Ординатура / Офтальмология / Английские материалы / Ocular Disease Mechanisms and Management_Levin, Albert_2010

Conclusion

Lipids play an important role in the stability of the tears and the health of the eyelid margin. Interactions of the lipids with proteins such as mucin and lipocalin in the tear film provide additional stabilization of the tear film, in addition to limitation of evaporation of the tear film. Disease of the glands of the eyelid margin is a common clinical problem

Key references

associated with compositional and functional changes of the lipids produced by the glands of the eyelid margin. Our understanding of the composition, structure, and function of the lipids helps explain the behavior of the lipids and their response to changes in temperature.

The implications of the structure and function of lipid behavior to therapy of eyelid margin disease and dry eye are important both to direct clinical treatment and also to develop better medications to control those diseases.

2.Foulks GN, Bron AJ. Meibomian gland dysfunction: a clinical scheme for description, diagnosis, classification, and grading. Ocular Surf 2003;1:107–126.

7.Sullivan DA, Sullivan BD, Evans JE, et al. Androgen deficiency, meibomian gland dysfunction, and evaporative dry eye. Ann NY Acad Sci 2002;966:211–222.

9.Tiffany JM. Individual variations in human meibomian lipid composition. Exp Eye Res 1978;27:289–300.

10.Nicolaides N, Kaitaranta JK, Rawdah TN, et al. Meibomian gland studies: comparison of steer and human lipids. Invest Ophthalmol Vis Sci 1981;20:522– 536.

12.Butovich IA, Uchiyama E, McCulley JP. Lipids of human meibum: massspectrometric analysis and structural elucidation. J Lipid Res 2007;48:2220– 2235.

14.Borchman D, Foulks GN, Yappert MC, et al. Spectroscopic evaluation of human

tear lipids. Chem Phys Lipids 2007;147: 87–102.

15.Borchman D, Foulks GN, Yappert MC, et al. Temperature-induced conformational changes in human tearlipids hydrocarbon chains. Biopolymers 2007;87:124–133.

21.Nagymihalyi A, Dikstein S, Tiffany JM. The influence of eyelid temperature on the delivery of meibomian oil. Exp Eye Res 2004;78:367–370.

26.Glasgow BJ, Marshall G, Gasymov OK, et al. Tear lipocalins: potential lipid scavengers for the corneal surface. Invest Ophthalmol Vis Sci 1999;40:3100– 3107.

29.Mathers WD, Lane JA. Meibomian gland lipids, evaporation, and tear film stability. Adv Exp Med Biol 1998;438: 349–360.

30.Shine WE, McCulley JP. Meibomianitis: polar lipid abnormalities. Cornea 2004;23:781–783.

35.Ong BL, Larake JR. Meibomian gland dysfunction: some clinical, biochemical and physical observations. Ophthalm Physiol Opt 1990;10:144–148.

39.Jester JV, Nicolaides N, Kiss-Polvolgyi I, et al. Meibomian gland dysfunction II. The role of keratinization in a rabbit model of MGD. Invest Ophthalmol Vis Sci 1989;30:936–945.

43.McCulley JP, Shine WE. Changing concepts in the diagnosis and management of blepharitis. Cornea 2000;19:650–658.

51.Dougherty JM, McCulley JP, Silvany RE, et al. The role of tetracycline in chronic blepharitis. Inhibition of lipase production in staphylococci. Invest Ophthal Vis Sci 1991;32:2970–

2975.

In 2007, the Report of the International Dry Eye Workshop

(DEWS)1 defined dry eye as “a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability, with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.” The comprehensive DEWS report summarizes the current knowledge of the disease, its classification, symptoms and signs, epidemiology, diagnostic methods, and management and therapy. Research into dry eye is also summarized, and a hypothesis as to the mechanisms of dry eye is put forward (Figure 18.1). As indicated in Figure 18.1, mucin loss from the tear film and the ocular surface glycocalyx is proposed to be a core mechanism of the disease. This chapter will describe current understandings of the ocular surface and tear mucins – focusing on their character, origins, and alterations in drying eye diseases – as well as therapeutics targeted toward mucin restoration.

