Essential Role for c-Jun N-Terminal Kinase 2 in Corneal Epithelial Response to Desiccating Stress

Paiva, Cintia S. de; Pangelinan, S. B.; Chang, Emmanuel; Yoon, Kyung-Chul; Farley, William J.; Li, Dequan; Pflugfelder, Stephen C.

doi:10.1001/archophthalmol.2009.316

Cited by 39 publications

(35 citation statements)

References 33 publications

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“…MMP-9 has been reported both in the apical and in the basal surface of the epithelium, depending on whether the protein, RNA, or activity was evaluated. Although constitutive protein expression of MMP-9 has been reported in the superficial layers of normal cornea, which greatly increased when challenged with desiccating stress, 31 in situ gelatin zymography on untreated cornea localized a stronger gelatinolytic activity in the basal layer of the epithelium, increasing throughout the epithelium in dry eye conditions. 32 Furthermore, an in situ hybridization technique revealed that MMP-9 RNA, undetected in normal epithelium, is induced after injury and sustained during epithelial stratification within the basal layer, 33 suggesting that MMP-9 is produced essentially by the basal cells where EMMPRIN is localized.…”

Section: Discussionmentioning

confidence: 90%

EMMPRIN Modulates Epithelial Barrier Function through a MMP–Mediated Occludin Cleavage

Huet

Vallée

Delbé

et al. 2011

The American Journal of Pathology

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Dry eye is a common disease that develops as a result of alteration of tear fluid, leading to osmotic stress and a perturbed epithelial barrier. Matrix metalloproteinase-9 (MMP-9) may be important in dry eye disease, as its genetic knockout conferred resistance to the epithelial disruption. We show that extracellular matrix metalloproteinase inducer (EMMPRIN; also termed CD147), an inducer of MMP expression, participates in the pathogenesis of dry eye through MMPmediated cleavage of occludin, an important component of tight junctions. EMMPRIN expression was increased on the ocular surface of dry eye patients and correlated with those of MMP-9. High osmolarity in cell culture, mimicking dry eye conditions, increased both EMMPRIN and MMP-9 and resulted in the disruption of epithelial junctions through the cleavage of occludin. Exogenously added recombinant EMMPRIN had similar effects that were abrogated in the presence of the MMP inhibitor marimastat. Membrane occludin immunostaining was markedly increased in the apical corneal epithelium of both EMMPRIN and MMP-9 knock-out mice. Furthermore, an inverse correlation between EMMPRIN and occludin membrane staining was consistently observed both in vitro and in vivo as a function of corneal epithelial cells differentiation. These data suggest a possible role of EMMPRIN in regulating the amount of occludin at the cell surface in homeostasis beyond pathological situations such as dry eye disease, and EMMPRIN may be essential for the formation and maintenance of organized epithelial structure. (Am J Pathol

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Section: Discussionmentioning

confidence: 90%

EMMPRIN Modulates Epithelial Barrier Function through a MMP–Mediated Occludin Cleavage

Huet

Vallée

Delbé

et al. 2011

The American Journal of Pathology

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“…Secondary goat-anti rabbit or donkey anti-goat Alexa-Fluor 488 conjugated IgG antibodies were used, as previously described. 24 The images were captured and photographed by a Nikon fluorescence microscope (Eclipse E400 equipped with a DS–F1 digital camera; Nikon, Melville, NY).…”

