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      Effects of Acetylcysteine and Dexamethasone on Experimental Corneal Wounds in Rabbits

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          Abstract

          Corneal wound healing often leads to the development of scar tissue with loss of transparency. Reconstitution of transparent corneal stroma depends on the regulation of the biosynthetic activities of postlesional keratocytes as well as to a large extent on the limitation of matrix degradation. It has been shown that 3% concentration of N-acetylcysteine (NAC) improves the healing time of corneal wounds but some corneal haze remains. On the other hand, topical corticosteroids may retard the corneal wound healing but decrease the haze. Thus, the aim of the study was to evaluate whether adding dexamethasone to NAC could reduce the side effects of the two drugs. In this study, experimental corneal wounds were created surgically, up to the depth of one half of the stroma in the center of both eyes of all rabbits. The left eyes were treated topically with 0.9% NaCl as controls and the right eyes were treated with a combination of one drop of 3% NAC and one drop of 0.1% dexamethasone, 6 times per day. Corneal wounds were measured by fluorescein staining every day. The results indicated that the combination of acetylcysteine and dexamethasone significantly increased the mean healing time compared to the control group (p < 0.05). Clinical and histopathologic examinations revealed that the corneal haze in the treatment group was greater than in the control group. It is concluded that treatment of the eyes by a combination of 3% acetylcysteine and 0.1% dexamethasone (if used from the first day of ulceration) may retard the corneal wound healing in rabbits.

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          Most cited references19

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          Cell-matrix and cell-cell interactions during corneal epithelial wound healing.

          K. Suzuki (2003)
          The corneal epithelium serves as a barrier and contributes to the maintenance of corneal transparency and rigidity. In most instances, corneal epithelial defects caused by simple injury are resurfaced promptly. However, in individuals with certain clinical conditions, such as herpes simplex virus infection, neurotrophic keratopathy or diabetic keratopathy, corneal epithelial defects persist and do not respond to conventional treatment regimens because of delayed epithelial wound healing. After the corneal epithelium is removed by injury, the remaining epithelial cells migrate over the denuded surface of the cornea in a manner that is dependent both on the interaction of the cells with the underlying substrate and on cell-cell adhesion. In this review, we describe the specific roles of cell-matrix and cell-cell interactions during the course of corneal epithelial wound healing. The clinical implications of the basic research findings are also discussed.
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            Differential roles for two gelatinolytic enzymes of the matrix metalloproteinase family in the remodelling cornea.

            We have documented changes in collagenolytic/gelatinolytic enzymes of the matrix metalloproteinase family (MMP) in remodelling rabbit cornea. MMP-2 (65 kDa gelatinase) in the proenzyme form is synthesized by the cells of the normal corneal stroma. After keratectomy the level of MMP-2 is increased in the stroma and enzyme appears in both pro- and activated forms. In addition, corneal cells synthesize MMP-9 (92 kDa gelatinase) in the proenzyme form after keratectomy; expression occurs in both the epithelial as well as stromal corneal layers. Changes in expression of both enzymes are precisely localized to the repairing portion of cornea, but demonstrate important differences in timing that correlate with the timing of specific events of matrix remodelling. Our data suggest that each of the gelatinases plays a different role in tissue remodelling after injury. We hypothesize that MMP-2 performs a surveillance function in normal cornea, catalyzing degradation of collagen molecules that occasionally become damaged. After wounding, this enzyme appears to participate in the prolonged process of collagen remodelling in the corneal stroma that eventually results in functional regeneration of the tissue. MMP-9 expression does not correlate with stromal remodelling, but we suggest that the enzyme might play a part in controlling resynthesis of the epithelial basement membrane.
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              Role of matrix metalloproteinases and their inhibition in cutaneous wound healing and allergic contact hypersensitivity.

              Normal wounds can heal by secondary intention (epidermal migration to cover a denuded surface) or by approximation of the wound edges (e.g., suturing). In healing by secondary intention, epidermis-derived MMPs are important. Keratinocyte migration begins within 3-6 hr post injury, as basal cells detach from underlying basal lamina and encounter a dermal substratum rich in type I collagen. Cell contact with type I collagen in vitro stimulates collagenase-1 expression, which is mediated by the alpha 2 beta 1 integrin, the major keratinocyte collagen-binding receptor. Collagenase-1 activity alone is necessary and sufficient for keratinocyte migration over a collagen subsurface. Stromelysins-1 and -2 are also found in the epidermis of normal acute wounds. Stromelysin-2 co-localizes with collagenase-1 and may facilitate cell migration over non-collagenous matrices of the dermis. In contrast, stromelysin-1 is expressed by keratinocytes behind the migrating front and which remain on basal lamina, i.e., the proliferative cell population. Studies with stromelysin-1-deficient mice that suggest this MMP plays a role in keratinocyte detachment from underlying basement membrane to initiate cell migration. In chronic ulcers, MMP levels are markedly elevated, in contrast to their precise temporal and spatial expression in acute wounds. Both collagenase-1 and stromelysin-1 are found in fibroblasts underlying the nonhealing epithelium, and stromelysin-1 expression is especially prominent. Two key questions underlie the use of MMP inhibitors and wound healing: (1) will these agents impair normal reepithelialization in wounds that heal by secondary intention; and (2) can MMP inhibitors be effective therapy for chronic ulcers? The answer to neither is known. Batimastat and marimastat appear not to interfere with normal wound healing, but only in sutured surgical wounds, a situation in which MMP expression has practically no role. We also show the first example of an in vivo immune response, contact hypersensitivity, which is dependent upon MMP activity. Using gene-deficient mice, we demonstrate that stromylysin-1 (MMP-3) is required for sensitization, whereas gelatinase B (MMP-9) is required for timely resolution of the reaction to antigenic challenge.
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                Author and article information

                Journal
                ORE
                Ophthalmic Res
                10.1159/issn.0030-3747
                Ophthalmic Research
                S. Karger AG
                0030-3747
                1423-0259
                2008
                December 2007
                20 November 2007
                : 40
                : 1
                : 41-48
                Affiliations
                aDepartment of Clinical Studies, bDepartment of Pathobiology and cSchool of Veterinary Medicine, University of Shiraz, Shiraz, Iran
                Article
                111158 Ophthalmic Res 2008;40:41–48
                10.1159/000111158
                18025839
                a394c48d-33f9-494b-8195-50d086e7dbc7
                © 2007 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 17 January 2007
                : 07 March 2007
                Page count
                Figures: 9, Tables: 1, References: 57, Pages: 8
                Categories
                Original Paper

                Vision sciences,Ophthalmology & Optometry,Pathology
                Wound healing,Acetylcysteine,Dexamethasone,Rabbits,Corneal wounds

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