Dry eye disease is one of the most common forms of morbidity encountered in ophthalmic and optometric practices. It appears that lacrimal fluid production can be decreased by anticholinergic actions of commonly prescribed systemic medications
1 ; moderately elevated levels of serum prolactin
2 ; age-related, anatomic atrophy of the lacrimal acinar epithelium; stenosis of elements of the intraglandular duct system
3,4 ; obstruction within or at the orifices of the main excretory ducts; and physiologic dysfunction associated with lymphocytic infiltration.
Lymphocytic infiltration is common. One study found infiltrates in 20% of glands from females of reproductive-age, young males and elderly males, and in 65% of glands from elderly females.
5 Another report indicates that infiltrates were present in 83% of orbital glands from both males and females over 40 years of age.
6 These estimates are 3-fold or more higher than estimates of the prevalence of dry eye disease.
7,8 The actual disparity between histopathology and physiologic dysfunction might be even more pronounced, given that recent work
9–11 suggests that dry eye disease most often begins when age- and hormone-related changes in meibomian gland function
12 alter the thickness or composition of the lipid layer of the tear film
13 and that lacrimal fluid production subsequently decreases.
The examples of Sjögren's disease and von Mikulicz's disease suggest a general explanation for the evident disparity. The focal, B-cell–, and CD4
+ T-cell–rich infiltrates of Sjögren's disease can be associated with physiologic dysfunction even before gross changes in acinar- and ductal architecture become evident, whereas pervasive infiltration by the IgG
4-expressing plasmacytes of von Mikulicz's disease can have little impact on lacrimal fluid production.
14 Thus, some of the more common immunopathologic processes may impair physiologic function, and some may not.
Studies of biopsied labial salivary glands from patients with Sjögren's disease and of salivary and lacrimal glands of rodent models thought to mimic Sjögren's pathophysiology have provided evidence that both autoantibodies and also paracrine mediators released by the infiltrating immune cells can cause intact-appearing parenchymal tissues to be functionally quiescent.
15–17 Anti-M
3 acetylcholine receptor (M
3AChR) autoantibodies, present in sera of patients with Sjögren's syndrome, acutely suppress cholinergically induced elevations of cytosolic Ca
2+ in human labial salivary glands.
18 Nitric oxide, typically present in inflamed tissues, acutely potentiates, but then persistently attenuates, cholinergically induced elevations of cytosolic Ca
2+ in labial salivary gland preparations.
19 The inflammatory cytokines, IL-1α, IL-1β, and TNF-α, inhibit cholinergically induced glycoprotein secretion in ex vivo murine lacrimal gland models.
20
Exposure to elevated levels of prolactin, which functions as both a paracrine mediator and a hormone, causes acinar cells to redirect cholinergically induced merocrine protein secretion from the exocrine direction to the paracrine direction, without altering the total amount secreted.
21,22 Exposure to mediators that are not cytokines but, rather, G protein–coupled receptor agonists, can also interfere with cholinergically induced Ca
2+ elevation and exocrine β-hexosaminidase secretion. These include the muscarinic cholinergic agonist, carbachol (CCh), at a submaximal dose,
23 and the biogenic amines, histamine, and serotonin (5-HT).
24
The mechanisms of fluid secretion are largely distinct from the mechanism of merocrine protein secretion. They depend on H
2O transport proteins (aquaporins [AQPs])
25–27 and ion transport proteins
28–32 arrayed in the cells' apical- and basal-lateral plasma membranes. The ion transport proteins in the acini include Na
+/H
+ exchangers (NHE),
29 Cl
−/HCO
3 − exchangers (AE),
30 and Na
+-K
+-2Cl
− cotransporters (NKCC1)
31 —which function in the basal-lateral plasma membranes, Cl
− selective channels (ClC3 and CFTR)
32,33 —which function in the apical membranes,
34 and Na
+/K
+ exchange pumps (Na,K-ATPase), which some evidence indicates function in both the apical- and the basal-lateral membranes.
28 The mechanism in the acini secretes Cl
− ions into the lumens, thereby generating a negative transepithelial voltage difference; the voltage difference presumably drives Na
+ ions into the lumens via the zonulae occludens and zonulae adherens that link adjacent epithelial cells,
35 and the osmotic imbalance that results from the net secretion of Cl
− and Na
+ draws H
2O through the epithelium.
The ion transport proteins are largely quiescent in resting cells, and evidence indicates that each cycles between a relatively small plasma membrane pool and a much larger intracellular pool distributed through the endosomes and trans-Golgi network.
36–38 Therefore, mediators that cause lacrimal physiologic dysfunction may do so by interfering with neurotransmitter receptor signaling or intracellular signal transduction; with the biosynthetic turnover of one or more key transport proteins; with the proper plasma membrane insertion of one or more transport proteins; or with the activation of one or more transport proteins.
The microscopic scale of the lacrimal acinus-duct unit has made it difficult to determine whether the mediators that suppress agonist-induced Ca
2+ elevation or merocrine protein secretion exert the predicted influences on either fluid production or the ion fluxes that drive fluid production. The introduction of a new ex vivo model, an epithelial monolayer reconstituted from isolated rabbit lacrimal gland acinar cells,
39 has now made it possible to address this question. The magnitude of the secretory Cl
− flux the monolayer generates can be measured as the amount of current—referred to as the short-circuit current (
I SC)—that must be delivered through an external circuit to eliminate the voltage difference across the monolayer. The results described in the following text indicate that some mediators can suppress
I SC; some exert no influence; some potentiate it; and one, prolactin, exerts biphasic, concentration-dependent influences.