Trabecular Outflow Resistance Research Articles

Profile of netarsudil ophthalmic solution and its potential in the treatment of open-angle glaucoma: evidence to date.

Netarsudil ophthalmic solution is a novel topical intraocular pressure (IOP)-lowering agent that has recently been approved by the US Food and Drug Administration (FDA) for the treatment of ocular hypertension and open-angle glaucoma. Its unique pharmacology allows for IOP lowering as a result of direct reduction in trabecular outflow resistance in addition to a decrease in episcleral venous pressure and aqueous humor production. The efficacy of netarsudil has been shown in animal studies and human clinical trials. It has been shown to be noninferior to the therapy with topical timolol in individuals with baseline IOP <25 mmHg. Importantly, netarsudil has been shown to reduce IOP to the same degree, regardless of baseline levels. There are no known systemic safety issues associated with netarsudil. The most common local adverse effects relate to conjunctival hyperemia. The once-daily dosing schedule is advantageous for individuals who have difficulties with medication adherence. Further studies of a combination of netarsudil and latanoprost agents are currently underway.

Update on Microinvasive Glaucoma Surgery.

Update on Microinvasive Glaucoma Surgery.

Intraocular Pressure and the Mechanisms Involved in Resistance of the Aqueous Humor Flow in the Trabecular Meshwork Outflow Pathways.

Intraocular pressure (IOP), the critical risk factor for glaucoma, is generated and maintained by the aqueous humor circulation system. Aqueous humor is secreted from the epithelial layers of the ciliary body and exits the eye through the trabecular meshwork or the uveoscleral outflow pathways. IOP builds up in response to a resistance to aqueous humor flow in the trabecular outflow pathways. The trabecular outflow resistance is localized in the inner wall region, which comprises the juxtacanalicular connective tissue (JCT) and the inner wall endothelium of Schlemm's canal (SC). Outflow resistance in this region is lowered through the relaxation of contractile myofibroblast-like cells in trabecular meshwork and the adjacent scleral spur, or the contraction of the ciliary muscle. In primary open-angle glaucoma, the most frequent form of glaucoma, outflow resistance of the inner wall region is typically higher than normal. There is evidence that the increase in resistance is related to characteristic biological changes in the resident cells of the JCT, which more and more acquire the structural and functional characteristics of contractile myofibroblasts. The changes involve an augmentation of their actin cytoskeleton and of their surrounding fibrillary extracellular matrix, which connects to JCT cells via integrins. This scenario leads to an overall stiffening of the inner wall region, and is modulated by transforming growth factor-β/connective tissue growth factor signaling. Essentially comparable changes appear to occur in SC endothelial cells. Stiffening of JCT and SC cells is very likely a critical causative factor for the increase in trabecular outflow resistance in POAG.

Emerging Trabecular Outflow Drugs

Emerging Trabecular Outflow Drugs

Comparisons of actin filament disruptors and Rho kinase inhibitors as potential antiglaucoma medications

Dynamics of the actin cytoskeleton in the trabecular meshwork play a crucial role in the regulation of trabecular outflow resistance. The actin filament disruptors and Rho kinase inhibitors affect the dynamics of the actomyosin system by either disrupting the actin filaments or inhibiting the Rho kinase-activated cellular contractility. Both approaches induce similar morphological changes and resistance decreases in the trabecular outflow pathway, and thus both have potential as antiglaucoma medications. Although the drugs might induce detrimental changes in the cornea following topical administration, lower drug concentrations in larger volumes as used clinically, but not higher drug concentrations in smaller volumes as used experimentally, could minimize corneal toxicity. Additionally, developments of trabecular meshwork-specific actin filament disruptors or Rho kinase inhibitors, prodrugs and new drug-delivery methods might avoid the drugs’ toxicity to the cornea. Gene therapies with cytoskeleton-modulating proteins may mimic the effects of the cytoskeleton-modulating agents and have the potential to permanently decrease trabecular outflow resistance.

Immunohistochemical distribution of type VI collagen in normal and glaucomatous human trabecular meshwork.

