Fursultiamine Alleviates Choroidal Neovascularization by Suppressing Inflammation and Metabolic Reprogramming.

Purpose: To assess the therapeutic effects of fursultiamine on choroidal neovascularization (CNV) through its modulation of inflammation and metabolic reprogramming in the retinal pigment epithelium (RPE). Methods: The anti-angiogenic effects of fursultiamine were assessed by measuring vascular leakage and CNV lesion size in the laser-induced CNV mouse model. Inflammatory responses were evaluated by quantitative polymerase chain reaction, western blot, and ELISA in both CNV eye tissues and in vitro cell cultures using ARPE-19 cells or primary human RPE (hRPE) cells under lipopolysaccharide (LPS) treatment or hypoxia. Mitochondrial respiration was assessed by measuring oxygen consumption in ARPE-19 cells treated with LPS with or without fursultiamine, and lactate production was measured in ARPE-19 cells subjected to hypoxia with or without fursultiamine. Results: In laser-induced CNV, fursultiamine significantly decreased vascular leakage and lesion size, as well as the numbers of both choroidal and retinal inflammatory cytokines, including IL-1ß, IL-6, IL-8, and TNF-α. In LPS-treated ARPE-19 cells, fursultiamine decreased proinflammatory cytokine secretion and nuclear factor kappa B phosphorylation. Furthermore, fursultiamine suppressed LPS-induced upregulation of IL-6, IL-8, and monocyte chemoattractant protein-1 in a dose-dependent and time-dependent manner in primary hRPE cells. Interestingly, fursultiamine significantly enhanced mitochondrial respiration in the LPS-treated ARPE-19 cells. Additionally, fursultiamine attenuated hypoxia-induced aberrations, including lactate production and inhibitory phosphorylation of pyruvate dehydrogenase. Furthermore, fursultiamine attenuated hypoxia-induced VEGF secretion and mitochondrial fission in primary hRPE cells that were replicated in ARPE-19 cells. Conclusions: Our findings show that fursultiamine is a viable putative therapeutic for neovascular age-related macular degeneration by modulating the inflammatory response and metabolic reprogramming by enhancing mitochondrial respiration in the RPE.

Uveitis with occult choroiditis due to Mycobacterium kansasii: limitations of interferon-gamma release assay (IGRA) tests (case report and mini-review on ocular non-tuberculous mycobacteria and IGRA cross-reactivity).

Ocular tuberculosis is difficult to diagnose but should be suspected when uveitis fails to respond to inflammation suppressive therapy. Interferon-gamma release assays (IGRAs) represent a substantial help to diagnose suspected ocular tuberculosis especially in non-endemic areas. Indocyanine green angiography (ICGA) is able to detect clinically silent choroiditis that, when associated with a positive IGRA test, should lead the clinician to suspect ocular tuberculosis, warranting specific therapy. The fact that IGRA tests can also react with some atypical strains of mycobacteria is not always known. We report here a case with resistant post-operative inflammation that presented with occult ICGA-detected choroiditis and a positive IGRA test that was most probably due to the non-tuberculous mycobacterium (NTM) Mycobacterium kansasii. A 66 year-old man presented with a resistant cystoid macular oedema (CMO) in his left eye after combined cataract and epiretinal membrane surgery. At entry, his best-corrected visual acuity (BCVA) was 0.5 for far and near OS. Intraocular inflammation measured by laser flare photometry was elevated in the left eye (54.4 ph/ms) and also in the right eye (50.9 ph/ms). Four subTenon's injections of 40 mg of triamcinolone did not produce any substantial improvement. Therefore a complete uveitis work-up was performed. Fluorescein angiography showed CMO OS and ICGA showed numerous hypofluorescent dots and fuzziness of choroidal vessels in both eyes. Among performed laboratory tests, the QuantiFERON®-TB Gold test was positive. After a pulmonological examination disclosing a right upper lobe infiltrate, the patient was started on a triple anti-tuberculous therapy. Bronchial aspirate, obtained during bronchoscopy, was Ziehl-positive and culture grew M. kansasii. Nine months later, BCVA OS increased to 1.0 and flare decreased to 40.2 ph/ms. The CMO OS resolved angiographically and did not recur with a macula still slightly thickened on OCT. Suspected ocular tuberculosis based on clinical findings and a positive IGRA test can, in rare instances, be due to atypical mycobacteria that also produce positive IGRA tests such as M. kansasii, M. szulgai, M. gordonae, M. flavescens and M. marinum. In our case failure to isolate the atypical mycobacterium would not have had negative therapeutic consequences, as M. kansasii is sensitive to the standard anti-tuberculous treatments, which is not the case with other NTMs.

