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Paul A. Knepper, Ryan D. McCarty, Algis Grybauskas, Jeffrey P. Mayer, Robert A. Burdi, Edward Wagner, John R. Samples, Jeffrey M. Liebmann, Robert Ritch; Low Molecular Weight Hyaluronic Acid and Hyaluronic Acid Binding Protein-2: A Theory for Hemorrhages in POAG. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2797.
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Although optic disc hemorrhages are well recognized as a clinical feature of primary open-angle glaucoma (POAG); recently, and somewhat suprisingly, nail bed hemorrhages were observed in 20% of POAG. The purpose of this study was to determine the concentration and molecular weight profile of hyaluronic acid (HA) in POAG patients with well defined clinical status, identify hyaluronic acid binding protein-2 (HABP-2; a serine protease) and correlate these findings to a theoretical explanation of hemorrhages in the optic nerve and nail bed.
Pooled aqueous humor samples of 3 stages of POAG-- early, moderate, and advanced (n=6 in each pool) and age-matched control subjects (n=6) were analyzed for HA using highly sensitive mini-slab 15% Tris/borate/EDTA gels with pulsed electrophoresis, and stained with 0.05% Stains-All as previously described. Each group was analyzed for protein content and equal amounts of proteins were resolved by SDS polyacrylamide gel electrophoresis and immunoblotted with a panel of anti-HABP-2 antibodies and the Western blots were analyzed by integrated optical densitometry.
The HA concentration in normal aqueous was ~3.0 ng/ul whereas the HA concentration in POAG was considerably lower and the majority of the HA was less than 110 kD. All POAG aqueous samples were postive for HABP-2. The relative amounts of HABP-2 were: early POAG, 0.98; moderate POAG,1.22; and advanced POAG, 1.28 relative to normal aqueous.
A working hypothesis in POAG is that the "prime mover" is low molecular weight HA which: 1) disrupts vascular endothelial barriers, 2) activates HABP2-- a serine protease-- which in turn, 3) activates tissue factor VII to 4) promote thrombosis and subsequent hemorrhage. This putative low molecular weight HA signaling pathway and its clinical significance could be an explanation for both the optic disc and nail-bed hemorrhages. These recent findings of low molecular weight HA signaling through innate immune receptor complex --CD44-Toll-4-MD-2 --suggests a previously unappreciated unifying cell signaling pathway and is the first cell signaling pathway explanation of the vascular events and their sequelae in POAG.
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