The ocular renin-angiotensin system: a therapeutic target for the treatment of ocular disease.

The renin-angiotensin system (RAS) is most well-known for its role in regulation and dysregulation of blood pressure as well as fluid and electrolyte homeostasis. Due to its ability to cause cardiovascular disease, the RAS is the target of a multitude of drugs that antagonize its pathophysiological effects. While the "classical" RAS is a systemic hormonal system, there is an increasing awareness of the existence and functional significance of local RASs in a number of organs, e.g., liver, kidney, heart, lungs, reproductive organs, adipose tissue and adrenal. The eye is one of these organs where a compelling body of evidence has demonstrated the presence of a local RAS. Individual components of the RAS have been shown to be present in many structures of the eye and their potential functional significance in ocular disease states is described. Because the eye is one of the most important and complex organs in the body, this review also discusses the implications of dysregulation of the systemic RAS on the pathogenesis of ocular diseases and how pharmacological manipulation of the RAS might lead to novel or adjunctive therapies for ocular disease states.

Assessment of corneal thickness and keratocyte density in a rabbit model of laser in situ keratomileusis using scanning laser confocal microscopy.

PURPOSE: To determine the repeatability of corneal thickness and keratocyte density using in vivo confocal scanning laser microscopy in a rabbit model of laser in situ keratomileusis. DESIGN: Prospective, experimental animal study. METHODS: En face tomographic images of corneal tissue were captured from 5 New Zealand white rabbits. Central corneal thickness was compared with conventional ultrasonic pachymetry. Keratocyte density was measured as a function of stromal depth at baseline and 6 weeks after a 130-µm lamellar incision in the following regions: first countable stromal image (30 to 39 µm), anterior stroma (40 to 75 µm), incision zone (76 to 150 µm), mid stroma (151 to 250 µm), and deep stroma (251 to 400 µm). RESULTS: The mean residual difference between ultrasonic and confocal corneal thickness measurements was 2.1 µm (95% confidence interval [CI], -7.0 to 11.2 µm; P = .61). Before the lamellar incision, keratocyte density was highest in the first countable frame of the anterior stroma, 53 800 cells/mm(3) (95% CI, 35 000 to 72 000 cells/mm(3)) and was least in deep stroma, 27 100 cells/mm(3) (95% CI, 22 400 to 32 000 cells/mm(3)). Six weeks after stromal lamellar incision, keratocyte density was unchanged in the first countable frame of the anterior stroma, 43 700 cells/mm(3) (95% CI, 31 800 to 55 500 cells/mm(3); P = .29). There were no changes in cell density in deeper stromal regions. CONCLUSIONS: There was excellent agreement between ultrasonic and confocal microscopy measurements of corneal thickness. In vivo repeatability of keratocyte density estimation using scanning laser confocal microscopy is comparable with the results of previous reports using tandem-scanning confocal microscopy. Keratocyte density was more varied, but not significantly different, in the anterior-most corneal stroma 6 weeks after a lamellar incision.

Corneal pharmacokinetics of topically applied azithromycin and clarithromycin.

PURPOSE: To determine corneal levels of topically administered azithromycin and clarithromycin in a rabbit model. DESIGN: Experimental animal study. METHODS: Corneas of New Zealand albino rabbits were treated with topical azithromycin (2 mg/ml or 4 mg/ml) or clarithromycin (10 mg/ml). Topical azithromycin was prepared from an intravenous solution and topical clarithromycin from a suspension for oral use. All rabbits received one drop every 2 hours on the right eye. Groups of rabbits were treated for the following intervals: 6, 12, 24, and 48 hours (four rabbits for each combination of time point, drug, and dose). Corneal tissue was removed 1 hour after the last application. To investigate stability of tissue azithromycin levels, an additional group of four rabbits was treated for 24 hours, but corneal tissue was not removed until 24 hours later. Samples were homogenized, and drug concentrations were measured using high-pressure liquid chromatography (HPLC) analysis and bioactivity assay. RESULTS: Corneal concentrations of azithromycin increased with drug dosage and duration of application. Rabbits treated with azithromycin tolerated the drug well without signs of irritation. Clarithromycin was undetectable in corneal tissue by HPLC and bioactivity assay for all rabbits. Some rabbits treated with clarithromycin had signs of ocular surface irritation. CONCLUSION: Measurable concentrations of azithromycin are achieved in corneal tissue after topical application in a rabbit model, and the drug is well tolerated. Azithromycin may be a useful antibiotic for the topical treatment of human corneal infections, but clarithromycin, in currently available formulations, may not be effective because of poor tissue penetration.

Mitigation of neutrophil infiltration in a rat model of early Staphylococcus aureus endophthalmitis.

PURPOSE: Infectious endophthalmitis is characterized by neutrophil migration into the eye. The purpose of this study was to determine whether systemic neutrophil depletion mitigates the ocular influx of neutrophils during the early phases of experimental endophthalmitis. METHODS: Endophthalmitis was induced in rats by intravitreal injection of Staphylococcus aureus. Animals received a single systemic dose of an anti-neutrophil-depleting antibody (dAb) or normal rabbit serum (NRS) 6 or 12 hours after intravitreal injection. Inflammation was graded both in vivo and by histopathology. Myeloperoxidase (MPO) was used as a biomarker of neutrophil infiltration. Bacterial clearance was evaluated by determining the amount of viable bacteria recovered from ocular specimens. RESULTS: Rats that received dAb 6 hours after bacterial injection exhibited significantly lower clinical scores, MPO activity, fewer vitreous exudates, and higher vitreous bacterial counts at 24 hours (P < 0.05). As the neutrophil population returned in this group, measured by the number in the peripheral blood, increasing intraocular inflammation was observed. Rats receiving dAb 12 hours after vitreous injection also demonstrated significantly lower clinical scores, MPO activity and less vitreous exudates at the 24-hour time point (P < 0.05). No significant differences from the control were detected at any of the subsequent time points, except in bacterial counts and MPO activity. CONCLUSIONS: Depletion of neutrophils early in the inflammatory response delayed the onset of severe ocular inflammation but also prevented adequate bacterial clearance. These results confirm the important role of neutrophils in ocular host defense during the early stages of experimental endophthalmitis.

Laser flare photometry and complications of chronic uveitis in children.

PURPOSE: To investigate possible relationships between laser flare photometry values, complications of uveitis, and outcomes in children with chronic uveitis. DESIGN: Retrospective chart review. METHOD: We evaluated patients with active, noninfectious anterior, intermediate, or panuveitis who were 16 years of age or younger and who had laser flare photometry at one of two academic institutions. Complications enumerated at baseline and during follow-up were compared with laser flare photometry values and to anterior chamber cell counts. RESULTS: At least one laser flare photometry value ("flare"), defined as baseline measurement, was available for 59 patients (41 girls, 18 boys; mean age, 10.3 +/- 3.5 years); 38 of these patients had at least one additional measurement during follow-up (median 11 months). Complications of uveitis were present in 35 patients (59%) at baseline. There was a positive association between increased laser flare photometry values and complications at baseline (any complication [P =.007], posterior synechiae [P =.003]). The development of complications during follow-up was associated with the presence of complications at baseline (P =.018). A subgroup of patients with low flare at baseline had no complications during follow-up regardless of treatment given. CONCLUSIONS: There is a positive relationship between laser flare photometry values and the prevalence of complications of uveitis in children. Laser flare photometry provides a novel way to monitor children with uveitis. Future study will be needed to determine whether values have prognostic importance and whether a treatment strategy that minimizes flare results in fewer uveitic complications.