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Innovations in the Treatment of Dry Eye Disease: Mucin Stimulators and Hormone Replacement

The tear film is traditionally described as a trilaminar structure with an innermost mucin layer that is closely applied to the conjunctival and corneal surface, an outermost lipid layer, and, sandwiched in between and constituting the bulk of the tear film, an aqueous layer.1,2 A more recent modification of this simplistic architecture describes the tear film as consisting of an outer lipid layer covering an aqueous-mucin gel in which there exists a gradient of mucin concentration, which is maximal toward the epithelium and least concentrated toward the lipid layer.³ Whatever the structure, the tear film behaves as a single functional unit in preserving the health and function of the ocular surface.

The lipid layer, secreted principally by the meibomian glands with contributions from the glands of Zeis and Moll, is made up of triglycerides, free fatty acids, waxes, esterified cholesterol, and some proteins (lipocalins) that bind to tear film lipids and enhance their stability. The lipid layer plays a key role in limiting evaporative loss of tear fluid.⁴ The aqueous component of tears, under basal conditions, is derived primarily from the accessory lacrimal glands of Krause and Wolfring. The main lacrimal gland provides the bulk of the volume during reflex secretion and most of the tear film proteins.

Mucins (high-molecular-weight glycoproteins) are secreted by the conjunctival goblet cells and the apical cells of the corneal and conjunctival epithelium. Mucins are adsorbed onto the glycocalyx covering of the ocular surface epithelium and enhance its wettability.^5–7 Of the 15 known mucin genes, six to eight are associated with mucins related to the ocular surface.^7,8 The mucins produced by the goblet cells (O-linked mucins) are slightly different structurally from mucins produced by the epithelial cells (N-linked mucins). The corneal and conjunctival epithelia produce transmembrane mucins, such as MUC1, MUC2, and MUC4, whereas goblet cells produce the gel-forming secretory mucin MUC5AC. The lacrimal gland produces MUC7. Interactions between the different mucins at the ocular surface ensure stability of the tear film.⁹

The dry eye effect of mucin deficiency is similar to dry eye caused by deficiency of any of the other major component of the tear film. There are no specific symptoms or signs of dry eye that can be attributed to mucin, lipid, or aqueous deficiency. In some forms of dry eye though, increased mucin production or concentration leads to a stringy discharge of strands of mucous, which can lead to ocular surface irritation.

The regulatory mechanisms influencing the secretion of mucous, aqueous, and lipid phases of the tear film are predominantly neuronal and hormonal. Distinct innervation of meibomian and lacrimal glands has been demonstrated, but direct nerve supply to the goblet cells has not been anatomically identified. If neuronal regulation of goblet cell mucin occurs, it is likely to be indirect through hormonal, autocrine, or paracrine mechanisms. Hormonal regulation of tear fluid secretion is well accepted, but the exact mechanisms remain to be elucidated. Sex hormones, principally androgens, play a major role. They exert effects on the structure, function, and immune-mediated defense of the lacrimal and meibomian glands and possibly of the goblet cells. Receptors for steroid hormones have also been identified in the ocular surface epithelium.¹⁰ Other hormones—such as luteinizing hormone, follicle stimulating hormone, prolactin, thyroid stimulating hormone, progesterone, and estrogens—are also believed to influence lacrimal gland function in health and disease.⁷ The frequent association of dry eye symptoms with the onset of menopause suggests that estrogens may be particularly implicated.

♦ Mucin Stimulators

Most treatment regimens for dry eye conditions invoke the principles of tear replacement or tear conservation. Examples include the use of tear substitutes for the former and punctal occlusion for the latter. The concept of stimulating tear production is not new. Attempts at stimulating or increasing production of tear film components have been in vogue for some time. Many of the agents used toward this end have other undesirable effects that limit their use. Cholinergic agents such pilocarpine¹¹ and cevimeline,¹² which are administered orally, have been shown to stimulate tear secretion and decrease the severity of oral and ocular dryness associated with keratoconjunctivitis sicca. Systemic side effects are common, however. In the early 1990s, several topically applied secretagogues such as isobutyl methylxanthine and eledoisin, agents that increase cyclic nucleotide levels and can increase tear secretion, were tested in experimental animals and were demonstrated to decrease tear osmolarity by increasing secretion of tear fluid.^13–15

Agents to specifically stimulate mucin secretion are at various stages of laboratory and clinical investigation. These hold promise for the future not only for more targeted treatment of dry eye problems but also in helping to understand better the pathophysiology of dry eye.

