Sustained Subconjunctival Delivery of Infliximab Protects the Cornea and Retina Following Alkali Burn to the Eye

Zhou, Chengxin; Robert, Marie-Claude; Kapoulea, Vassiliki; Lei, Fengyang; Stagner, Anna M.; Jakobiec, Frederick A.; Dohlman, Claes H.; Paschalis, Eleftherios I.

doi:10.1167/iovs.16-20339

Cited by 59 publications

(77 citation statements)

References 32 publications

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“…IL-1β and TNFα are two key pro-inflammatory cytokines involved in inflammatory reactions. Their levels are upregulated after corneal injury and overactive IL-1β and TNFα exaggerate corneal inflammation and impair wound healing [ 22 – 26 ]. To determine whether Sirt6 could directly regulate inflammation in corneal epithelial cells, we specifically reduced Sirt6 protein levels using siRNA knockdown in cultured primary human corneal epithelial cells in vitro and determined their response to IL-1β and TNFα.…”

Section: Resultsmentioning

confidence: 99%

Sirt6 deficiency impairs corneal epithelial wound healing

Zhu

et al. 2018

Aging

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Corneal transparency, dependent on the integrity of epithelial cells, is essential for vision. Corneal epithelial damage is one of the most commonly observed ocular conditions and proper wound healing is necessary for corneal transparency. Sirt6, a histone deacetylase, has been shown to regulate many cellular events including aging and inflammation. However, its specific role in corneal epithelial wound healing remains unknown. Here we demonstrated that Sirt6 was expressed in corneal epithelial cells and its expression decreased with age. In an in vivo corneal epithelial wound healing model, Sirt6 deficiency resulted in delayed and incomplete wound healing and was associated excessive inflammation in the corneal stroma and dysfunction of Notch signaling, leading to keratinization of the corneal epithelium and corneal opacity. Aging Sirt6-deficient mice spontaneously developed corneal keratitis with extensive infiltration of inflammatory cells into the cornea. In vitro experiments demonstrated that primary corneal epithelial cells with Sirt6 downregulation expressed increased basal levels of inflammatory genes and exhibited hyper-inflammatory reactivity to IL-1β and TNFα treatment. These results provide compelling evidence that Sirt6 is a critical regulator of inflammation in the cornea, and is responsible for corneal epithelial wound healing, thus contributing to the maintenance of epithelial integrity and corneal transparency.

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Section: Resultsmentioning

confidence: 99%

Sirt6 deficiency impairs corneal epithelial wound healing

Zhu

et al. 2018

Aging

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“…Optic nerve cross sections were processed using a modified paraphenylenediamine (PPD) staining protocol to stain the myelin sheath of all axons and the axoplasma of damaged axons, as previously described ( 66 ). Optic nerves were fixed with half-strength Karnovsky’s fixative [2% formaldehyde + 2.5% glutaraldehyde in 0.1 M sodium cacodylate buffer, pH 7.4 (Electron Microscopy Sciences)] for a minimum of 24 h at 40 °C.…”

Section: Methodsmentioning

confidence: 99%

Permanent neuroglial remodeling of the retina following infiltration of CSF1R inhibition-resistant peripheral monocytes

Paschalis

Lei

Zhou

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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SignificanceThis work contributes to the understanding of the enigmatic progressive retinal damage following acute ocular surface injury. Clinical findings in patients suggest that such injuries can adversely affect the retina. This study demonstrates that corneal injury leads to rapid infiltration of blood-derived monocytes into the retina and to subsequent remodeling of the neuroglial system. In contrast to previously held belief, this study shows that the blood-derived monocytes engraft permanently into the retina and differentiate into microglia-like cells. Although these cells are morphologically indistinguishable from native microglia, they retain a distinct signature and insensitivity to CSF1R inhibition and exhibit a reactive phenotype which persists long after the noxious stimuli is removed, ultimately contributing to progressive neuroretinal degeneration.

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“…To determine the therapeutic efficacy of anti-VEGF DDS in corneal NV reduction, an established corneal NV model was used. 21,25,30 CNV analysis revealed that superior CNV was completely inhibited with anti-VEGF DDS throughout the study period (Figs. 3Q, 3S), (P < 0.05 mixed ANOVA).…”

Section: Anti-vegf Dds Inhibits Corneal Neovascularization After Cornmentioning

confidence: 98%

“…Immunohistochemical evaluation was performed as previously described. 21 Primary antibodies diluted in 1% bovine serum albumin were incubated with the tissue samples overnight at 4°C, followed by secondary antibody incubation for two hours at room temperature. Detail information of the antibodies is provided in the Supplementary Methods section.…”

Section: Histological and Immunohistochemical Evaluation Of The Corneamentioning

confidence: 99%

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Microporous Drug Delivery System for Sustained Anti-VEGF Delivery to the Eye

Zhou

Singh

Qian

et al. 2020

Trans. Vis. Sci. Tech.

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To describe a novel microporous drug delivery system (DDS) for sustained antivascular endothelial growth factor (VEGF) delivery to the eye and to evaluate its efficacy in a corneal injury model. Methods: A macro-porous DDS (1.5 × 1.5 × 4 mm) loaded with 2 mg of bevacizumab was implanted subconjunctivally in three Dutch-belted pigmented rabbits after corneal alkali injury (2N NaOH). Three rabbits received sham DDS. Animals were followed for three months and assessed in vivo and ex vivo for corneal neovascularization (NV), epithelial defect, stromal scarring, endothelial cell loss, and expression of angiogenic and inflammatory markers in the cornea and retina. Results: Anti-VEGF DDS treatment led to complete inhibition of superior cornea NV and complete corneal re-epithelialization by day 58 whereas sham DDS resulted in severe cornea NV and persistent epithelial defect (9%∼12% of total cornea area) through the end of the study. Histologically, anti-VEGF DDS significantly reduced CD45 + and F4/80 CD11b + cell accumulation (79%, P < 0.05) in the cornea, ameliorated tumor necrosis factor-α expression (90%, P < 0.05), reduced corneal stromal scarring and prevented corneal endothelial cell loss, as compared to sham DDS. Moreover, anti-VEGF DDS achieved retinal penetration and reduction in retinal VEGF levels at 3 months. Conclusions: Use of subconjunctival anti-VEGF DDS suppresses cornea NV, inflammation, stromal scarring, prevents endothelial cell loss, and abrogates retinal VEGF upregulation in a rabbit corneal alkali burn model. Moreover, it delivers anti-VEGF antibodies to the retina for three months. This delivery platform could enable antibody therapy of other corneal and retinal vascular pathologies. Translational Relevance: We describe a method for sustained anti-VEGF delivery to the eye for the treatment of ocular injuries.

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Sustained Subconjunctival Delivery of Infliximab Protects the Cornea and Retina Following Alkali Burn to the Eye

Cited by 59 publications

References 32 publications

Sirt6 deficiency impairs corneal epithelial wound healing

Sirt6 deficiency impairs corneal epithelial wound healing

Permanent neuroglial remodeling of the retina following infiltration of CSF1R inhibition-resistant peripheral monocytes

Microporous Drug Delivery System for Sustained Anti-VEGF Delivery to the Eye

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