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A. K. Mircheff, M. L. McDonald, Y. Wang, T. Nakamura, S. Selvam, S. C. Yiu, M. D. Trousdale, J. E. Schechter; Derangement of Lacrimal Acinar Function During Chronic Stimulation With Inflammatory Mediators. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5418.
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Chronic inflammation of the lacrimal gland may mediated by diverse pathophysiologic mechanisms. Sjögren’s syndrome is a CD4 T cell - IgG B cell disease; AIDS-associated diffuse lymphocytosis is a CD8 T cell disease. However, most dry eye cases may be associated with chronic, low-grade dacryoadenitis (CLGD), the pathophysiology of which is poorly understood. In rodents, CLGD is characterized by increased numbers of lymphocytes and mast cells and by marked changes in epithelial cytoarchitecture. The present study addressed the influence of chronic stimulation by the mast cell mediators, histamine (H) and serotonin (5-HT), on an ex vivo model of acinar cells from rabbit lacrimal gland.
Acinar cells were isolated and maintained for 3- to 4 d on Matrigel-coated coverslips or multiwell plates. β-hexosaminidase secretion and cytoarchitectural features were assessed after acute, i.e., 20 m, stimulation with carbachol (CCh), H, or 5-HT; after chronic, i.e., 20 h, stimulation; and after chronic stimulation followed by acute stimulation.
As others have described for rat lacrimal gland, H and 5-HT were protein secretagogues for rabbit acinar cells. While they were relatively potent, eliciting maximal responses at 1 µM and 10 µM, respectively, the secretory responses were lost as the agonist concentrations increased. In contrast, CCh does not elicit a supramaximal response. CCh activation of protein secretion is accompanied by recruitment of p150Glued, an adaptor for the microtubule-based molecular motor, cytoplasmic dynein, to the subapical actin microfilament meshwork. In contrast, acute H and 5-HT recruited p150Glued only at supramaximal concentrations. Chronic supramaximal H prevented acute CCh from eliciting protein secretion, while optimal H and 5-HT and supramaximal 5-HT did not. Chronic H and 5-HT at all concentrations expanded the acinar lumena; thickened the subapical actin meshworks; and caused the appearance of numerous cytoplasmic vacuoles, which occasionally appeared subjacent to the basal-lateral plasma membranes.
The results suggest that mediators released from mast cells during chronic low grade dacryoadenitis may impair protein secretion. Moreover, by altering the vesicle-mediated traffic of proteins within lacrimal epithelial cells, they may increase the exposure of autoantigens and perpetuate the inflammatory process.
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