Investigation of multifocal choroiditis with panuveitis by three-dimensional high-penetration optical coherence tomography.

A single case of multifocal choroiditis with panuveitis (MFCPU) was investigated by a three-dimensional (3-D) high-penetration optical coherence tomography. The HP-OCT is based on a swept-source OCT technology, uses a probe beam with a center wavelength of 1060 nm, and possesses a depth resolution of 10.4 micromin tissue. Two eyes of an MFCPU patient were involved in this study. The eyes were also examined by color fundus photograph, fluorescein angiography (FA), and indocyanine green angiography (ICGA). Findings in these four modalities are comparatively discussed. The OCT scans revealed the following characteristic properties of the lesion sites. Thinning of the retina, destructuring of the retinal layers, and disappearance of the junction of the inner and outer segments of the photoreceptor (IS/OS). Due to the high penetration of this OCT system, the following characteristic properties of the lesions were also observed: localized thinning of the choroid, occlusion of the choroidal vessels, and localized hyper-reflectivity that may represent hyper-pigmentation of the choroid.

SDF1-alpha is associated with VEGFR-2 in human choroidal neovascularisation.

Endothelial progenitor cells (EPCs) have been shown to contribute to experimentally induced choroidal neovascularisation (CNV) in animal models. The recruitment pathway for EPCs is dependent on the chemokine stromal cell derived factor 1-alpha (SDF) and its receptor CXCR4 on the progenitor cell. We examined 23 specimens of CNV occurring secondary to a variety of aetiologies (10 secondary to age-related macular degeneration (AMD), 4 inflammatory, 4 idiopathic and 5 melanoma-associated) for the presence and distribution of SDF and CXCR4 in order to determine if this pathway may play a role in neovascularisation. Specimens were examined by immunohistochemistry using a panel of antibodies against SDF, CXCR4, vascular endothelial growth factor receptor 2 (VEGFR-2), CD34 (endothelial cells), CD68 (macrophages) and cytokeratins (retinal pigment epithelium; RPE). SDF was detected in 2 cases of CNV in AMD, 1 inflammatory CNV, 3 idiopathic CNVs and in 3 cases of CNV associated with melanoma. A significant association was found between SDF and VEGFR-2 immunostaining in individual membranes (p<0.001). Localisation of SDF immunostaining to the presumed RPE was also significant (p<0.05). CXCR4 immunostaining was widespread in all membranes in keeping with the published work of other investigators. Our study suggests that SDF, which may be produced by the RPE, could play a role in CNV.

Retino-choroidal changes in endotoxin-induced uveitis in the rat.

A single injection of 100 micrograms of lipopolysaccharide from Salmonella typhimurium in the foot pads of Lewis rats induced acute inflammation of the eye. Clinically, the disease started as early as 0.5 h and peaked 18 h after the inoculation. The aqueous protein concentration was increased after the inoculation. Histopathologically, cellular infiltrates and proteinaceous exudates were observed in the anterior segment (anterior chamber, iris and ciliary body). In addition to those changes described in previous reports, the examination of the posterior segment showed retinal vasculitis, hemorrhagic exudates, focal destruction of photoreceptor cells and choroidal infiltration.