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Effects of Topical Antiglaucoma Medications on Corneal Epithelium As Evaluated by Gene Expression Patterns Yuka Okada, MD, Phd

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Effects of Topical Antiglaucoma Medications on Corneal Epithelium As Evaluated by Gene Expression Patterns Yuka Okada, MD, Phd JOBNAME: corn 26#Suppl. 1 2007 PAGE: 1 OUTPUT: Thursday July 26 14:59:59 2007 tsp/corn/146793/ICO200709 ARTICLE Effects of Topical Antiglaucoma Medications on Corneal Epithelium as Evaluated by Gene Expression Patterns Yuka Okada, MD, PhD Key Words: cyclooxygenase-2, antiglaucoma medication, corneal Purpose: To examine the expression pattern of the stress-related epithelium, transcription factor genes c-fos and c-jun, which encode the 2 major components of activator protein (AP)-1, and cyclooxygenase (COX)-2 in rat corneal (Cornea 2007;26(Suppl. 1):S46–S54) epithelium treated with topical antiglaucoma medications and benzalkonium chloride (BAK) preservative. Methods: Eighty-eight male Wistar rats were used. We instilled antiglaucoma eye drops (0.5% Timoptol, 0.005% Xalatan, or 0.12% opical b-blocker (timolol, 0.5% Timoptol) and prosta- Rescula), their chemical constituents (active ingredients), or BAK Tglandin (PG)F2a analogs (latanoprost, Xalatan; isopropyl preservative (0.005%, 0.01%, or 0.02%) in 1 eye of each rat. Fellow unoprostone, Rescula) are widely used in the management of eyes served as controls. The eyes were enucleated after various glaucoma and ocular hypertension. Because antiglaucoma intervals. In situ hybridization and immunohistochemistry were used drugs are used for long time periods, chronic side effects are to detect expression of c-fos, c-jun, and COX-2. a major concern. Among these side effects, ocular surface disorders attributable to the drug itself or to drug preser- Results: Expression of c-fos, c-jun, and COX-2 was minimally vatives are relatively common.1–4 Benzalkonium chloride observed in uninjured rat corneal epithelium. Thirty minutes to 1 hour (BAK), the most commonly used preservative in ophthalmic after applying the antiglaucoma eye drops, signals for c-fos and c-jun preparations,5,6 is used at an average concentration of 0.01% mRNA were detected in the corneal epithelium. Ninety minutes after (range, 0.005%–0.02%) in topical multidose solutions.6 applying 0.005% Xalatan, 0.12% Rescula, or their chemical con- BAK is a quaternary ammonium compound7 that has been stituents, but not 0.5% Timoptol, COX-2 was detected in corneal shown to adversely affect both the cornea and conjunctiva.8,9 epithelium. Expression of c-fos and c-jun seemed more marked with One in vitro study concluded that ocular damage associated prostaglandins than with timolol. Thirty minutes to 1 hour after with BAK is dose dependent.10 Therefore, ocular surface instillation of 0.02% BAK preservative, signals for c-fos and c-jun complications seen in glaucoma patients might be attrib- mRNA were detected in the corneal and conjunctival epithelium. utable to taking antiglaucoma drugs. The purpose of this COX-2 was not induced by 0.5% Timoptol or BAK preservative. study was to examine the expression pattern of stress-related COX-2 mRNA was not affected by applying 0.005% or 0.01% genes c-fos and c-jun, which encode the 2 major com- BAK preservative. Proteins of these components were also detected, ponents of activator protein (AP)-1, and cyclooxygenase indicating that each mRNA expression was followed by protein (COX)-2 in rat corneal and conjunctival epithelium treated synthesis. with topical antiglaucoma medications with or without Conclusions: Corneal and conjunctival epithelial cells are BAK preservative. transcriptionally activated transiently at an early phase after topical AP-1, which regulates gene expression by binding to the administration of antiglaucoma medications and BAK preservative. AP-1 binding site located upstream of various target genes, is 11–13 Stimulatory effects of prostaglandin drugs on corneal epithelial a dimer composed