Alerts User Alerts. You will receive an email whenever this article is corrected, updated, or cited in the literature. You can manage this and all other alerts in My Account. This feature is available to authenticated users only. Get Citation Citation. Get Permissions. The conference, funded by The ARVO Foundation for Eye Research through a grant from Pfizer Ophthalmics, provided an opportunity to gather experts from within and outside ophthalmology to develop strategies to improve research and clinical care in areas of ophthalmology related to preventable vision loss and blindness.
A working group of 31 researchers on aqueous outflow, 8 scientists working on interests other than aqueous humor outflow but with expertise in areas relevant to the field, and 11 observers from ARVO, Pfizer, and clinical and basic ophthalmic research convened on April 28, , to evaluate the current understanding of the aqueous humor outflow pathway. The goals were to compare similarities between ocular aqueous humor outflow and fluid flow in other tissues of the body, to critique conventional ideas, to identify the most important scientific questions, and to discuss strategies to answer these questions.
The meeting format emphasized discussion and concentrated on questions within four general areas of outflow research: Session I: Conventional Outflow: Cell Function in the Aqueous Humor Outflow Pathway. Each session began with a minute overview by an outflow researcher followed by a minute talk by one of the outside experts. Parallels between their fields of expertise and the eye were included in these talks. The remainder of each session was used to discuss questions pertinent to the main topic and provided an opportunity for attendees to voice their opinions and work together to define questions that are still unanswered.
The lively discussions were successful in defining old and new ideas that are essential to a better understanding of aqueous humor outflow. This conference summary highlights the ideas discussed and introduces areas that need further exploration.
Aqueous humor is produced by the ciliary body epithelium in the posterior chamber and flows into the anterior chamber. It is a complex mixture of electrolytes, organic solutes, growth factors, and other proteins that supply nutrients to the nonvascularized tissues of the anterior chamber i.
The TM is a filter made up of extracellular matrix e. Although advances have been made toward understanding the biochemical and molecular characteristics of the trabecular cells, still needed is the identification of molecules unique to specific cell phenotypes. The use of laser capture microdissection 4 followed by microarray analysis may be a valuable tool for dissection of individual cell types and as an aid in the identification of molecular markers specific for each cell type.
Identifying the means by which the TM cells sense and react to their environment fluid-flow, shear stress, or stretch will improve our understanding of how aqueous outflow is regulated. Do all TM cells react in a similar fashion to environmental stimuli or stress?
Cell—environment interactions may include stimuli at both the apical and basal sides of the cell. Changes that affect the apical side of a cell may alter cellular responses at the basal side, resulting in a decentralized signaling pattern. Are these changes similar to those of vascular endothelial cells during shear stress?
Several structures have been identified that appear to be associated with fluid movement within the conventional pathway. These are pressure-sensitive cellular protrusions that occur within and between canal cells. Whether giant vacuoles serve as conduits for aqueous entry into the canal in conjunction with pores or instead function as a mechanism to sense pressure by stretching and allow greater fluid flow in the neighboring intercellular junctions is unknown.
New techniques are needed to help identify whether these structures are physiologic. The use of fluorescence recovery after photobleaching may be useful in tracking fluorescent tracers distributed throughout the perfusing fluid.
What is the function of the cytoskeleton and the cell membrane, and how do the cells attach and detach from the extracellular matrix? Conventional Outflow: Role of the Extracellular Matrix. Although cells produce and regulate the amount of extracellular matrix, the matrix works with cells to help regulate cell function.
This process occurs through interactions with integrins and cell adhesion molecules. The extracellular matrix of the TM is made up of an intricate arrangement of collagen, laminin, fibronectin, proteoglycans, glycosaminoglycans GAGs , and matricellular proteins.
Matricellular proteins e. In the normal TM, these proteins are found in relatively high abundance, but their specific roles within the tissue is unclear.
