Advances in corneal stem-cell transplantation in rabbits with severe ocular alkali burns

Gimeno, Federico; Lavigne, V.; Gatto, S.; Croxatto, J. Oscar; Correa, L.; Gallo, Juan E.

doi:10.1016/j.jcrs.2007.07.020

Cited by 35 publications

(20 citation statements)

References 34 publications

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“…Induced chemical injury typically extends to the limbus resulting in a depletion of corneal limbal stem-cells. In fact, the alkali burn is commonly used to induce limbal stem-cell deficiency (LSCD) in an experimental setting (Gimeno et al 2007) to study LSCD in people, a common sequela to chemical injury (Tseng 1989, Puangsricharern and Tseng 1995, Fatima et al 2008). As a consequence of LSCD, corneal repair mechanisms are significantly altered, resulting in persistent ulceration, neovascularization and loss of transparency (Huang and Tseng 1991, Gu and Hu 2013).…”

Section: Discussionmentioning

confidence: 99%

Development of a novel in vivo corneal fibrosis model in the dog

Gronkiewicz

Giuliano

Kuroki

et al. 2016

Experimental Eye Research

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The aim of this study was to develop a novel in vivo corneal model of fibrosis in dogs utilizing alkali burn and determine the ability of suberanilohydroxamic acid (SAHA) to inhibit corneal fibrosis using this large animal model. To accomplish this, we used seven research Beagle dogs. An axial corneal alkali burn in dogs was created using 1 N NaOH topically. Six dogs were randomly and equally assigned into 2 groups: A) vehicle (DMSO, 2 μL/mL); B) anti-fibrotic treatment (50 μM SAHA). The degree of corneal opacity, ocular health, and anti-fibrotic effects of SAHA were determined utilizing the Fantes grading scale, modified McDonald-Shadduck (mMS) scoring system, optical coherence tomography (OCT), corneal histopathology, immunohistochemistry (IHC), and transmission electron microscopy (TEM). The used alkali burn dose to produce corneal fibrosis was well tolerated as no significant difference in mMS scores between control and treatment groups (p=0.89) were detected. The corneas of alkali burned dogs showed significantly greater levels of α-smooth muscle actin, the fibrotic marker, than the controls (p=0.018). Total corneal thickness of all dogs post-burn was significantly greater than baseline OCT images irrespective of treatment (p=0.004); TEM showed that alkali burned corneas had significantly greater minimum and maximum interfibrillar distances than the controls (p=0.026, p=0.018). The tested topical corneal alkali burn dose generated significant opacity and fibrosis in dog corneas without damaging the limbus as evidenced by histopathology, IHC, TEM, and OCT findings, and represents a viable large animal corneal fibrosis in vivo model. Additional in vivo SAHA dosing studies with larger sample size are warranted.

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Section: Discussionmentioning

confidence: 99%

Development of a novel in vivo corneal fibrosis model in the dog

Gronkiewicz

Giuliano

Kuroki

et al. 2016

Experimental Eye Research

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“…1 Treatment of the chronic phases, including the anatomical sequelae, sometimes require a multidisciplinary approach and, very often, surgical procedures such as amniotic membrane, keratolimbal stem cell, or cornea transplantation. 2 Although these approaches have slightly improved visual outcomes, visual outcomes from these injuries still poor, in large part due to inadequate control of inflammatory and proteolytic components of the wound healing response. Among the treatments proposed, several inhibitors of MMPs and inflammation have been used with some success.…”

Section: Introductionmentioning

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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“…Until now, only one model of congenital LSCD can be found in the spontaneously vascularized corneas of corn1 and Pax6 þ/À mice with conjunctival invasion, 13 and heterozygosity for Pax6 deficiency (Pax6 þ/À ) results in aniridia. Acute limbal destruction, as with severe chemical burns 14 and surgical removal of limbal tissues, 5 has been used for the induction of acquired LSCD in animals. However, the understanding of progressively developed LSCD is still limited by lack of animal models resulting from chronic and long-term stress over the ocular surface.…”

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confidence: 99%

A Mouse Model of Limbal Stem Cell Deficiency Induced by Topical Medication With the Preservative Benzalkonium Chloride

Zhong

Zhou

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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METHODS. BAC solutions (0%-0.5%) were applied to the mouse ocular surface for 4 weeks. Corneal neovascularization, inflammation, and epithelial status were observed under slit-lamp microscope. The eyeball and ocular surface tissues were collected at 4 and 12 weeks and labeled with a series of antibodies. Limbal structure was evaluated by light and transmission electron microscopy (TEM). Corneal impression cytology was performed at 12 weeks, and specimens were labeled with periodic acid Schiff (PAS) reagents.RESULTS. BAC (0.5%) four times per day for 28 days successfully induced the typical manifestations of LSCD, including corneal neovascularization, severe inflammation in the stroma, and diffuse epithelial defect (P < 0.001). Conjunctival epithelium markers K19 and K13 were positive on the corneal surface. Expression of the putative limbal stem cell markers P63 and ABCG2 was abolished in the limbal epithelium. b-catenin was negative in the basal layer. TEM revealed the irregular basement membrane and the loss of stem cell-specific ultrastructure in the limbal basal epithelium. In the 0.5% BAC group, goblet cells could not be observed on day 28 but emerged after the cessation of BAC, and remained over the cornea after 8 weeks. K13-positive cells were still present over the cornea with the loss of K12.CONCLUSIONS. Topical administration of BAC at high concentration and frequency in mouse induces ocular surface changes resembling those of LSCD in humans, representing a novel model of LSCD.

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Advances in corneal stem-cell transplantation in rabbits with severe ocular alkali burns

Abstract: Autologous limbal epithelial cell transplantation improved the corneal surface in eyes with LSCD. Photocoagulation of neovessel ingrowth was effective over the 1-year follow-up. Results may facilitate the application of this technique in patients.

Cited by 35 publications

References 34 publications

Development of a novel in vivo corneal fibrosis model in the dog

Development of a novel in vivo corneal fibrosis model in the dog

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

A Mouse Model of Limbal Stem Cell Deficiency Induced by Topical Medication With the Preservative Benzalkonium Chloride

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