The Ocular Surface System

The tear film is essential for vision, functioning to maintain hydration and lubrication of the surface of the eye and to provide the major refractive surface for the visual system. The tear film is composed of many products, all produced by the epithelia of the Ocular Surface System2,3; these include water, protective antimicrobials, cytokines, lipids, and mucins (Box 18.1).

The Ocular Surface System is responsible for producing and maintaining the all-important tear film on the surface of the cornea (Figure 18.2). The system includes the surface or glandular epithelia of the cornea, conjunctiva, lacrimal glands, accessory lacrimal glands and meibomian glands, the nasolacrimal duct, as well as the eyelashes, with their associated glands of Moll and Zeis. Also included are the extracellular matrices and their resident cells, which underlie the epithelia, the vasculature, and migrating immune system cells, which survey the tissues. All components of the system are integrated functionally by continuity of the epithelia, by innervation from the trigeminal nerves, and by the endocrine, vascular, and immune systems.2

The rationale for the concept of “the Ocular Surface System” is that all regions of the epithelia are derived from the surface ectoderm, that each region is continuous with

another, and that all regions produce components of the tear film. For example, the hydrophilic mucins, responsible for holding tears on the surface of the eye, are products of the conjunctival and corneal epithelia. Water and protective proteins are secreted by the epithelia of the lacrimal and accessory lacrimal glands, and the superficial lipid layer, which prevents tear evaporation, is provided by the epithelia of the meibomian glands.2 When one or more components of the system is defective, the normal function of the ocular surface tear film is disrupted, which can result in chronic dry-eye disease and, at end stage, loss of the tear film with keratinization of the epithelia.

The early hypothesis of tear film structure separated the several secreted components into different layers: the lipid, aqueous, and mucin layers. While it is known that the superficial lipid layer, a product of the meibomian glands, is a distinct layer at the tear surface, recent data suggest that the aqueous tears are a mixture of lacrimal fluid and soluble mucins, without a distinct mucin layer (Figure 18.3).4 The interface between the tear film and the corneal and conjunctival epithelia is composed of the hydrophilic and heavily glycosylated glycocalyx, a major component of which is membraneor cell surface-associated mucins (MAMs).

Mucins expressed by the ocular surface epithelium

Mucins are high-molecular-weight glycoproteins. The common features of the 20 mucin gene products known to date are: (1) the presence of tandem repeats of amino acids, in their protein backbone, that have high levels of serine, threonine, and proline – with the serines and threonines being sites for O-glycan attachment; and (2) a major portion of mass of mucin molecules being made up of O-linked carbohydrate (Box 18.2).5 The heavy glycosylation of mucins gives molecules of this class their hydrophilic, lubricating character.

As indicated above, two types of mucins have been identified: secreted and cell-associated or membrane spanning. To date, 7 mucins have been described as secreted mucins and 10 as membrane-associated; several mucins remain uncharacterized as to type. Human mucins have been designated in

Xerophthalmia Ocular allergy preservatives CL wear?

Tear film instability

Box 18.1  The Ocular Surface System

The Ocular Surface System is responsible for producing and maintaining the all-important tear film on the surface of the cornea. The tear film is essential for vision, functioning to maintain hydration and lubrication of the surface of the eye, and to provide the major refractive surface for the visual system. All components of the system are integrated functionally by continuity of the epithelia, by innervation from the trigeminal nerves, and by the endocrine, vascular, and immune systems

Box 18.2  Mucins expressed by the ocular surface

epithelium

The high-molecular-weight glycoproteins, known as mucins, share two common features: (1) the presence of tandem repeats of amino acids in their protein backbone that have high levels of serine, threonine, and proline – with the serines and threonines being sites for O-glycan attachment; and (2) a mass primarily made up of O-linked carbohydrates. Two types of mucins have been identified: secreted, and membrane-associated or membrane-spanning. Of the 20 mucins identified to date, 7 have been described as secreted and 10 as membrane-associated; several mucins remain uncharacterized as to type. Mucins are named in order of their characterization – MUC1, MUC2, etc. The ocular surface epithelia express mucins of both types. The major mucin of the conjunctival goblet cell is the secreted mucin MUC5AC. Three major membrane mucins expressed by the ocular surface epithelia include MUCs 1, 4, and 16

order of discovery as MUC1, -2, -3, etc., with mouse homologs designated Muc1, -2, etc.

