Dexamethasone alters F-actin architecture and promotes cross-linked actin network formation in human trabecular meshwork tissue.
Elevated intraocular pressure is an important risk factor for the development of glaucoma, a leading cause of irreversible blindness. This ocular hypertension is due to increased hydrodynamic resistance to the drainage of aqueous humor through specialized outflow tissues, including the trabecular meshwork (TM) and the endothelial lining of Schlemm's canal. We know that glucocorticoid therapy can cause increased outflow resistance and glaucoma in susceptible individuals, that the cytoskeleton helps regulate aqueous outflow resistance, and that glucocorticoid treatment alters the actin cytoskeleton of cultured TM cells. Our purpose was to characterize the actin cytoskeleton of cells in outflow pathway tissues in situ, to characterize changes in the cytoskeleton due to dexamethasone treatment in situ, and to compare these with changes observed in cell culture. Human ocular anterior segments were perfused with or without 10(-7) M dexamethasone, and F-actin architecture was investigated by confocal laser scanning microscopy. We found that outflow pathway cells contained stress fibers, peripheral actin staining, and occasional actin "tangles." Dexamethasone treatment caused elevated IOP in several eyes and increased overall actin staining, with more actin tangles and the formation of cross-linked actin networks (CLANs). The actin architecture in TM tissues was remarkably similar to that seen in cultured TM cells. Although CLANs have been reported previously in cultured cells, this is the first report of CLANs in tissue. These cytoskeletal changes may be associated with increased aqueous humor outflow resistance after ocular glucocorticoid treatment.
Clark
Abbot F
AF
Glaucoma Research, Alcon Research, Ltd. Fort Worth, Texas 76134, USA. abe.clark@alconlabs.com
Brotchie
Daniel
D
Read
A Thomas
AT
Hellberg
Peggy
P
English-Wright
Sherry
S
Pang
Iok-Hou
IH
Ethier
C Ross
CR
Grierson
Ian
I
D008841:Actin Cytoskeleton / Q000187:drug effects* / Q000648:ultrastructure*; D000199:Actins / Q000187:drug effects / Q000648:ultrastructure*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology* / Q000627:therapeutic use; D005901:Glaucoma / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects*; D009924:Organ Culture Techniques; D022502:Stress Fibers / Q000187:drug effects / Q000648:ultrastructure; D014129:Trabecular Meshwork / Q000187:drug effects* / Q000378:metabolism
D000199:Actins; D003907:Dexamethasone