Excess Fibronectin Accumulation in the Trabecular Meshwork: A Potential Mechanism for Increasing Aqueous Outflow Resistance

Purpose:Substantial evidence indicates that extracellular matrix accumulation in trabecular meshwork (TM) is associated with aqueous outflow resistance. The purpose of this study is to determine whether excess fibronectin (FN) accumulation in TM contributes to outflow resistance by downregulating synthesis of FN overexpression by the TM cells in primary open angle glaucoma. Methods:Cryosections of anterior chambers were prepared from normal, glaucomatous, and diabetic human eyes and examined for FN, collagen IV (Coll IV), and laminin (LM) expression by immunohistochemistry. In addition, organ cultures of anterior chambers from normal, glaucomatous, and diabetic eyes were perfused with antisense oligonucleotides (AS-oligos) against FN transcript (FN AS-oligos) and the aqueous outflow measured. To determine the FN AS-oligo efficacy, TM tissues of the anterior chamber were fixed after FN AS-oligo perfusion and immunostained for FN. Results:In TM of glaucomatous and diabetic eyes, FN immunostaining was significantly increased compared to those of the control eyes (160.2±43.2% of control; p < 0.05, 143.5±29.4% of control; p < 0.05, respectively). At 48 hours post-FN AS-oligo treatment, the aqueous outflow facility was significantly increased in perfusion organ cultures of normal, glaucomatous, and diabetic eyes (116±4%, 129±3%, and 125±2% of baseline value, respectively). Coll IV and LM immunostaining in TM of glaucomatous and diabetic eyes showed increased expression but not significantly compared to those of normal eyes. Conclusions:Our results suggest that excess FN accumulation in TM contributes to aqueous outflow resistance in glaucomatous and diabetic human eyes. ASoligo strategy may be useful in facilitating aqueous outflow and possibly reducing intraocular pressure in patients with glaucoma. CR: T. Oshitari, None; N. Wang, None; A. Li, None; T. Sato, None; S. Roy, None. Support: NEI, NIH, the American Diabetes Association, Fight for Sight, the Massachusetts Lions Eye Research Fund Inc. 1838 B119 Shear Stress and Interleukin-1 Induce Nuclear Factor Kappa B and Nitric Oxide Synthase in Cultured Schlemm’s Canal Cells