Secreted mucins

Of the secreted mucins, two types have been characterized: the so-called large, gel-forming mucins and the small, soluble mucins (one of each type is expressed by the ocular surface epithelia). The large, gel-forming mucins include MUCs 2, 5AC, 5B, 6, and 19, and the smaller, soluble mucins MUCs 7 and 9.

The five large mucins are termed gel-forming because they are responsible for the rheological properties of mucus. They share common structural motifs, including cysteine-rich, von Willebrand factor-like D domains at the amino terminal and carboxy termini that allow intermolecular associations among mucins of the same gene product. They are encoded by the largest genes known (15.7–17 kb), and their deduced proteins are at least 600 kDa. These gel-forming mucins are expressed by the goblet cells of the conjunctival, respiratory, gastrointestinal, and endocervical epithelia. However, there is a tissueand cell-specific pattern of expression of specific mucins. The major mucin of this class expressed by the goblet cells of the conjunctiva is MUC5AC (Figure 18.4).6 For a complete description of the structure of MUC5AC, see Gipson and Argüeso7 and Gipson.4

The second category of secreted mucins, small soluble mucins, includes MUC7 and MUC9, which are present pre-

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dominantly as monomeric species and lack cysteine-rich D domains. MUC7 is produced by lacrimal gland epithelia,8 but MUC7 is not present in the tear film.9

Membrane-associated mucins

The 10 mucins that have been categorized as cell MAMs include MUCs 1, 3A, 3B, 4, 12, 13, 15 16, 17, and 20. Mucins of this type are present on all the wet-surfaced epithelia of the body. All MAMs have a short cytoplasmic tail, and the majority have a large, extended extracellular domain, also known as the ectodomain, which is formed by heavily O- glycosylated tandem repeats of amino acids. The ectodomains may extend 200–500 nm from the cell surface and comprise a major portion of the glycocalyx. The ectodomain functions as a protective, disadhesive surface, preventing cell and pathogen adherence.10 Ectodomains of MAMs are found in fluids at the surface of wet-surfaced, mucosal epithelia, including the tear film. The ectodomains are proteolytically cleaved or released from the apical membranes, giving rise to the soluble form, or in some instances (particularly MUC1), the soluble form may be a result of splice variants that lack the membrane-spanning domain.4

MUC1, MUC4, and MUC16 are MAMs that are expressed by ocular surface epithelia (Figure 18.5). MUC1 mRNA is expressed by all the epithelia of the Ocular Surface System. The protein is expressed in apical surface cells of the corneal epithelium and in apical and subapical cells of the

Glycocalyx

Epithelium

Figure 18.3  Diagram of the structure and composition of the tear film and the apical surface of the cornea, with emphasis on the mucin components. Goblet cell mucin MUC5AC is shown as being soluble in the tear fluid rather than as a distinct layer beneath the aqueous layer, as previously described (for review, see Gipson and Argüeso7). The membrane-spanning mucins form the glycocalyx at the tear–epithelial interface, where they form a hydrated, lubricating barrier that also prevents pathogen adherence. These membrane-spanning mucins are tethered to the tips of the surface membrane ridges, termed microplicae (see Figure 18.6). (Modified from Gipson IK. The ocular surface: the challenge to enable and protect vision: the Friedenwald lecture. Invest Ophthalmol Vis Sci 2007;48:4390–4398. © The Association for Research in Vision and Ophthalmology (2007).)

Conjunctival epithelium

Figure 18.4  Diagram of sections of corneal and conjunctival epithelia demonstrating cellular localization of mucin expression. The apical cells of the stratified corneal and conjunctival epithelium express three membraneassociated mucins: MUC1, MUC4, and MUC16. These membrane-tethered mucins provide a barrier to protect the ocular surface against pathogen invasion and provide a hydrating, lubricating surface. The conjunctival epithelium also has interspersed within it goblet cells that produce the large mucin MUC5AC. MUC5AC is secreted into the tear film. The lids move the soluble mucin over the surface of the eye to trap and remove foreign debris. (Modified from Gipson IK. Distribution of mucins at the ocular surface. Exp Eye Res 2004;78:379–388. © Elsevier (2004).)