Are they present in the TM because of stresses—particularly the stretching and configuration changes seen with variations in intraocular pressure IOP? Does this indicate a reaction to potential damage caused by this tissue movement? Use of antisense or small interfering si RNAs to decrease the amount of specific molecules may help to improve our understanding of matricellular protein function in the TM. For example, a reduction in SPARC could lead to a reduction in the deposition of extracellular matrix molecules.
The role of GAGs in outflow resistance remains unclear. GAGs are negatively charged molecules found primarily on the surfaces of cells and in the extracellular matrix. Molecules in this family can create increased viscosity within solutions due to their extended conformation. In cartilage, one role of GAGs is to hold water and slowly release it under pressure. These eyes have less hyaluronic acid and more chondroitin sulfate than do healthy eyes.
Does the TM contain substantial amounts of GAGs making these molecules responsible for outflow resistance? At present, histologic techniques to verify the amount of GAGs in the TM may cause a partial or complete loss of these molecules during processing.
Preservation of the tissue by freezing with isopentane may provide a deeper and more instant freeze and help in the preservation of these molecules.
Also, the use of newer microscopy techniques, such as environmental scanning electron microscopy, 28 may provide better preservation of the extracellular matrix, enabling visualization of the GAG molecules. The use of cytoskeleton-modifying agents H7 and latrunculin A and B has been shown to lower IOP, suggesting the actin cytoskeleton as a target for regulating aqueous outflow.
This question has been debated for more than years. Evidence now suggests that both cells and the extracellular matrix affect outflow resistance. However, on a longer time scale hours or more , the extracellular matrix seems likely to modulate outflow resistance significantly. Therefore, both the cells and the extracellular matrix are essential in the task of maintaining aqueous outflow.
Since its first description in the s, the unconventional pathway uveoscleral outflow has been more difficult to study than the conventional pathway and hence is less well understood. The conference discussion topics focused on what precisely is the uveoscleral outflow pathway, how are relevant physiological parameters within uveoscleral outflow measured e.
In uveoscleral outflow, aqueous humor enters the ciliary muscle and exits through the supraciliary space and across the anterior or posterior sclera, through the emissarial canals around the vortex veins, or into the choroidal vessels.
Until recently, the uveoscleral outflow pathway was largely considered a passive and minor route for aqueous humor outflow. Identification of the changes that occur in the uveoscleral pathway with age is needed to explain the reduced uveoscleral flow.
Calculations based on the modified Goldmann equation are the only way to estimate uveoscleral outflow in clinical studies. New techniques for the measurement of uveoscleral flow are clearly needed. Using the uveoscleral pathway for therapeutic purposes could involve both lowering of IOP and drug delivery via a transscleral approach. Current understanding of the mechanism of the IOP decrease caused by prostaglandin treatments involves permeability changes in the ciliary body. Can scleral permeability be altered by drugs such as prostaglandins to allow diffusion of drugs from the orbit into the eye?
POAG is a heterogeneous disease that becomes increasingly common with age. With the increasing sophistication of techniques in molecular biology and biochemistry, analysis of TM specimens and aqueous humor proteins has revealed a variety of molecules that differ between normal and glaucomatous eyes. A recent proteomics study found proteins in the TM, with 52 present only in glaucomatous TM and present only in normal TM.
Furthermore, in investigations of specific protein levels in aqueous humor, the relative concentrations of the molecules should be expressed as a proportion of total aqueous protein, to help gauge whether the aqueous humor is mixed with contaminating proteins. As the population ages, more attention is being paid to damage caused by various forms of oxidative stress. Has the antioxidative potential of aqueous humor been compromised, enabling an imbalance between free radical production and antioxidative defense mechanisms?
Improved understanding of the oxidative stresses, the antioxidant potential, and the effect of oxidative damage on the cellular function of the outflow pathway will help identify the possible role of oxidative stress in the etiology of POAG.
