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Much more than water
  1. Health Partners Research Foundation and the Departments of Ophthalmology, HealthPartners Medical Group Regions Hospital, 640 Jackson Street, St Paul, MN 55101, USA and the University of Minnesota, Minneapolis, Minnesota, USA

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    The belief that the tear film is aqueous based and the ocular surface changes seen in Sjögren’s syndrome are due to desiccation, cause eye care practitioners to water the dry eye. Studies show the tear film is dominated by mucin and not water.1 2 It is not a 7–10 μm thin film, but a 30–35 μm thick mucin gel. Bicarbonate may be critical to forming this gel as it is in forming the bicarbonate mucin gel that protects the stomach from autodigestion.3 The hallmark of the aqueous deficient dry eye, rose bengal staining of the conjunctiva, is not produced by desiccated cells, but is due to a deficiency in the protective mucin gel.4

    The first major innovation in the treatment of the dry eye seen in Sjögren’s syndrome was the introduction of preservative-free artificial tears. Although the absence of preservatives allowed frequent topical application, the improvement seen in these severe dry eyes was more the result of the elimination of toxic preservatives than increased frequency of use. Preservative-free artificial tears allowed for more frequent watering of the dry eye, but watering alone does not reverse the ocular surface changes seen in Sjögren’s syndrome.

    The ocular surface changes include conjunctival squamous metaplasia, loss of integrity of cell membranes and junctional structures (fluorescein staining), and loss of the integrity of the mucin layer (rose bengal staining). Rose bengal staining and squamous metaplasia are not improved by the frequent application of non-preserved preparations.5 Bicarbonate and electrolyte solutions promote recovery of barrier function and ultrastructure in damaged ocular surface cells6 and increase corneal glycogen and goblet cell density.7 These solutions, however, do not totally reverse ocular surface disease seen in Sjögren’s syndrome. Even with the addition of electrolytes and bicarbonate to artificial tears, watering the dry eye is not enough.

    In this issue of the journal, Tsubota and colleagues (p 390) demonstrate that the application of autologous serum improved fluorescein and rose bengal scores and squamous metaplasia. It also resulted in significant upregulation of MUC-1 in conjunctival epithelial cell cultures. The authors speculate that the epidermal growth factor (EGF), vitamin A, and transforming growth factor β (TGF-β) found in serum represent critical components missing from the tears of patients with Sjögren’s syndrome.

    Certain cytokines may play an important role in the regulation of proliferation, differentiation, and maturation of the ocular surface epithelium. Other cytokines may prove harmful.8Experimental studies demonstrate that EGF9 10 and hepatocyte growth factor (HGF),11 12 which are present in human tears and secreted by the lacrimal gland, are important in corneal wound healing. Both also increase as aqueous tear production increases. TGF-α13 and TGF-β14 are found in human tears. Both are probably involved in corneal epithelial cell growth and differentiation.15 Retinol, also secreted by the lacrimal gland and found in the tear film, is necessary for the maintenance of healthy ocular surface epithelium.16 Not only may the tear film of patients with Sjögren’s syndrome be missing critical components, tears may actually contain substances that lead to ocular surface injury. Cytokines may be produced in or by the lacrimal gland in response to inflammation. These factors, delivered to the ocular surface by the tear fluid, may lead to inflammation of the ocular surface. mRNA for interleukins IL-1 and IL-6 has been detected in the lacrimal glands of autoimmune female MRL/lpr mice.17 Increased levels of IL-1 induce keratocyte apoptosis18 and metalloproteinases.19 IL-6 induces lymphocytic differentiation.

    In Sjögren’s syndrome, reflex tearing decreases with increased lymphocytic infiltration of the lacrimal gland.20 Reflex tearing flushes debris from the ocular surface, dilutes substances in the tear film, and delivers higher amounts of certain cytokines to the ocular surface. The loss of reflex tearing results in reduced tear clearance causing prolonged retention of substances in the tear film.21 It is likely that the loss of reflex tearing also results in the lack of delivery of cytokines and retinol critical to the growth and differentiation of ocular surface epithelial cells.

    The upregulation of MUC-1 suggests there are substances in serum which promote reformation of the mucin gel and, therefore, resolution of rose bengal staining. Similar substances, that are important in the maintenance of the mucin gel, are probably missing in the Sjögren’s dry eye.

    The use of serum tears is not new.22 However, Tsubota and colleagues show it is what is in tears that counts. The presence of cytokines and retinol are critical for the growth, differentiation, and wound healing of the ocular surface. Artificial tears flush out debris, dilute substances trapped in the tear film, and increase tear clearance. They do not, however, provide all the factors critical for the maintenance and repair of the ocular surface. That the application of serum tears reverses the ocular surface changes in Sjögren’s syndrome should open the door to new therapies as well as reinforce the fact that tears are much more than water.


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