conjunctival epithelium.4 MUC4 protein is most prevalent in conjunctival epithelium with a diminished amount in the cornea. MUC16 protein is present in apical cells of corneal epithelia and in apical and subapical cells of conjunctival epithelia.4 The membrane mucins, MUCs 1, 4, and 16, are considered to be multifunctional molecules, with the glycosylated region of their ectodomain serving to prevent adhesion of cells/pathogens, and their juxta­ membrane region and cytoplasmic tail serving additional functions. In studies of nonocular epithelia, MUC1 has signaling capabilities through its cytoplasmic tail, and MUC4 has been shown to have an epidermal growth factor (EGF)-like domain present extracellularly near its membrane-spanning domain.4 Studies of MUC16 function in human corneal epithelial cells have shown that it provides a disadhesive, protective barrier to the epithelial membrane, since, in siRNA knockdown experiments, the binding of Staphylococcus aureus was significantly increased with MUC16 suppression.11 Knockdown of MUC16 also allows penetrance of rose Bengal dye, a dye that is used in the diagnosis of dry eye.11 MUC16 is especially prevalent on the tips of microplicae at the tear film interface, and its cytoplasmic tail is linked to the actin cytoskeleton through a class of linker molecules known as ERMs (Figure 18.6).11

Through their hydrophilic carbohydrates, membrane mucins hold water on the cell membrane to provide surface

hydration on the eye as well as build an antiadhesive surface for the movement of secreted mucins across the ocular surface during the blink. The fact that there are several mucins of this class present at the tear film interface indicates their importance in protection and hydration of the ocular surface.

Detection of mucins in tear fluid

Tear fluid contains, in addition to the secreted goblet cell mucin MUC5AC, ectodomains of the MAMs MUCs 1, 4, and 16.9 To measure and detect levels of MUC5AC in tears, an enzyme-linked immunosorbent assay (ELISA) was developed using antibodies specific to the N-terminal domain of MUC5AC. Pretreatment of tear proteins with neuraminidase to remove terminal sugars enhanced antibody binding.12 Within an individual, the level of MUC5AC is consistent over several samples, but there is variation among individuals in amount of MUC5AC in tears. MUC5AC in tears can also be assayed by immunoblot analysis of tear proteins separated on agarose gels.9 Low levels of gel-form- ing mucin MUC2 RNA and protein have also been detected in conjunctival RNA13 and tears,9 respectively, but the cellular source of the mucin is unknown. The amount of ectodomains of the MAMs in tears, MUCs 1, 4 and 16, also varies among individuals, with MUC16 being the most prevalent.

Figure 18.5  Diagram showing the structural motifs within the three membrane-associated mucins expressed by the ocular surface epithelia. A common characteristic of all mucins is the presence of a large ectodomain at the amino terminus (NH2) that has a variable number (n) of tandem repeats (TR) of amino acids rich in serine and threonine that are highly O-glycosylated (). Each has a membrane-spanning domain (M) and a short cytoplasmic tail (CT) at the carboxy terminus (COOH). MUC1 CT has 69 amino acids, phosphorylation sites (P) and a β, γ catenin-binding site. MUC4 has several epidermal-like growth factor (EGF)-like domains in the ectodomain area near the membrane. MUC16 has several sea urchin, enterokinase, agrin (SEA) module domains in the ectodomain (MUC1 has only one) near the membrane, and its CT has an ERM-binding domain that links it to the actin cytoskeleton.

Box 18.3  Alteration of mucins in ocular surface

epithelium

Dry-eye syndrome, perhaps the most common of the ocular surface diseases, is characterized by stinging, burning, or foreign-body sensation – symptoms ascribed to the fact that either there are not enough tears to keep the surface wet and comfortable, or that tears are not being retained at the ocular surface. Current understanding of mucin character and patterns of expression at the ocular surface, as well as the development of assay methodologies, makes it possible to measure specific variation in mucins in patients with dry eye. Studies of mucins in dry eye suggest that there is an alteration in amount of secreted mucin on the ocular surface, and either alteration in amount or glycosylation of membrane-associated mucins

