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CE Crosson, A Ferrell, T Shearer; Chronic Dexamethasone Treatment Inhibits Stretch-Induced Activation of MAP Kinases and Matrix Metalloproteinase Secretion from Trabecular Cells . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1027.
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Purpose: The chronic administration of steroids can increase IOP; however, the cellular mechanisms responsible for this rise in IOP are not understood. The purpose of these studies was to evaluate how chronic exposure of trabecular cells to dexamethasone (DEX) alters stretch-induced responses. Methods: The HTM-3 trabecular cell line was maintained in the presence or absence of DEX (10-6 mol/L) for 2 or 6 days on 6-well flex plates in DMEM with 10% serum. Cells were serum-starved for 16 hours prior to the start of stretch stimulus. Cellular stretch was controlled using the Flexcell system. The activation of ERK and p38 MAP kinases and matrix metalloproteinase-9 (MMP9) were evaluated following cellular stretch. Results: Cells maintained in normal media for 2 or 6 days, cyclic stretch (1 cycle/2 minutes; 20% elongation) induced a rapid (5 minute) activation (3- to 5-fold) of ERK and p38 MAP kinases. In addition, stretch for 6 hours induced a 4-fold increase in MMP9 secretion over basal levels, which was dependent on early activation of ERK and p38. Cells maintained in media with DEX for 2 days showed no significant difference from control cells in stretch-induced activation of MAP kinase pathways or MMP9 secretion. However, cells maintained in media with DEX for 6 days exhibited significant reduction in stretch-induced activation of ERK and p38 MAP kinase, as well as an inhibition of MMP9 secretion. Cells in each group remained attached with no change in viability or alteration in ERK or p38 protein expression. Conclusion: Mechanical stretch may provide an intrinsic system within the eye to regulate trabecular cell function. These studies provide evidence that in trabecular cells stretch-induced secretion of MMP9 requires the early activation of ERK and p38 MAP. Chronic exposure of trabecular cells to DEX inhibits the secretion of MMP9, and this inhibitory response appears to involve the inhibition of MAP kinase pathways in these cells. These results provide evidence that chronic steroid treatment may increase IOP by disrupting MAP kinase signaling, thus leading to a reduction in MMP secretion from trabecular cells.
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