A contemporary concept of the blood–aqueous barrier

doi:10.1016/j.preteyeres.2012.10.004

Progress in Retinal and Eye Research

Volume 32, January 2013, Pages 181-195

https://doi.org/10.1016/j.preteyeres.2012.10.004 Get rights and content

Abstract

This review traces the evolution of the concept of the blood–aqueous barrier (BAB) during the past 20 years. The Classical model simply stipulated that the tight junctions of the iris vasculature and ciliary epithelium excluded plasma proteins from the aqueous humor (AH). It failed to reconcile the presence of AH protein levels equal to 1% of that found in plasma. Moreover, models of barrier kinetics assumed that the processes of AH secretion and plasma protein entry were directly linked. Thus, elevations of AH protein levels could only be explained by a pathological breakdown of the BAB. Over the last 20 years it has been shown that the plasma proteins in normal AH by-pass the posterior chamber entirely. Instead, these proteins diffuse from the capillaries of ciliary body stroma, into the iris stroma and then into the anterior chamber. This creates a reservoir of plasma-proteins in the iris stroma that is not derived from the iris vessels. This reservoir is prevented from diffusing posteriorly by tight junctions in the posterior iris epithelium. The one-way valve created by the pupil resting on the anterior lens capsule, combined with the continuous, forward flow of AH through the pupil, prevents protein reflux into the posterior chamber. Importantly, in the new paradigm, secretion of AH and the entry of plasma proteins into AH, are semi-independent events. This opens the possibility that AH protein levels could increase in the absence of breakdown of the BAB. Clinical consequences of this new paradigm of the BAB are discussed.

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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A contemporary concept of the blood–aqueous barrier

Abstract

Graphical abstract

Highlights

Introduction

Section snippets

Early studies of the blood–aqueous barrier

The Classical model of the BAB

The original two-compartment model

The three-compartment model

In-vivo demonstration of the anterior diffusional pathway

The New model of the blood–aqueous barrier

The relationship between the new model of the blood–aqueous barrier and the blood–retinal barrier

Possible ramifications on aqueous 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?

Summary and future considerations

Acknowledgments

Am. J. Ophthalmol.

Am. J. Ophthalmol.

Exp. Eye Res.

Prog. Retin. Eye Res.

Prog. Ret. Eye Res.

Exp. Eye Res.

Exp. Eye Res.

Exp. Eye Res.

Ophthalmology

Exp. Eye Res.

Exp. Eye Res.

Exp. Eye Res.

Med. Hypoth.

Exp. Eye Res.

Exp. Eye Res.

Am. J. Ophthalmol.

Am. J. Ophthalmol.

Am. J. Ophthalmol.

Exp. Eye Res.

Exp. Eye Res.

Exp. Eye Res.

Exp. Eye Res.

Exp. Eye Res.

Physiological variations of the aqueous flare density in normal human eyes

Acta Ophthalmol. (Copenh.)

Influence of light on the 24-hour variation in aqueous flare density and intra-ocular pressure in normal rabbits' eyes

Acta Ophthalmol. (Copenh.)

Fundam. Clin. Pharmacol.

Simultaneous measurement of changing intraocular pressure and outflow facility in the vervet monkey by constant pressure infusion

Invest. Ophthalmol. Vis. Sci.

The source of protein in the aqueous humor of the normal monkey eye

Invest. Ophthalmol. Vis. Sci.

Demonstration of an anterior diffusional pathway for solutes in the normal human eye: high spatial resolution contrast-enhanced dynamic MR imaging

Invest. Ophthalmol. Vis. Sci.

The effects of pilocarpine on the dynamics of aqueous humor in a primate Macaca irus

Invest. Ophthalmol. Vis. Sci.

Capillary permeability to and extravascular dynamics of myoglobin, albumin and gammaglobulin in the uvea

Acta Physiol. Scand.

Uveoscleral drainage of aqueous humor in human eyes

Exp. Eye Res.

The blood–aqueous barrier

Trans. Ophthalmol. Soc. U. K.

LXII Edward Jackson Lecture: open angle glaucoma after vitrectomy

Am. J. Ophthalmol.

Proteome analysis of human aqueous humor

Invest. Ophthalmol. Vis. Sci.

The blood–retinal barriers system. Basic concepts and clinical evaluation

Exp. Eye Res.

Blood–retinal barrier

Eur. J. Ophthalmol.

The penetration of large water-soluble molecules into the aqueous humour

J. Physiol. (Lond.)

Physiology of the Ocular and Cerebrospinal Fluids

The intraocular fluids

Investigation of the “fines” hypothesis of primary open angle glaucoma; the possible role of alpha crystallin

Ophthalmic Res.

Das Sauerstoff-Bedurfnis des Organismus

Primary trabecular meshwork cells incubated in human aqueous humor differ from cells incubated in serum supplements

Invest. Ophthalmol. Vis. Sci.

The homogeneous structure of blood vessels in the vascular tree of Macaca mulatta

Invest. Ophthalmol. Vis. Sci.

Freeze-fracture analysis of the interendothelial junctions in blood vessels of the iris in Macaca mulatta

Invest. Ophthalmol. Vis. Sci.