Oxidative stress can also occur through the accumulation of advanced glycation end AGE products. Accumulation of AGE products may interfere with the structural properties of the protein, potentially resulting in deleterious effects. AGE products have been found in the cornea, lens, vitreous, and retina, and an increase in AGE products in age-related macular degeneration suggests that they have a role in many ocular diseases. It is interesting to note that accelerated AGE production occurs in diabetes.
Older studies found a relationship, 64 65 whereas the recent Ocular Hypertension Treatment Study did not. The outflow pathways maintain a stable IOP despite transient elevations of IOP that occur due to various eye movements blinking, squeezing the eyes shut, rubbing the eyes. How does the TM handle levels of stress stretch, shear?
What happens to the actin cytoskeleton during these events? Does outflow resistance change at night? Recent studies finding elevation of IOP at night 68 are surprising, in view of the decrease in aqueous humor flow.
Given our growing understanding of the importance of cell—extracellular matrix interactions on cellular physiology, cell culture conditions that do not match the normal cell-extracellular matrix profile may be outdated.
Comparisons of cultured cells in different conditions are needed, with the ultimate goal of matching the characteristics cell markers of fresh, noncultured cells. Although POAG is mainly a human disease, naturally occurring glaucoma has been identified in rhesus monkeys 73 and certain strains of dogs. A systematic screening of the eyes in existing knockout mouse models may find important glaucoma-associated changes or anatomic changes in the outflow pathways that will help to improve our understanding of outflow physiology.
An alternative approach would be to use chemical mutagenesis 76 and identify abnormal outflow in mice. This method would enable the screening of many point mutations within the mouse. The identification of a glaucoma phenotype in the mouse would provide the foundation for a genetic survey and identification of genes associated with the disease. From the ciliary body, aqueous humor flows through the pupil and into the anterior chamber.
Aqueous humor then leaves the anterior chamber through a structure called the drainage angle. Once inside the drainage angle, the aqueous fluid leaves the eye through a spongy tissue called the trabecular meshwork.
Imbalances in the amount of aqueous produced and aqueous drained can lead to ocular hypertension , or high eye pressure. This can occur because of an overproduction of aqueous humor or an insufficient drainage of it. As mentioned earlier, aqueous humor leaves the eye through the drainage angle. The narrower the drainage angle becomes, the more difficult it is for the aqueous humor to drain. This type of glaucoma is rare and may occur gradually or suddenly called acute angle closure.
Many times, when glaucoma development is gradual, a person may experience few to no symptoms. Indentation tonometry tends to underestimate IOP when compared to the applanation gold standard. In primary open-angle glaucoma, the secretion of aqueous humor remains normal. Though elevated IOP is associated with glaucoma, this parameter does not sufficiently explain its pathogenesis: patients with normal IOP may have glaucoma, and patients with high IOP may not have glaucoma. Aqueous humor is clinically significantly related to IOP and, therefore, glaucoma, as described above.
The systematic review showed insufficient evidence to recommend screening these patients. The suggested evaluation frequency increased with age: every 2 to 4 years in patients between 40 and 50, every 1 to 3 years in those between 55 and 64, and every 1 to 2 years in those over The AAO made further recommendations for patients who have diabetes mellitus or other risk factors for glaucoma.
Yearly examination was recommended for patients with type 1 diabetes, beginning five years after disease onset. The annual examination was also recommended for patients with type 2 diabetes but beginning at diagnosis. Lastly, a biennial examination was recommended for any patient with risk factors for glaucoma, regardless of age. The International journal of developmental biology. Leske MC, Ocular perfusion pressure and glaucoma: clinical trial and epidemiologic findings.
Current opinion in ophthalmology. PLoS biology. Survey of ophthalmology. Progress in retinal and eye research. Experimental eye research. Middle East African journal of ophthalmology. Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures.
American journal of ophthalmology. Leske MC, The epidemiology of open-angle glaucoma: a review. American journal of epidemiology.
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