Sjögren’s syndrome and in cicatrizing diseases. Recent data indicate that in patients with Sjögren’s syndrome, the number of RNA transcripts for MUC5AC in the conjunctival epithelium, detected by real-time polymerase chain reaction, as well as the protein levels of MUC5AC in the tear fluid, measured by ELISA, are significantly lower than in normal individuals.12 In another study, a reduction of MUC5AC-positive conjunctival cells, as detected by flow cytometry of impression cytology samples, was found in patients with dry eye.14 The data in these studies correlate with a decrease in the density of goblet cells in the conjunctival epithelium, thus indicating that the assay of MUC5AC mucin in tear fluid provides a noninvasive method for assessing goblet cell density. With increasing severity of the disease, the number of goblet cells decreases further and as a consequence squamous metaplasia and keratinization of the ocular surface occur.

Alteration of mucins in ocular surface diseases

Dry eye

Characteristic symptoms of dry-eye syndrome are stinging, burning, or foreign-body sensation. These symptoms are ascribed to the fact that either there are not enough tears to keep the surface wet and comfortable, or that tears are not being retained at the ocular surface. The absence and alteration of mucins, which are especially responsible for retaining water/tears at the ocular surface, is considered one of the core mechanisms of dry eye (Figure 18.1; Box 18.3).3 The current understanding of mucin character and patterns of expression at the ocular surface, and the development of assay methodologies, make it possible to measure specific mucins in patients with drying ocular surface diseases. The variation in mucins in patients with dry eye ranges from a decreased number of goblet cells in the conjunctival epithelium, with concomitant alteration in the amount of MUC5AC mucin mRNA and protein, to alteration in distribution and/ or glycosylation of MAMs.

Decreased goblet cells and levels of goblet-cell-associated mucin MUC5AC

It has long been known that goblet cells are lost in the conjunctival epithelium in severe dry eye, such as that in

Alteration of membrane-associated mucins

Not only is goblet cell density and, thus, MUC5AC mucin reduced in dry eye, but MAMs also appear to be altered. Assay of MUC16 distribution on the surface of the conjunctiva has been done on impression cytology samples of normal subjects and patients with non-Sjögren’s dry eye, using an antibody designated H185, which recognizes a carbohydrate epitope on MUC16.15 The typical binding pattern in apical cells of conjunctival epithelium of H185 antibody is altered in patients with non-Sjögren’s dry eye.16 The pattern of binding changes from a “cobblestone” binding pattern on the surface to one in which apical cell surface binding is increasingly reduced with severity of dry eye (Figure 18.7).16 It is not clear whether alteration in the binding pattern in dry eye is due to decreased expression of MUC16, increased shedding of its ectodomain into the tear film, or alteration of glycosylation of the mucin, such that the carbohydrate epitope recognized by the H185 antibody is lost.

Alteration of glycosylation of mucins

The character of the O-glycans on specific mucins can vary among different epithelial types and with disease. Although there is no direct evidence of alteration of O-glycans on specific mucins in dry eye, there is evidence that the expression of the enzymes that add sugars to O-glycans is altered in ocular cicatricial pemphigoid.17 In addition, lectin binding to conjunctival goblet cells is altered in dry-eye patients, as

compared to normal subjects, suggesting an alteration in MUC5AC glycosylation.18 A decrease in a sialylated Lewis A carbohydrate epitope on glycoconjugates/mucins in tears from patients with dry-eye syndrome has also been detected.19

Taken together, these studies of alterations of mucins in dry eye suggest that, not only is there an alteration in amount of secreted mucin on the ocular surface, but the membrane mucins are also altered, and glycosylation of both the mucin types appears to be altered.

Vitamin A deficiency (animal models)

Studies in animal models have shown that vitamin A influences the expression and production of membraneassociated and secreted mucins. Rats fed a casein-based vitamin A-deficient diet lost expression of the secretory mucin rMuc5AC and the MAM rMuc4 after 15–20 weeks;

however, the membrane-spanning mucin rMuc1 was not affected.20 Similar results were obtained in vitro, using a human conjunctival epithelial cell line.21 Expression of both MUC4 and MUC16 is regulated by retinoic acid, with the MUC16 regulation being mediated by secretory phospholipase A2. It is probable that the keratinization of the ocular surface in humans with vitamin A deficiency is accompanied by loss of mucin expression.