The agents discussed in the following sections are being investigated for their mucin stimulatory function (Table 10-1).

INS 365

Jumblatt and Jumblatt¹⁶ demonstrated that rabbit and human conjunctival cells contain functional P2Y2 nucleotide receptors that govern mucin secretion and suggested that stimulation of these receptors could provide a new approach to the treatment of dry eyes. They showed that the adenine analogues uridine 5’-triphosphate (UTP) and adenosine triphosphate (ATP) induced mucin secretion by conjunctival goblet cells in a concentration-dependent manner, acting by means of the P2Y2 receptor.

Diquafosol (INS 365 Ophthalmic) is a more stable P2Y2 receptor agonist that stimulates mucociliary clearance and also hydrates the mucosal surfaces. Phase II trials of diquafosol for dry eye are being conducted in Japan by Santen Pharmaceuticals.¹⁷ Foulks et al¹⁸ performed preliminary clinical trials with INS 365 on patients with dry eye disease and recorded an amelioration of clinical symptoms and signs. Phase I trials are also being conducted in the United Kingdom. Diquafosol eyedrops activate P2Y2 receptors on the surface of the eye and inner eyelids, enhancing the natural process of tear secretion. Stimulation of tear secretion with diquafosol causes the release of salt, water, mucin, and other components of the tear film, resulting in hydration of the surface of the eye.^17,19

Fujihara et al19 demonstrated in a rabbit model that topical instillation of INS 365 significantly increased release of mucin from goblet cells and suppressed desiccation-induced corneal damage.

In a 2004 phase III clinical trial, topical administration of diquafosol was shown to be safe and effective in ameliorating both symptoms and signs of dry eye disease, improving Schirmer’s 1 scores and reducing corneal staining.²⁰

15(S)-Hydroxyeicosatetraenoic Acid

The eicosanoid 15(S)-hydroxyeicosatetraenoic acid (15[S]-HETE) stimulates production of mucin glycoprotein by airway and ocular surface epithelium. In rabbits it has been shown that short-term exposure of the cornea to 15(S)-HETE causes a rapid-onset increase in the thickness of a layer of mucinlike glycoprotein on the surface of the corneal epithelium.²¹

Topically applied 15(S)-HETE also preserved corneal integrity in a rabbit model of desiccation-induced corneal defect. Both corneal staining and corneal thinning were significantly less when HETE was used compared with a control artificial tear substitute.²²

A recent announcement by Alcon Laboratories, Inc. (Fort Worth, TX) stated that a clinical study using a controlled adverse environment chamber to evaluate the efficacy of 15(S)-HETE did not show any difference when compared with a placebo.²³ The study is under way, and final data analysis is awaited.

Using segments of human conjunctiva, Jumblatt et al²⁴ showed that 15(S)-HETE (10^-8 to 10^-6 M) stimulated secretion of conjunctival mucins in a concentration-dependent manner. It was further shown that 15(S)-HETE differentially stimulates secretion of MUC1 with no detectable effects on MUC2, MUC4, or MUC5AC release. This indicates that 15(S)-HETE is a selective stimulant of MUC1, at least in isolated conjunctival samples. Other effects of this agent may limit its clinical usage, however, as it has been shown to stimulate new vessel growth in experimental laboratory studies.²⁵

Gefarnate

Some drugs used to treat gastric ulcers also increase the secretion of gastric mucus. Gefarnate is one such drug, which has no autonomic, anticholinergic, ganglion blocking, or antihistamine effects.²⁶ In animal experiments it has been shown^27,28

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