New Tools for the Evaluation of Toxic Ocular Surface Changes in the Rat

Pauly, Aude; Brignole-Baudouin, Françoise; Labbé, Antoine; Liang, Hong; Warnet, Jean‐Michel; Baudouin, Christophe

doi:10.1167/iovs.06-0728

Cited by 113 publications

(74 citation statements)

References 36 publications

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“…Preservatives could also induce apoptosis at low concentrations and necrosis at high concentrations 17 in cell cultures and animals, as well as in humans. 20 These alterations may stimulate production of a series of biological mediators in the ocular surface and lead to subsequent proinflammatory and inflammatory response and the creation of a vicious circle. Our results indicated a BAC-induced severe inflammatory condition in the ocular surface, including the upregulation of inflammatory factors such as TNF-a (data not shown) and the infiltration of CD4-positive T cells, reflecting chronic and immune responses under longstanding BAC administration.…”

Section: Discussionmentioning

confidence: 99%

“…20 The cornea was divided into four quadrants, which were scored individually. The measurement of vessels was quantified by the ratio of the largest length of vessels to the corneal radius, briefly as follows: no vessels grown into clear cornea, 0; one-quarter or less but not zero, 1; between onequarter and one-half, 2; between one-half and three-quarters, 3; and more than three-quarters, 4.…”

Section: Measurement Of New Vessels and Inflammationmentioning

confidence: 99%

“…Ninety seconds later, corneal epithelial damage was graded with a cobalt blue filter under a slit-lamp microscope. The cornea was divided into four quadrants, which were scored respectively as previously described 20 with essential modification, briefly as follows: absent, 0; slightly punctate staining less than 30 spots, 1; punctate staining more than 30 spots, but not diffuse, 2; severe diffuse staining but no positive plaque, 3; positive fluorescein plaque, 4. The scores of each quadrant were added to arrive at a final grade (total, 16 points).…”

Section: Evaluation Of Fluorescein Stainingmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Measurement Of New Vessels and Inflammationmentioning

confidence: 99%

Section: Evaluation Of Fluorescein Stainingmentioning

confidence: 99%

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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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“…However, the complex physiological environment is absent in these systems. Non-invasive, in vivo assays have also been developed including: pachymetry, a measurement of corneal thickness; tonometry, a measurement of intra-ocular pressure; electroretinography, a physiological measurement of retinal function; and in vivo confocal microscopy, an advanced laser scan of the cornea (Pauly, et al, 2007). However, these tests often only evaluate a single parameter related to visual morphology of function, they can be technically challenging and labour intensive, and they utilise significant numbers of higher vertebrate animals.…”

Section: -Current Assays For Visual Toxicitymentioning

confidence: 99%

Early safety assessment of human oculotoxic drugs using the zebrafish visualmotor response

Deeti

O’Farrell

Kennedy

2014

Journal of Pharmacological and Toxicological Methods

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Publication informationJournal of Pharmacological and Toxicological Methods, 69 (1): 1-8 Publisher ElsevierItem record/more information http://hdl.handle.net/10197/7931 Publisher's statementThis is the author's version of a work that was accepted for publication in Journal of Pharmacological and Toxicological Methods. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Journal of Pharmacological and Toxicological Methods (VOL 69, ISSUE 1, ((2014) Abstract Introduction: Many prescribed drugs can adversely affect the eye by causing damage to the function of visual pathways or toxicity to the retina. Zebrafish have the potential to efficiently predict drugs with adverse ocular effects at pre-clinical stages of development. In this study, we explore the potential of using a semi-automated visual behaviour assay to predict druginduced ocular toxicity in wild-type zebrafish larvae. Methods: 3 dpf larvae were treated with six known oculotoxic drugs and five control drugs in embryo medium containing 0.1% DMSO. After 48 hours, larvae were assessed using the visualmotor response (VMR), an assay which quantifies locomotor responses to light changes; the optokinetic response (OKR), a behavioural assay that quantifies saccadic eye responses to rotating stimuli; and the touch response, a locomotor response to tactile stimuli. Results: 9 of 10 negative control drugs had no effect on zebrafish visual behaviour. 5 of the 6 known oculotoxic drugs (digoxin, gentamicin, ibuprofen, minoxidil and quinine) showed adverse effects on zebrafish visual behaviour assessed by OKR or the more automated VMR. No gross morphological changes were observed in treated larvae. The general locomotor activity of treated larvae, tested using the touch response assay, showed no differences with respect to controls. Overall the VMR assay had a sensitivity of 83%, a specificity of 100% and a positive predictive value of 100%. Discussion: This study confirms the suitability of the VMR assay as an efficient and predictive pre-clinical approach to evaluate adverse ocular effects of drugs on visual function in vivo.

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“…5 days of treatment with the different eye drops (BID), the tissue alterations were scored according to the scale established by Pauly et al 31,32 and Liang et al 33 ( Fig. 2B).…”

Section: Corneal Wound Healing Following Mechanical Debridementmentioning

confidence: 99%

Comparison of the anti‐inflammatory effects of artificial tears in a rat model of corneal scraping

Daull¹,

Feraille²,

Elena³

et al. 2012

Acta Ophthalmologica

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Purpose: Artificial tears (ATs) are used routinely to alleviate the symptoms of mild to moderate dry eye. Preservative-free cationic emulsions (eg, Cationorm Ò ) are an innovative approach for the management of signs and symptoms of dry eye. The aim of the present exploratory experiment was to evaluate the efficacy of this cetalkonium chloride (CKC)-containing cationic emulsion on debrided cornea and to characterize its effects on scraping-induced inflammation. Methods: Four ATs were assessed in a rat model of corneal scraping. The upper part of the corneal epithelium was scraped before a 5-day treatment, followed by clinical evaluations and fluorescein staining to evaluate cornea recovery. The anti-inflammatory efficacy of the ATs was assessed in vivo and in vitro. Results: In vivo confocal microscopy (IVCM) revealed a trend toward better corneal clinical signs (lower IVCM scores) for the animals treated with the unpreserved ATs. Benzalkonium chloride treatment decreased goblet cell count by 37.5%. While the soft-preserved Systane Balance Ò and Optive Ò and the preservative-free Vismed Ò had no effect on the goblet cell count, Cationorm increased this count by almost 40%. Interestingly, inflammatory cell infiltration in the stroma was at its lowest following treatment with the preservative-free Cationorm. Cationorm is also the only AT decreasing IL6-and IL8-stimulated secretion by 59% and 74%, respectively. Conclusion: By restoring an adequately hydrated ocular surface environment, the different ATs promote corneal epithelium healing. These data position Cationorm as a promising AT for the management of signs and symptoms of dry eye in patients with mild to moderate dry eye disease presenting chronic subclinical levels of ocular inflammation.

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New Tools for the Evaluation of Toxic Ocular Surface Changes in the Rat

Cited by 113 publications

References 36 publications

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

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

Early safety assessment of human oculotoxic drugs using the zebrafish visualmotor response

Comparison of the anti‐inflammatory effects of artificial tears in a rat model of corneal scraping

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