A contemporary concept of the blood–aqueous barrier
Graphical abstract
A: Classical model -the tight junctions of the non-pigmented ciliary epithelium (•••••) and the iris vascular endothelium are the key elements. Plasma proteins are assumed to be part of aqueous as it is secreted. Elevation of protein concentrations can only be explained by an increase in blood-aqueous barrier permeability. B: New Model - Plasma proteins in aqueous humor diffuse from the ciliary body stroma, to the anterior chamber and outflow pathways (arrows). Protein entry is semi-independent of aqueous production and thus concentration can change within limits, without altering barrier permeability. The anterior and posterior chambers are different environments, with unidirectional aqueous flow and tight junctions of the iris epithelium (•••••) separating them.
Highlights
► The source and route of plasma protein entry into aqueous humor is described. ► The blood–aqueous barrier is not primarily a barrier between blood and aqueous. ► The blood–aqueous barrier separates different environments in front of and behind the iris. ► Not all clinically observable anterior chamber flare is pathological.
Introduction
The notion that certain tissues of the body do not reach equilibrium with all constituents of plasma originated in the late 1880's (Ehrlich, 1885) and more definitively in the early 1900's when the vital dye Trypan Blue was injected intravenously and found to permeate virtually all of the body tissues except the brain (Goldmann, 1913). With time, as additional tissues were examined in greater detail, others were found to exhibit significant restrictions in the extent to which plasma constituents were permitted to reach equilibrium with the extracellular environment of the tissues being served by those vessels. Among these was the eye.
Traditionally, two barriers have been described in the eye – a blood–aqueous barrier and a blood–retinal barrier. The blood–retinal barrier is commonly presented as having an “inner” and outer” component. The “inner” component is provided by the interendothelial tight junctions of the intraretinal vasculature and the “outer” component of the barrier is provided by the tight junctions of the retinal pigmented epithelium. Several high caliber reviews of the blood–retinal barrier are available elsewhere and thus this discussion will be limited to the blood–aqueous barrier (BAB) and an integral concept of how the two barriers are inter-related (Cuhna-Vaz, 2004; Cuhna-Vaz et al., 2011).
Section snippets
Early studies of the blood–aqueous barrier
The earliest studies of the BAB were biochemical comparisons between the ionic and molecular constituents of the aqueous humor (AH) and plasma (Davson, 1953, 1956, 1969). One of the most significant differences found between plasma and aliquots of aqueous humor obtained by paracentesis from the anterior chamber, was that the plasma-derived protein concentration in AH was about 1% of that found in plasma (Tripathi et al., 1989). The answers to the questions of how and where that small amount of
The Classical model of the BAB
The Classical model of the BAB that was in use until the mid to late-1990s included the tight junctions of the iris vascular endothelium as one critical element (Fig. 2). This was presumed to be critical because the anterior surface of the iris is not covered by an epithelium and therefore aqueous humor freely permeates the iris stroma. The tight junctions of the iris vasculature kept plasma proteins from leaking into the iris stroma. The apico-lateral tight junctions of the non-pigmented
The original two-compartment model
When presented as a computational model, a two compartment model was used in which solutes moved directly from the blood into the AH, governed by a single barrier transfer coefficient (Goldmann, 1951; Nagataki, 1975) (Fig. 3). Diffusional losses to the corneal stroma were also considered. In efforts to collect non-invasive data on BAB kinetics using such methods as fluorophotometry, several investigators began to notice that the two compartment model failed to adequately predict the time course
The three-compartment model
Following up on these studies, McLaren et al. (1993) completed a series of studies in both rabbits and in normal human subjects exploring whether replacing the “time-delay” concept of Wilson and Barany (1983) with a defined third compartment would provide a better match with the actual kinetics of fluorescein entry from the blood into the AH of the anterior chamber. When the actual data were plotted along the predicted curves for both the two compartment and three compartment models, the
In-vivo demonstration of the anterior diffusional pathway
The computational modeling, fluorophotometric and morphological tracer studies all pointed toward the source of the small amount of plasma-derived protein present in the AH by-passing the posterior chamber and entering the AH of the anterior chamber from the iris root. But the actual events occurring in the posterior chamber of the eye had to be inferred from the kinetics of tracer entry into the anterior chamber using computational modeling. Kolodny et al. (1996) were able to provide the first
The New model of the blood–aqueous barrier
The New model of the BAB differs in several important respects from the Classical model. Most of these differences are depicted in Fig. 10.
Like the Classical model, the tight junctions of the non-pigmented ciliary epithelium and of the iris vascular endothelium are key elements. Under normal conditions they prevent plasma-derived proteins from entering the aqueous humor of the anterior and posterior chambers. One of the things that has changed is that we now know the source and the pathway
The relationship between the new model of the blood–aqueous barrier and the blood–retinal barrier
Taken out of isolation and viewed in the broader context of the blood–ocular barriers generally, the new model of the BAB changes the relationship between the blood–aqueous and blood–retinal barriers. In the new model, the BAB is less a barrier between the blood and the aqueous than it is a separation between the more restrictive environment behind the iris and the more permissive environment required by the metabolic needs of the avascular tissues facing the anterior chamber. The tight
Possible ramifications on aqueous outflow
Clearly, the anterior diffusional pathway for plasma-derived proteins and other macromolecules enters the anterior chamber at the anterior chamber angle. At this location, it would be reasonable to predict that some fraction of the solutes delivered to the surfaces of the iris and the ciliary body band is immediately carried into the aqueous outflow pathways through the trabecular meshwork (Fig. 11). Computational modeling suggested that the amount of plasma-derived protein reaching the outflow
What are the proteins that enter the anterior chamber via this pathway and how does this new model of the BAB alter the ways in which the avascular tissues of the eye interact with posterior and anterior chamber aqueous humor?
As methods for protein analysis of small volumes of fluid have improved, it has become feasible to perform increasingly sophisticated protein analyses on aliquots of aqueous humor-all of which have been obtained from the anterior chamber. Progressing from 2-d gels (Tripathi et al., 1989) to mass spectrometry (Rohde et al., 1998), to more complex proteomic analyses, it has become possible to identify a large number of proteins in AH. Some are produced by tissues within the eye and others enter
Summary and future considerations
The new paradigm, if understood in its complete form, fundamentally changes the concept of the blood–aqueous barrier. Viewed in its full context, the BAB is less a barrier between blood and aqueous per se, than it is a complex system designed to separate the pristine environment behind the iris from the more permissive environment required to sustain the avascular tissues at, or anterior to, the iris plane including the cornea, trabecular meshwork and the metabolically-active anterior
Acknowledgments
The work of the author cited in this article has been supported by NIH RO1 EY-04567, RO1 EY-13825 to TFF, by RO1 EY-09699 to Dr. Mark Johnson (MIT and Northwestern University), by The Whitaker Foundation, by National Glaucoma Research, a program of the American Health Assistance Foundation, by Fight for Sight in support of Nathan Neville, O.D., M.S. and The Massachusetts Lions Eye Research Fund, Inc. The long term loan of a Kowa Flare-Cell meter from Alcon Laboratories, Inc. and critical
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Percentage contribution of the author: 100%.