HIF-1α-dependent upregulation of angiogenic factors by mechanical stimulation in retinal pigment epithelial cells.

Mechanical stimulation as a mimic of drusen formation in the eye increases the expression of angiogenic factors in retinal pigment epithelial (RPE) cells, but the underlying molecular mechanisms remain unclear. We investigated and characterized the effects of mechanical stimulation on the expression of angiogenic factors in RPE cells both in vitro and in a mouse model. Mechanical stimulation increased the expression of vascular endothelial growth factor (VEGF, encoded by VEGFA) and other angiogenesis-related genes in cultured RPE1 cells. The presence of hypoxia-inducible factor 1α (HIF-1α, encoded by HIF1A) was also increased, and both knockdown of HIF-1α and treatment with the HIF-1α inhibitor CAY10585 attenuated the effect of mechanical stimulation on angiogenesis factor gene expression. Signaling by the tyrosine kinase SRC and p38 mitogen-activated protein kinase was involved in HIF-1α activation and consequent angiogenesis-related gene expression induced by mechanical stimulation. Our results suggest that SRC-p38 and HIF-1α signaling are involved in the upregulation of angiogenic factors in RPE cells by mechanical stimulation. Such in vivo suppression of upregulated expression of angiogenesis-related genes by pharmacological inhibitors of HIF-1α suggests a new potential approach to the treatment of age-related macular degeneration.

Two Cases of Atopic Dermatitis Patients With Scleral Perforation After Recurrent Scleritis Induced by Scleral-Sutured Posterior Chamber Intraocular Lens Implantation.

This report describes two cases of atopic dermatitis patients with scleral perforation after recurrent scleritis induced by suture exposure after scleral-sutured posterior chamber intraocular lens (PC-IOL) implantation. The first patient was a 41-year-old man (case 1), and the second was a 46-year-old man (case 2). Both had a history of atopic dermatitis and scleral-sutured intraocular lens (IOL) implantation. Scleritis recurred at the suture site after scleral-sutured IOL implantation in both patients. Although the scleritis was controlled by topical and/or systemic anti-inflammatory drugs, the sclera was perforated in both cases because of exposure of the suture knots (after seven years in case 1 and after 11 years in case 2). In case 1, the superotemporal IOL haptic was also exposed over the conjunctiva, and in case 2, the ciliary body was incarcerated in the scleral hole with deformation of the pupil superonasally. Considering that there were no signs of severe intraocular inflammation, surgical intervention was performed in both cases. In case 1, IOL repositioning was performed with oral prednisolone cover at a dosage of 15 mg/day, starting two weeks prior to the surgery. The steroid dosage was gradually tapered off until two months after the surgery. In case 2, the scleral patch underwent without IOL extraction, and no steroid or immunosuppression cover was administered. There was no recurrence of scleritis after surgery in either case, and visual acuity was preserved in both cases. The scleral perforation that occurred after scleral-sutured IOL implantation in these patients was thought to be the result of recurrent scleritis caused by suture exposure and chronic mechanical irritation by a suture knot. The scleritis subsided without removal of the IOL by moving the suture site of the IOL haptic and covering the suture with a scleral flap or patch graft.

Faricimab for Diabetic Macular Edema in Patients Refractory to Ranibizumab or Aflibercept.

Background and Objectives: Faricimab is the first intravitreal injection of vascular endothelial growth factor-A and angiopoietin-2 bispecific monoclonal antibody. Here, we evaluate the functional and anatomical outcomes of faricimab treatment in patients with diabetic macular edema (DME) that was refractory to ranibizumab or aflibercept. Materials and Methods: We performed a retrospective, observational, consecutive-case study of patients who had DME that was refractory to treatment with ranibizumab or aflibercept and were treated with faricimab between July 2022 and January 2023 under a pro re nata regimen. All the participants were followed for ≥4 months after the initiation of faricimab. The primary outcome was a recurrence interval of ≥12 weeks, and the secondary outcomes were the changes in best-corrected visual acuity (BCVA) and central macular thickness (CMT). Results: We analyzed 18 eyes of 18 patients. The mean recurrence interval of previous anti-VEGF injection was 5.8 ± 2.5 weeks, which was significantly extended to 10.8 ± 4.9 weeks (p = 0.0005) by the switch to faricimab. Eight patients (44.4%) achieved a recurrence interval of ≥12 weeks. A history of subtenon injection of triamcinolone acetonide (p = 0.0034) and the presence of disorganization of the retinal inner layers (p = 0.0326) were found to be significantly associated with a recurrence interval of <12 weeks. The mean BCVAs were 0.23 ± 0.28 logMAR and 0.19 ± 0.23 logMAR, and the mean CMTs were 473.8 ± 222.0 µm and 381.3 ± 219.4 µm at baseline and 4 months, respectively, but these changes were not statistically significant. None of the patients experienced serious adverse events. Conclusions: Faricimab may extend the treatment interval for patients with DME that is refractory to ranibizumab or aflibercept. DME previously treated with the subtenon injection of triamcinolone acetonide or associated with disorganization of the retinal inner layers may be less likely to be associated with a longer recurrence interval after switching to faricimab.