Therapeutics for dry eye targeted toward mucin production

Artificial tears have been and still are the main therapy for dry eye, but recently several drugs/agents have been developed to induce mucin expression or secretion. These drugs target both secretory and MAM types (Box 18.4).

Box 18.4  Therapeutics for dry eye targeted toward

mucin production

Artificial tears have been and still are the main therapy for dry eye, but recently several drugs/agents have been developed to induce mucin expression or secretion. These drugs target both secretory and membrane-associated mucin types. Current treatments used or being explored include the following: ciclosporin A (topical), P2Y2 receptor, the eicosanoid 15-(S)-HETE, gefarnate, corticosteroids, autologous serum, and vitamin A (retinoic acid)

Dry-eye syndrome is associated with inflammation and an increased expression of several inflammatory markers (human leukocyte antigen (HLA)-DR, intercellular adhesion molecule-1) by conjunctival epithelial cells.3 Topical treatment with the immunosuppressive agent ciclosporin A, used for treating inflammatory diseases such as rheumatoid arthritis and psoriasis, has been reported to be clinically effective in patients with dry eye.22,23 It reduces the amount of inflammatory markers,24 and after a 6-month treatment there is an increase in the number of goblet cells in the conjunctiva.25 Reduction of inflammation by ciclosporin A may result in an increase in goblet cell differentiation in the conjunctival epithelium. A topical emulsion ciclosporin A (Restasis: Allergan, Irvine, CA) is currently the only drug approved by the US Food and Drug Administration for dry eye.

The nucleotide P2Y2 receptor, found in many cell types,26 is expressed by corneal and conjunctival epithelia of rabbit and monkeys.27 Adenosine triphosphate and uridine 5’- triphosphate are P2Y2 receptor agonists that stimulate mucin secretion through a poorly understood mechanism in human conjunctiva.28 A stable P2Y2 receptor agonist INS365 increases tear secretion in a rat dry-eye model29; however, it is not known if this drug influences goblet cell MUC5AC expression or whether it affects shedding of the MAM from the ocular surface. Clinical trials using INS365 for dry eye are under way.

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As a metabolite of arachidonic acid, the eicosanoid 15-(S)-hydroxy-5,8,11,13-eicosatetraenoic acid (HETE) is known to be a stimulator of mucus secretion in airway epithelia.30 Topical application of 15-(S)-HETE to the rabbit ocular surface has been reported to enhance the thickness of the mucin layer on the corneal epithelial cell surface.31 In human conjunctiva, this agent has been reported to increase the amount of MUC1 protein, as measured by dot-blot assay,13,32 but there was no observable effect on MUCs 2, 4, 5AC, or 7. These data suggest that 15-(S)-HETE has an effect on some of the MAMs, but not on the secreted mucins.

Gefarnate is widely used to treat patients with gastritis or gastric ulcers. Its mechanism of action is to enhance mucous secretion in the stomach (as reviewed by Nakamura et al33). Treatment with gefarnate (3.7-dimethyl- 2.6-octadienyl-5.9.13-trimethyl-4.8.12-tetradecatrienoate) in animal models showed an increased presence of mucinlike proteins on the cornea, reduced desiccation in rabbit cornea and, after 7 days, an increased goblet cell density in the conjunctiva.33,34 Other studies showed an induction of goblet cell secretion and differentiation, and after 4 weeks, the amount of MUC5AC in tears of monkeys had also increased.35

Anti-inflammatory drugs such as corticosteroids reportedly have a positive influence on dry-eye disease.36,37 A comparison of the efficacy of corticosteroid fluoromethalone to treatment with the nonsteroidal anti-inflammatory fluribiprofen in keratoconjunctivitis sicca patients revealed that the corticosteroid was more efficacious.37 The corticosteroid provided the greatest increase in goblet cell numbers as well as a decrease in HLA-DR-positive cells and symptom severity.

