstract

Purpose: To describe the cause and consequence of tear dysfunction-related corneal disease.

Design: Perspective on effects of tear dysfunction on the cornea.

Methods: Evidence is presented on the effects of tear dysfunction on corneal morphology, function, and health, as well as efficacy of therapies for tear dysfunction-related corneal disease.

Results: Tear dysfunction is a prevalent eye disease and the most frequent cause for superficial corneal epithelial disease that results in corneal barrier disruption, an irregular optical surface, light scattering, optical aberrations, and exposure and sensitization of pain-sensing nerve endings (nociceptors). Tear dysfunction-related corneal disease causes irritation and visual symptoms such as photophobia and blurred and fluctuating vision that may decrease quality of life. Dysfunction of 1 or more components of the lacrimal functional unit results in changes in tear composition, including elevated osmolarity and increased concentrations of matrix metalloproteinases, inflammatory cytokines, and chemokines. These tear compositional changes promote disruption of tight junctions, alter differentiation, and accelerate death of corneal epithelial cells.

Conclusions: Corneal epithelial disease resulting from tear dysfunction causes eye irritation and decreases visual function. Clinical and basic research has improved understanding of the pathogenesis of tear dysfunction-related corneal epithelial disease, as well as treatment outcomes.

Figure 1

Inferior tear meniscus measured by optical coherence tomography (OCT) just before (left) and 1 second after (right) a blink. Blinking decreased the tear meniscus area by two-thirds through upward pull over the cornea and lacrimal drainage.

Figure 2

Integrated Lacrimal Functional Unit (LFU) that regulates secretion and delivery of tears to the cornea and ocular surface. Nociceptors in the cornea (yellow) synapse with autonomic, motor and higher sensory neurons in the brainstem that innervate the tear-producing glands and orbicularis muscle to initiate blinking. Reprinted with permission from: Beuerman R, Stern ME, Mircheff A, Pflugfelder SC. The Lacrimal Functional Unit in Dry Eye and the Ocular Surface, SC Pflugfelder, ME Stern and R Beuerman editors, Marcel Dekker, New York, 2004, pp 11-40.

Figure 3

The precorneal tear layer contains factors produced by the lacrimal glands, conjunctval goblet cells and surface epithelium that lubricate (mucins), heal (epidermal growth factor -EGF) and protect the cornea from infection (lactoferrin, defensins, IgA) and excessive inflammation (interleukin 1 receptor antagonist – IL-1RA, transforming growth factor beta - TGF-β and tissue inhibitor of matrix metalloproteinase 1 – TIMP1). MMP-9 = matrix metalloproteinase 9.

Figure 4

Tear dysfunction related alterations in tear composition, including increased osmolarity and inflammatory cytokines produced by epithelial cells (IL-1 and TNF-α) and activated CD4+ T cells (IFN-γ and IL-17) activate the c-jun n-terminal kinase (JNK) and nuclear factor kappa B (NFκB) stress signaling pathways leading to transcription of stress genes such as inflammatory cytokines and chemokines, matrix metalloproteinases (MMPs), pro-apoptotic factors and cornified envelop precursor proteins. (IFN-γ = interferon gamma)

Figure 5

Reduced tear production and desiccation in experimental dry eye in mice leads to proteolytic dissolution of tight junction protein occludin and accelerated desquamation in the apical epithelial cells (upper) resulting in exposure of less differentiated subapical epithelia and activated nociceptors that signal discomfort from the ocular surface (lower).