Section: Methodsmentioning

confidence: 99%

Differential Effects of Dexamethasone and Doxycycline on Inflammation and MMP Production in Murine Alkali-Burned Corneas Associated with Dry Eye

et al. 2016

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Alkali burns to the cornea are among the most devastating injuries to the eye. The purpose of this study was to evaluate the effects of dexamethasone (Dex) or doxycycline (Doxy) on protease activity and corneal complications in a combined model (CM) of alkali burn and dry eye. C57BL/6 mice were subjected to the CM for 2 or 5 days (D). Mice were topically treated either with Dex (0.1%), Dox (0.025%) or vehicle QID and observed daily for appearance of corneal perforation. Quantitative real time PCR was performed to measure expression of inflammation cytokines and matrix metalloproteinases (MMP) in whole cornea lysates. No perforations were observed in the Dex-treated corneas. All wounds in Doxy-treated corneas were closed 2D post-injury, and they had significantly lower corneal opacity scores at days 4 and 5 post-injury compared to BSS treatment. Dex-treated corneas had the lowest corneal opacity scores. Dex treatment significantly decreased expression of IL-1β, IL-6, MMPs -1, -9, -13, and TIMP-1 after 2 days but increased levels of MMP-8, while Doxy treatment significantly decreased IL-1β, IL-6, MMP-8, and -9, compared to vehicle. Decreased MMP -1, -9 and -13 immunoreactivity and gelatinolytic activity were seen in corneas treated with Doxy and Dex compared to vehicle. Increased neutrophil infiltration and myeloperoxidase activity was noted in the vehicle group compared to Dex 2 days post-injury. These findings demonstrate that early initiation of anti-inflammatory therapy is very efficacious in preserving corneal clarity and facilitating wound healing, while modulating MMP production and suppressing neutrophil infiltration.

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“…Chronic dry eye disease can desiccate the ocular surface and create corneal epithelial erosions that alter corneal smoothness and permeability [38][39][40]. Accordingly, corneal smoothness was monitored as a study parameter for the evaluation of nanowafer efficacy.…”

Section: Resultsmentioning

confidence: 99%

“…Because the illumination path is nearly coincident with the optical axis of the microscope, the viewing area is evenly illuminated and nearly shadowless. The projected ring light will reflect off a wet surface and the regularity of the reflected ring depends on the smoothness of the ocular surface [38][39][40].…”

Section: Evaluation Of Corneal Smoothnessmentioning

confidence: 99%

Dexamethasone nanowafer as an effective therapy for dry eye disease

Coursey

Henriksson

Marcano

et al. 2015

Journal of Controlled Release

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Dry eye disease is a major public health problem that affects millions of people worldwide. It is presently treated with artificial tear and anti-inflammatory eye drops that are generally administered several times a day and may have limited therapeutic efficacy. To improve convenience and efficacy, a dexamethasone (Dex) loaded nanowafer (Dex-NW) has been developed that can release the drug on the ocular surface for a longer duration of time than drops, during which it slowly dissolves. The Dex-NW was fabricated using carboxymethyl cellulose polymer and contains arrays of 500 nm square drug reservoirs filled with Dex. The in vivo efficacy of the Dex-NW was evaluated using an experimental mouse dry eye model. These studies demonstrated that once a day Dex-NW treatment on alternate days during a five-day treatment period was able to restore a healthy ocular surface and corneal barrier function with comparable efficacy to twice a day topically applied dexamethasone eye drop treatment. The Dex-NW was also very effective in down regulating expression of inflammatory cytokines (TNF-α, and IFN-γ), chemokines (CXCL-10 and CCL-5), and MMP-3, that are stimulated by dry eye. Despite less frequent dosing, the Dex-NW has comparable therapeutic efficacy to topically applied Dex eye drops in experimental mouse dry eye model, and these results provide a strong rationale for translation to human clinical trials for dry eye.

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Essential Role for c-Jun N-Terminal Kinase 2 in Corneal Epithelial Response to Desiccating Stress

Cited by 39 publications

References 33 publications

EMMPRIN Modulates Epithelial Barrier Function through a MMP–Mediated Occludin Cleavage

EMMPRIN Modulates Epithelial Barrier Function through a MMP–Mediated Occludin Cleavage

Differential Effects of Dexamethasone and Doxycycline on Inflammation and MMP Production in Murine Alkali-Burned Corneas Associated with Dry Eye

Dexamethasone nanowafer as an effective therapy for dry eye disease

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