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E. Evans, D. A. Gamache, S. F. Hamm-Alvarez; The Effect of Cilomilast, a Specific PDE4 Inhibitor, on Lacrimal Acinar Cell Secretion. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4166.
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Inflammation plays a role in the pathogenesis of dry eye and affects ocular surface tissues including the lacrimal gland. Therapy with anti-inflammatory drugs may provide benefits for treatment of dry eye. Here we investigate the use of Cilomilast, a specific PDE4 inhibitor, as a secretagogue in lacrimal gland acinar cells (LGAC).
Rabbit LGAC cultured for 2 days were treated with Cilomilast, a specific PDE4 inhibitor, (0-100µM) for 0-24hrs and analyzed without and with carbachol (CCH; 100µM, 30min). For secretion studies, β-hexosaminidase (βhex) and bulk protein were measured biochemically and secretory component (SC) was detected by Western blotting. Distributions of secretory markers and actin filaments were analyzed by immunofluorescence and confocal microscopy.
Treatment of rabbit LGAC with Cilomilast, a specific PDE4 inhibitor, (10-100µM, 4hr) revealed significant increases in bulk protein and βhex secretion. A time-course study revealed significant increases in bulk protein, βhex, and SC secretion at 4- and 8-hrs with 30µM Cilomilast, a specific PDE4 inhibitor. CCH-stimulation of LGAC treated with Cilomilast, a specific PDE4 inhibitor, (30µM, 4hr) did not further enhance secretion of any of the secretory markers although Cilomilast-treated cells responded to CCH stimulation. The LGACs treated with Cilomilast, a specific PDE4 inhibitor, for 4hrs were able to respond to CCH stimulation after a 3-hr washout. Confocal microscopy showed changes in luminal actin filament structure in LGAC treated with Cilomilast, a specific PDE4 inhibitor, (30µM, 4hr) including enlarged lumena and actin-coated secretory vesicles. Cilomilast, a specific PDE4 inhibitor, also elicited a change in the subcellular localization of rab3D, SC, and βhex that were comparable to LGAC stimulated with CCH alone, indicating presence of secretory activity.
Cilomilast, a specific PDE4 inhibitor, enhances the apical secretion of various secretory proteins from LGAC after sustained exposure, indicating it may be a good candidate for treatment of dry eyes. Studies exploring the mechanisms of its activity are underway.
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