Atorvastatin reduces IOP in ocular hypertension in vivo and suppresses ECM in trabecular meshwork perhaps via FGD4.

To explore the role of atorvastatin in regulating intraocular pressure (IOP) in glaucoma in vivo, and to investigate its related molecular pathway in vitro, an ocular hypertension model was generated by intravitreal injection of an adenoviral vector encoding transforming growth factor (TGF)­ß2 in the right eye of BALB/cJ mice, while the left was treated with an empty control adenovirus. To determine its anti­intraocular hypertension role, these induced hyper­IOP mice were gavaged with atorvastatin (20 mg/kg/day). Furthermore, extracellular matrix (ECM) factors were examined in the primary human trabecular meshwork (HTM) cells followed atorvastatin (0~200 µM) treatment in vitro. Whole genome microarray was employed to identify potential therapeutic target molecules associated with ECM regulation. Unilateral murine ocular hypertension was induced, via intravitreal injection of the adenoviral vector carrying the human TGF­ß2 gene (Ad.hTGF­ß2226/228), raising IOP from 12±1.6 to 32.3±0.7 mmHg (n=6, P<0.05) at day 15, which plateaued from day 15 to 30. Atorvastatin administration from day 15 to 30 decreased IOP from 32.3±0.7 to 15.4±1.1 mmHg (n=6, P<0.05) at day 30. Additionally, atorvastatin administration changed the morphology of cultured HTM cells from an elongated and adherent morphology into rounded, less elongated and less adherent cells, accompanied with suppressed expression of ECM. Gene Ontology and Genome analysis revealed that FGD4 (FYVE, RhoGEF and PH domain containing 4) might be a key factor contributing to these changes. Our data demonstrated that atorvastatin reduced TGF­ß2­induced ocular hypertension in vivo, perhaps via modifying cellular structure and decreasing ECM, using the FGD4 signaling pathway, as demonstrated in HTM cells. Our findings provide some useful information for the management of glaucoma, with statin therapy revealing a potential novel therapeutic pathway for glaucoma treatment.

Novel inflammatory cytokines (IL-36, 37, 38) in the aqueous humor from patients with chronic primary angle closure glaucoma.

Glaucoma eventually leads to optic nerve damage and vision loss without medical intervention. More than 50% of glaucoma caused blindness are attributed to primary angle closure glaucoma, particularly in Asians. It is reported that immune inflammation is involved in the progress of glaucoma. Increased inflammation cytokines are detected in the aqueous humor of chronic primary angle closure glaucoma (CPACG). IL-36, IL-37 and IL-38, are novel cytokines and are involved in many inflammatory diseases, including inflammatory bowel diseases and acute anterior uveitis, but the possible contributing role in the pathogenesis of CPACG is unclear. In our current study, increased IL-36, IL-37 and IL-38 were detected in the aqueous humor of CPACG compared with age-related cataract (ARC). Furthermore, a significant correlation was detected between mean deviation of visual field (MDVF) of CPACG and IL-36, IL-37 or IL-38, respectively. Our data suggest IL-36, IL-37 and IL-38 might contribute to the immunological mediated pathogenesis of CPACG, despite the eye being an immune-privileged organ under normal conditions. The precise underlying mechanism of these cytokines during the development of CPACG remains to be explored. Our findings may be useful in therapeutic targeting of specific pathology.

Diffusion Tensor Imaging Detects Microstructural Differences of Visual Pathway in Patients With Primary Open-Angle Glaucoma and Ocular Hypertension.

Ocular hypertension (OHT), the common situation in adult patients in the outpatients, occurs ∼5% worldwide. However, there are still some practical problems in differentiation of OHT with early primary open-angle glaucoma (POAG) using current standard methods. Application of high resolution diffusion tensor imaging (DTI) enables us to the differentiate axonal architecture of visual pathway between POAG and OHT subjects. Among 32 POAG patients recruited (15 OHT and 14 control subjects), 62.5% of glaucoma were in early stage for the current study. All subjects underwent ophthalmological assessments with standard automated perimetry and optical coherence tomography (OCT). DTI was applied to measure fraction anisotropy (FA) and mean diffusivity (MD) of optic tract (OT), lateral geniculate body (LGN) and optic radiation (OR) using voxel-based analysis. Our data demonstrated that FA values of bilateral OR in POAG were significantly lower in the right or left than that of OHT patients (left OR: 0.51 ± 0.04 vs. 0.54 ± 0.03, p < 0.05; right OR: 0.51 ± 0.05 vs. 0.54 ± 0.03, p < 0.05). In right LGN, MD values were higher in POAG patients compared with OHT subjects (9.81 ± 1.45 vs. 8.23 ± 0.62, p < 0.05). However, no significant difference of all of the DTI parameters was observed between OHT and control subjects. DTI parameters in POAG patients were positively correlated with morphological and functional measurements (p < 0.05). Vertical cup to disc ratio (VCDR) was correlated with ipsilateral FA of OT (p < 0.05), ipsilateral MD of OT (p < 0.05), ipsilateral MD of LGN (p < 0.05), and contralateral MD of OT (p < 0.05). Mean deviation of visual field (MDVF) was correlated with ipsilateral FA of OT (p < 0.05), ipsilateral MD of OT (p < 0.05), and ipsilateral FA of LGN (p < 0.05). Our study demonstrated that DTI can differentiate POAG from OHT subjects in optic pathway, particularly in early POAG, and DTI parameters can quantify the progression of POAG.