Tear hyperosmolarity as a core mechanism of dry eye

From the above discussion, it can be seen that certain core mechanisms are envisaged at the center of the dry eye process that can initiate, amplify, and potentially change the character of dry eye over time. These are tear hyperosmolarity and tear film instability. The interactions of various etiologies with these core mechanisms are summarized in the figure Dry Eye Workshop (DEWS) mechanism of dry eye (2007).

Tear hyperosmolarity is regarded as the central mechanism causing ocular surface inflammation, damage, symptoms, and the initiation of compensatory events in dry eye. Tear hyperosmolarity arises as a result of water evaporation from the exposed ocular surface, in situations of a low aqueous tear flow, or as a result of excessive evaporation, or a combination of these events. Hyperosmolarity stimulates a cascade of inflammatory events in the epithelial surface cells, involving MAP kinases and NFkB signalling pathways and the generation of inflammatory cytokines (IL-1α; -1β; TNF-α) and MMPs (MMP9), which arise from or activate inflammatory cells at the ocular surface.

There is evidence that these inflammatory events lead to apoptotic death of surface epithelial cells, including goblet cells; thus, goblet cell loss may be seen to be directly related to the effects of chronic inflammation. Goblet cell loss is a feature of every form of dry eye, and consistent with this is the demonstration of reduced levels of the gel mucin MUC5AC in dry eye.

Dry Eye Workshop (DEWS) mechanism of dry eye (2007)*

 

*Lemp MA. The Definition and Classification of Dry Eye Disease: Report of the Definition and Classification Subcommittee of the International Dry eye Workshop (DEWS). The Ocular Surface, April 2007, Vol. 5, NO. 2: 75-91 (www.theocularsurface.com)

The core mechanisms of dry eye are driven by tear hyperosmolarity and tear film instability. The cycle of events is shown on the right of the figure. Tear hyperosmolarity causes damage to the surface epithelium by activating a cascade of inflammatory events at the ocular surface and a release of inflammatory mediators into the tears. Epithelial damage involves cell death by apoptosis, a loss of goblet cells, and disturbance of mucin expression, leading to tear film instability. This instability exacerbates ocular surface hyperosmolarity and completes the vicious circle. Tear film instability can be initiated, without the prior occurrence of tear hyperosmolarity, by several etiologies, including xerophthalmia, ocular allergy, topical preservative use, and contact lens wear.

The epithelial injury caused by dry eye stimulates corneal nerve endings, leading to symptoms of discomfort, increased blinking and, potentially, compensatory reflex lacrimal tear secretion. Loss of normal mucins at the ocular surface contributes to symptoms by increasing frictional resistance between the lids and globe. During this period, the high reflex input has been suggested as the basis of a neurogenic inflammation within the gland.

The major causes of tear hyperosmolarity are reduced aqueous tear flow, resulting from lacrimal failure, and/or increased evaporation from the tear film. This is indicated by the arrow at the top-center of the figure. Increased evaporative loss is favoured by environmental conditions of low humidity and high air flow and may be caused clinically, in particular, by meibomian gland dysfunction (MGD), which leads to an unstable tear film lipid layer.

The quality of lid oil is modified by the action of esterases and lipases released by normal lid commensals, whose numbers are increased in blepharitis. Reduced aqueous tear flow is due to impaired delivery of lacrimal fluid into the conjunctival sac. It is unclear whether this is a feature of normal aging, but it may be induced by certain systemic drugs, such as antihistamines and antimuscarinic agents. The most common cause is inflammatory lacrimal damage, which is seen in autoimmune disorders such as Sjögren's syndrome and also in non-Sjogren's syndrome dry eye (NSSDE). Inflammation causes both tissue destruction and a potentially reversible neurosecretory block. A receptor block may also be caused by circulating antibodies to the M3 receptor. Inflammation is favoured by low tissue androgen levels.

Tear delivery may be obstructed by cicatricial conjunctival scarring or reduced by a loss of sensory reflex drive to the lacrimal gland from the ocular surface. Eventually, the chronic surface damage of dry eye leads to a fall in corneal sensitivity and a reduction of reflex tear secretion.
Various etiologies may cause dry eye acting, at least in part, by the mechanism of reflex secretory block, including: refractive surgery (LASIK dry eye), contact lens wear and the chronic abuse of topical anesthetics.

In the initial stages of dry eye, it is considered that ocular surface damage caused by osmotic, inflammatory or mechanical stresses (loss of surface lubrication) results in reflex stimulation of the lacrimal gland. Reflex trigeminal activity is thought to be responsible for an increased blink rate and a compensatory response, increased lacrimal secretion. In the case of lacrimal gland insufficiency (SSDE or NSSDE), the reflex secretory response will be insufficient to fully compensate for the tear film hyperosmolarity, and in the steady state, this form of dry eye will be characterized by a hyperosmolarity state with low tear volume and flow. In evaporative dry eye (eg, caused by MGD), it can be hypothesized that, since the lacrimal gland is initially healthy in this situation, lacrimal secretory compensation is at first able to compensate for tear film hyperosmolarity. Ultimately it would be expected that in the steady state, dry eye would be a condition of hyperosmolarity with a tear volume and flow greater than normal.

In some forms of dry eye, tear film instability may be the initiating event, unrelated to prior tear hyperosmolarity.

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