Autologous serum is a potential treatment for dry-eye diseases, since it contains a number of growth factors, vitamin A, and anti-inflammatory factors known to affect mucin gene expression. Protein and mRNA levels of MUCs 1, 4, and 16 in cultured human conjunctival epithelial cells are upregulated by serum, although studies concerning secreted mucins have not been performed.38 Several clinical reports describe the efficacy of applying autologous serum

to treat Sjögren’s dry eye,39,40 suggesting that the treatment may be related to upregulation of MAMs.

It is well known that vitamin A is essential for maintenance of a healthy, differentiated ocular surface. Vitamin A deficiency in humans leads to keratinization. As stated earlier, in animal models, a vitamin A-free diet causes a loss of expression of Muc5AC and Muc4 in ocular surface epithelia, while Muc1 levels are not altered. The retinoid is used as a treatment for severe squamous metaplasia,41,42 and it is also reported that treatment with 100 nM retinoic acid causes higher expression of MUC4 and -16 mRNA and protein in cultured human conjunctival epithelial cells.38

Key references

Summary

Alteration in production of both secreted and MAMs has been reported to occur in dry eye. Loss of secreted goblet cell mucins and goblet cells leads to surface keratinization, and loss of the membrane-spanning mucins can cause damage, as indicated by rose Bengal staining. Therapies targeted toward amelioration of inflammation appear to replenish the mucin-producing goblet cells, while retinoids and autologous serum appear to upregulate mucins of the membraneassociated type.

1.Research in dry eye: report of the Research Subcommittee of the International Dry Eye WorkShop. Report of the International Dry Eye WorkShop (DEWS). Ocul Surf 2007;5:179–193.

2.Gipson IK. The ocular surface: the challenge to enable and protect vision: the Friedenwald lecture. Invest Ophthalmol Vis Sci 2007;48:4390–4398.

3.Report of the International Dry Eye WorkShop (DEWS). Ocul Surf 2007;5: 67–202.

8.Jumblatt MM, McKenzie RW, Steele PS, et al. MUC7 expression in the human lacrimal gland and conjunctiva. Cornea 2003;22:41–45.

10.Gipson IK, Hori Y, Argüeso P. Character of ocular surface mucins and their alteration in dry eye disease. Ocul Surf 2004;2:131–148.

13.Jumblatt JE, Cunningham LT, Li Y, et al. Characterization of human ocular mucin secretion mediated by 15(S)-HETE.

Cornea 2002;21:818–824.

15.Argüeso P, Spurr-Michaud S, Russo CL, et al. MUC16 mucin is expressed by the human ocular surface epithelia and

carries the H185 carbohydrate epitope. Invest Ophthalmol Vis Sci 2003;44: 2487–2495.

16.Danjo Y, Watanabe H, Tisdale AS, et al. Alteration of mucin in human conjunctival epithelia in dry eye. Invest Ophthalmol Vis Sci 1998;39:2602– 2609.

17.Argüeso P, Tisdale A, Mandel U, et al. The cell-layer- and cell-type-specific distribution of GalNAc-transferases in the ocular surface epithelia is altered during keratinization. Invest Ophthalmol Vis Sci 2003;44:86–92.

18.Versura P, Maltarello MC, Cellini M, et al. Detection of mucus glycoconjugates in human conjunctiva by using the lectin-colloidal gold technique in TEM. II. A quantitative study in dry-eye patients. Acta Ophthalmol (Copenh) 1986;64:451–455.

22.Sall K, Stevenson OD, Mundorf TK, et al. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 3 Study Group [published erratum appears in

Ophthalmology 2000;107:1220].

Ophthalmology 2000;107:631–639.

25.Kunert KS, Tisdale AS, Gipson IK. Goblet cell numbers and epithelial proliferation in the conjunctiva of patients with dry eye syndrome treated with cyclosporine. Arch Ophthalmol 2002;120:330–337.

37.Avunduk AM, Avunduk MC, Varnell ED, et al. The comparison of efficacies of topical corticosteroids and nonsteroidal anti-inflammatory drops on dry eye patients: a clinical and immunocytochemical study. Am J Ophthalmol 2003;136:593–602.

40.Tsubota K, Goto E, Fujita H, et al. Treatment of dry eye by autologous serum application in Sjögren’s syndrome. Br J Ophthalmol 1999;83: 390–395.