Effects of Ripasudil, a Rho-Kinase Inhibitor, on Scar Formation in a Mouse Model of Filtration Surgery.

PURPOSE: Glaucoma is a leading cause of blindness worldwide. Characteristic changes occur in the optic nerve and visual field of patients with glaucoma; optic nerve damage can be mitigated by lowering intraocular pressure. Treatment modalities include drugs and lasers; filtration surgery is necessary for patients with insufficient intraocular pressure reduction. Scar formation often contributes to glaucoma filtration surgery failure by increasing fibroblast proliferation and activation. Here, we examined the effects of ripasudil, a Rho-associated protein kinase (ROCK) inhibitor, on postoperative scar formation in human Tenon's fibroblasts. METHODS: Collagen gel contraction assays were used to compare contractility activity among ripasudil and other anti-glaucoma drugs. The effect of Ripasudil in combination with other anti-glaucoma drugs and transforming growth factor-ß (TGF-ß), latanoprost and timolol-induce contractions were also tested in this study. Immunofluorescence and Western blotting were used to study the expression of factors relating scarring formation. RESULTS: Ripasudil inhibited contraction in collagen gel assay and reduced α-smooth muscle actin (SMA) and vimentin (scar formation-related factors) expression, which was inversely promoted by latanoprost, timolol or TGF-ß. Ripasudil also inhibited contraction on TGF-ß, latanoprost and timolol-induced contraction. Furthermore, we investigated the effects of ripasudil on postoperative scarring in a mouse model; ripasudil suppressed postoperative scar formation by altering the expression of α-SMA and vimentin. CONCLUSIONS: These results suggest that ripasudil, ROCK inhibitor may inhibit excessive fibrosis after glaucoma filtering surgery vis inhibition the transdifferentiation of tenon fibroblast into myofibroblast and may have a potential effect as anti-scarring for glaucoma filtration surgery.

DRAINAGE RETINOTOMY IS A RISK FACTOR FOR SURGICAL FAILURE AFTER PARS PLANA VITRECTOMY IN PATIENTS WITH PRIMARY UNCOMPLICATED RHEGMATOGENOUS RETINAL DETACHMENT.

PURPOSE: To identify risk factors for recurrent retinal detachment after uncomplicated pars plana vitrectomy in patients with primary rhegmatogenous retinal detachment (RRD). METHODS: This single-center retrospective study included patients with primary RRD who underwent 23-gauge and 25-gauge pars plana vitrectomy at Hiroshima University Hospital between January 2016 and May 2021. All patients had ≥3 months of follow-up. Patients were excluded if they had preoperative proliferative vitreoretinopathy worse than Grade C1; giant retinal tears; tractional, exudative, or traumatic retinal detachment; or the use of perfluorocarbon liquid. Factors that influenced RRD treatment outcome and postoperative complications were evaluated. RESULTS: We analyzed 519 eyes of 509 patients who underwent pars plana vitrectomy for primary RRD. The primary and final success rates were 93.8% and 99.8%, respectively. Drainage retinotomy was a risk factor for surgical failure in both multivariate analysis (odds ratio 2.36, 95% confidence interval 1.08-5.15, P = 0.0314) and a propensity score-matching analysis (odds ratio 3.20, 95% confidence interval 1.14-9.04, P = 0.0277). Postoperative epiretinal membrane was associated with drainage retinotomy in multivariate analysis (odds ratio 1.93, 95% confidence interval 1.04-3.57, P = 0.0358). CONCLUSION: The avoidance of drainage retinotomy during small-gauge pars plana vitrectomy in patients with RRD may lead to better surgical success and less frequent epiretinal membrane formation.

Down-regulation of semaphorin 3F in rat retinal ganglion cells in response to optic nerve crush.

Glaucoma is characterized by degeneration of optic nerve axons and death of retinal ganglion cells (RGCs). Nerve crush and axotomy of the optic nerve are studied as models of RGC death in glaucoma and of axon regeneration. The mechanisms underlying the response of RGCs to axonal injury remain unclear, however. We have now examined the effects of optic nerve crush on the expression of members of the semaphorin family of neuronal guidance proteins in the rat retina. The expression of semaphorin 3F (Sema3F) in the retina was down-regulated at both the mRNA and protein levels at 7 days after optic nerve injury, whereas that of Sema3A, Sema3B or Sema3C remained unaffected. Immunohistofluorescence analysis and laser capture microdissection followed by reverse transcription-polymerase chain reaction analysis revealed that this loss of Sema3F expression occurred in the RGC layer of the retina. Furthermore, antibody-mediated neutralization of secreted Sema3F in retinal organ culture resulted in down-regulation of neuron-specific ßIII-tubulin (Tuj-1 antigen), a marker of RGCs. Our results suggest that Sema3F may contribute to the regulation of RGC function or survival and therefore warrants further investigation as a potential mediator of neuroprotection. Copyright © 2016 John Wiley & Sons, Ltd.