An abnormally increased presence of type VI collagen has been shown in the lamina cribrosa of patients with primary and secondary glaucoma. This study was undertaken to investigate the pattern of type VI collagen within the aqueous outflow structures of glaucoma patients. Trabecular meshwork samples of eight normal donor eyes and trabeculectomy specimens of 21 patients with different types of glaucoma were processed for either cryo-sectioning or for paraffin embedding. Immunohistochemical staining was conducted by use of polyclonal rabbit antibodies against human collagen type VI. Immunoreactivity for type VI collagen was evident in the cores of all trabecular beams. The strongest staining was detected in the uveal region of the human trabecular meshwork. Immunohistochemical labelling for type VI collagen was not more pronounced in the aqueous outflow structures of glaucoma patients than in normal eyes. Collagen type VI is a ubiquitous structural component of the extracellular matrix in the human trabecular meshwork. However, type VI collagen does not appear to be of greater importance for the increased trabecular outflow resistance in glaucoma patients than in normal eyes.

The Effect of Interleukin-1?? on Outflow Facility in Rat Eyes

The authors investigated whether regulation of the trabecular extracellular matrix turnover rate and remodeling plays an important role in decreasing outflow resistance by determining the effect of intracamerally given interleukin-1alpha, a known stimulator of the expression of trabecular matrix metalloproteinases, on outflow facility of albino rat eyes. Forty normal albino rats (Sprague-Dawley), weighing 250 to 300 g, were studied. Rats were anesthetized by intraperitoneal pentobarbital sodium (30 mg/kg) injection. The rats were separated into four groups and given 5, 10, 25, or 50 units of interleukin-1alpha injected intracamerally in one eye. Bovine serum albumin in phosphate-buffered saline, which was used to dissolve the interleukin-1alpha, was injected in the fellow eye as a control. Outflow facility was measured by two-level constant pressure perfusion 1, 3, and 7 days after injection. The eyes treated with 50 units of interleukin-1alpha showed a statistically significant increase of outflow facility by 37% compared with the contralateral control eyes 3 days after injection, but returned to normal levels in 7 days. The eyes treated with 5, 10, 25, or 50 units of interleukin-1alpha showed outflow facility increases of 12%, 20%, 39%, and 37%, respectively, 3 days after injection. Interleukin-1alpha increased the outflow facility, supporting the hypothesis that regulation of trabecular meshwork extracellular matrix plays a role in trabecular outflow resistance.

The role of the iris and the ciliary body in the drainage of aqueous humour: II. Studies in monkeys

Intraocular pressure (IOP), the critical risk factor for glaucoma, is generated and maintained by the aqueous humor circulation system. Aqueous humor is secreted from the epithelial layers of the ciliary body and exits the eye through the trabecular meshwork or the uveoscleral outflow pathways. IOP builds up in response to a resistance to aqueous humor flow in the trabecular outflow pathways. The trabecular outflow resistance is localized in the inner wall region, which comprises the juxtacanalicular connective tissue (JCT) and the inner wall endothelium of Schlemm's canal (SC). Outflow resistance in this region is lowered through the relaxation of contractile myofibroblast-like cells in trabecular meshwork and the adjacent scleral spur, or the contraction of the ciliary muscle. In primary open-angle glaucoma, the most frequent form of glaucoma, outflow resistance of the inner wall region is typically higher than normal. There is evidence that the increase in resistance is related to characteristic biological changes in the resident cells of the JCT, which more and more acquire the structural and functional characteristics of contractile myofibroblasts. The changes involve an augmentation of their actin cytoskeleton and of their surrounding fibrillary extracellular matrix, which connects to JCT cells via integrins. This scenario leads to an overall stiffening of the inner wall region, and is modulated by transforming growth factor-β/connective tissue growth factor signaling. Essentially comparable changes appear to occur in SC endothelial cells. Stiffening of JCT and SC cells is very likely a critical causative factor for the increase in trabecular outflow resistance in POAG.