Effect of dexamethasone on the expression of MMPs, adenosine A1 receptors and NFKB by human trabecular meshwork cells

ObjectivesSteroid-induced ocular hypertension and glaucoma are associated with extracellular matrix remodeling at the trabecular meshwork (TM) of the eye due to reduced secretion of matrix metalloproteinases (MMPs), a family of enzymes regulating extracellular matrix proteolysis. Several biological functions of steroids are known to involve regulation of adenosine A1 receptors (A1AR) and nuclear factor kappa B (NFKB). Since MMPs expression in TM has been shown to be regulated by A1AR as well as transcription factors, it is likely that dexamethasone-induced changes in aqueous humor dynamics involve reduced MMP and A1AR expression and reduced NFKB activation. Hence, the current study investigated the association of dexamethasone-induced reduction in MMP secretion with reduced NFKB activation and A1AR expression.MethodsHuman trabecular meshwork cells (HTMCs) were characterized by estimating myocilin and alpha smooth muscle actin expression and then were treated with dexamethasone 100 nM for 2, 5 and 7 days. The MMP secretion was estimated in culture media using Western blot. Immunocytochemistry (ICC) and ELISA were done to investigate the effect of dexamethasone on NFKB phosphorylation. A1AR expression in HTMCs was determined using Western blot and ELISA.ResultsDexamethasone caused a significant reduction in both MMP-2 and -9 expression compared to untreated group after five and seven days but not after two days of culture. Significantly reduced phosphorylated NFKB and A1AR protein levels were detected in dexamethasone treated compared to vehicle treated HTMCs after five days of culture.ConclusionsDexamethasone reduces MMP-2 and -9 secretion by HTMCs and this effect of dexamethasone is associated with reduced NFKB phosphorylation and A1AR expression.

Multiscale mathematical modeling of aqueous humor dynamics: Applications for precision care in glaucoma

Background and Hypothesis: Reduction of intraocular pressure (IOP) resulting from overproduction or impaired outflow of aqueous humor is, to date, the only approved medical treatment for the disease. IOP is determined by the balance between aqueous humor production at the ciliary body and drainage at the anterior chamber angle. A mathematical model describing aqueous humor (AH) flow was employed in order to study the effects of glaucoma medications and risk factors on IOP. Experimental Design or Project Methods: IOP can be calculated as the unknown variable in the mathematical balance between AH inflow (Jin) and outflow (Jout). Model simulations using MATLAB were used to calculate IOP in conditions of varied trabecular meshwork resistance (R) over changes in episcleral venous pressure (EVP), uveosclearal outflow facility (Cuv), and ciliary capillary blood pressure (cBP) in order to simulate the effects of EVP reducing medications, prostaglandin analogs, and systemic BP, respectively. Results: The simulated effects of EVP reducing medications and prostaglandin analogs led to IOP decrease of 13.12%, 5.51%, and 2.88% for conditions of R0, 3R0, and 6R0, respectively, where R0 is equal to the trabecular meshwork resistance when IOP = EVP. The simulated effects of prostaglandin analogs resulted an IOP decrease of 13.73%, 18.34%, and 19.83%, for conditions of R0, 3R0, and 6R0, respectively. The simulated effects of increasing systemic BP resulted in an IOP increase of 49.88%, 58.51%, and 60.71% for conditions of R0, 3R0, and 6R0, respectively. Conclusion and Potential Impact: The model simulations predict differential efficacy in IOP reducing medications in patients of varied R as well as the differential impact of systemic BP on IOP in patients of varied R. This model has the potential to predict the IOP reducing effect of medications in an individual as well as the impact of risk factors such as systemic BP on IOP.

Twenty-Four-Hour Contact Lens Sensor Monitoring of Aqueous Humor Dynamics in Surgically or Medically Treated Glaucoma Patients

Aim. This study assessed the 24 h circadian rhythm of intraocular pressure (IOP) using a contact lens sensor in three groups of patients with open-angle glaucoma. Methods. This study was a monocentric, cross-sectional, nonrandomized, prospective, pilot study. Eighty-nine patients were enrolled: 29 patients previously underwent an Ex-PRESS mini glaucoma device procedure (Group 1), 28 patients previously underwent Hydrus microstent implantation (Group 2), and 32 patients were currently being treated medically for primary open-angle glaucoma (Group 3). Circadian rhythm patterns were considered with five circadian indicators: fluctuation ranges, maximum, minimum, acrophase (time of peak value), and bathyphase (time of trough value). A two-tailed Mann–Whitney U-test was used to evaluate differences between groups. Results. All subjects exhibited a circadian rhythm and a nocturnal pattern. The signal fluctuation range was significantly smaller in the surgical groups than in the medically treated group (Group 1 vs. Group 3, p=0.003; Group 2 vs. Group 3, p=0.010). Subjects who underwent the Ex-PRESS procedure (Group 1) exhibited significant differences compared with the drug therapy group (Group 3) with regard to the minimum value (p=0.015), acrophase (p=0.009), and bathyphase (p=0.002). The other circadian indicators were not significantly different among groups. Conclusions. Patients who underwent IOP-lowering surgery had an intrinsic nyctohemeral rhythm. Both surgical procedures, Ex-PRESS and Hydrus, were associated with smaller signal fluctuations compared with medical treatment.