42.Soong HK, Martin NF, Wagoner MD, et al. Topical retinoid therapy for squamous metaplasia of various ocular surface disorders. A multicenter, placebo-controlled double-masked study. Ophthalmology 1988;95:1442– 1446.

S E C T I O N 3

Glaucoma

C H A P T E R 19

Steroid-induced glaucoma

Overview

Glucocorticoids (GCs) regulate normal physiological processes such as carbohydrate, lipid, and protein metabolism. However, GCs are most often used therapeutically because of their broad anti-inflammatory and immunosuppressive activities (Table 19.1). GCs block the production of proinflammatory molecules such as prostaglandins and cytokines, inhibit/decrease edema, block inflammatory and immune cell trafficking and activation, as well as inhibit the late stages of inflammation such as myofibroblast activation and scarring (Box 19.1). There are a variety of synthetic GCs with differing potencies, metabolic profiles, and biological halflives (Table 19.2). The widespread use of GCs for a variety of clinical conditions led to the discovery of significant side-effects associated with prolonged therapy, including metabolic effects (osteoporosis, myopathy, hyperglycemia, redistribution of body fat, and thinning of skin) and immunosuppression. Prolonged ocular administration of GCs (more commonly seen with topical ocular or intravitreal administration) can cause the development of posterior subcapsular cataracts, and the subject of this chapter, ocular hypertension and iatrogenic open-angle glaucoma in susceptible individuals.

Clinical background

to months after GC administration. The degree of IOP elevation also depends on the potency and dose of GC used as well as the frequency of dosing and route of administration. For example, intravitreal injections of the potent GC triamcinolone acetonide have been increasingly used to treat conditions of retinal edema and choroidal neovascularization, resulting in the increased prevalence of GC-induced ocular hypertension. This route of administration can lead to significantly elevated IOP in 10–40% of patients, who often require treatment with glaucoma medications or even filtration surgery.1 Although infrequent, even the use of intranasal and inhaled GCs can elevate IOP in certain individuals.

Epidemiology

There are population differences in this ocular response to GCs.2,3 Normal individuals receiving topical ocular administration of a potent GC for 4–6 weeks could be categorized into three groups: ~5% were high responders (IOP elevation of >15 mmHg or IOP >31 mmHg), 33% were moderate responders (IOP elevation 6–15 mmHg or IOP >20 mmHg), while those remaining were considered nonresponders (no effect of IOP elevation <6 mmHg). In contrast, the majority of POAG patients are high-to-moderate responders, and interestingly, descendants of POAGs are more likely to be GC-responsive compared to the normal population. There may be a genetic predilection for the development of GCinduced ocular hypertension, and this merits additional research.

Key symptoms and signs

The elevated intraocular pressure (IOP) and secondary glaucoma due to GC administration mimics the clinical presentation of primary open-angle glaucoma (POAG) in many ways. Affected individuals are unaware that they have ocular hypertension because the IOP increase is painless. The elevated IOP is due to impaired aqueous humor outflow. The IOP elevation causes very similar irreversible optic nerve head cupping and visual field loss. GC-induced ocular hypertension is different from POAG in that the damage to the aqueous outflow pathway is usually reversible upon discontinuation of GC therapy. However, there are instances of permanent IOP elevation in some patients treated with prolonged GC therapy.

A number of factors determine the ocular hypertensive effects of GC therapy. Elevated IOP generally develops weeks

Treatment

IOP elevation resulting from GC use is treated by halting, decreasing, or removing the source of the steroid, standard ocular hypotensive agents, or, if necessary, surgery. Anecortave acetate (AA) is an IOP-lowering cortisone currently in clinical trials; it lowers IOP in GC-induced ocular hypertensive and in glaucoma patients. It is an analog of cortisol acetate, which has been modified to remove GC activity.4 Topical ocular administration of AA lowers IOP in dexamethasone (DEX)-induced ocular hypertensive rabbits, and in an open-label, compassionate-use clinical study, topical ocular AA lowered the IOPs of patients with GC-induced ocular hypertension (Clark et al, unpublished oberservation), and in an open-label, compassionate-use clinical study, topical ocular AA lowered the IOPs of patients with