of various fos and jun family proteins. cells were more marked than those with timolol. Expression of Fos-Jun heterodimers, as well as Jun protein homodimers, bind COX-2 may potentially be involved in inflammatory response in the to DNA at AP-1 sites in the promoters of many genes and corneal epithelium. thereby regulate transcription. In addition to their roles as transcriptional factors (TFs), they influence the transcriptional activity of TFs through protein–protein interactions.14,15 c-fos, c-jun, and their family members are rapidly and transiently upregulated in quiescent cells in response to extracellular From the Department of Ophthalmology, Wakayama Medical University, stimuli such as mitogens, growth factors, and mechanical Wakayama, Japan. stimulation.16 Reprints: Y. Okada, Department of Ophthalmology, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-0012, Japan (e-mail: PGs, commonly known as lipid mediators of inflam- [email protected]). mation, are produced from arachidonic acid by COX enzymes, Copyright Ó 2007 by Lippincott Williams & Wilkins which exist in several isoforms. COX-1 is constitutively S46 Cornea Volume 26, Suppl. 1, October 2007 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. JOBNAME: corn 26#Suppl. 1 2007 PAGE: 2 OUTPUT: Thursday July 26 15:00:01 2007 tsp/corn/146793/ICO200709 Cornea Volume 26, Suppl. 1, October 2007 Antiglaucoma Medication and Corneal Epithelium FIGURE 1. Dark-field photomicrographs showing expression of c-fos mRNA in the corneal epithelium after instillation of antiglaucoma eye drops. Thirty minutes to 1 hour after applying antiglaucoma medications, c-fos mRNA was detected in the corneal epithelium. Bar = 100 mm. E, epithelium. expressed in many tissues. In contrast, COX-2, which is a concentration of 0.005%, 0.01%, or 0.02%. The affected normally expressed at low levels, is potently induced by eyes were allowed to heal for 15, 30, 60, 90, 120, and proinflammatory agents.17–19 180 minutes after treatment and then were enucleated. Fellow Previously, we showed that mRNA encoding AP-1 eyes served as controls. Eyes from untreated rats were components and COX-2 is transiently upregulated in healing also enucleated. corneal epithelium after epithelial debridement.20–22 In this study, we examined the expression pattern of AP-1 and COX-2 In Situ Hybridization for mRNA of in rat corneal epithelium treated with antiglaucoma eye drops AP-1 Components and BAK preservatives. In situ hybridization was carried out by using 35S- radiolabeled oligonucleotide probes as previously re- ported.20,23 Probes for detection of c-fos and c-jun mRNA MATERIALS AND METHODS were complementary to the nucleotides spanning amino acids 1to15ofratc-Fosprotein,24 the last 20 amino acids of Investigational Agents the predicted c-Jun,25 or 1421 to 1460 of rat COX-2 mRNA26 All experiments were performed in accordance with the sequences. A computer-assisted homology search revealed ARVO Resolution on the Use of Animals in Research. Adult no identical sequences in any genes in the database. The eyes male Wistar rats (n = 88) were used. In 1 eye of each rat, the were embedded in optimal cutting temperature (OCT) com- following were instilled: antiglaucomatous eye drops (0.5% pound and quickly frozen. Cryosections (5 mm) were fixed timolol, Timoptol; 0.005% latanoprost, Xalatan; or 0.12% with 4% paraformaldehyde in 0.1 M phosphate buffer (pH isopropyl unoprostone, Rescula), the chemical constituents 7.4) for 20 minutes, rinsed 3 times in 23 SSC, and de- (active ingredients) of Xalatan (0.005% latanoprost) and hydrated through a graded ethanol series. Hybridization was Rescula (0.12% unoprostone), or BAK preservative at performed as described previously15 by incubating sections q 2007 Lippincott Williams & Wilkins S47 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. JOBNAME: corn 26#Suppl. 1 2007 PAGE: 3 OUTPUT: Thursday July 26 15:00:20 2007 tsp/corn/146793/ICO200709 Okada Cornea Volume 26, Suppl. 1, October 2007 FIGURE 2. Dark-field photomicrographs showing expression of c-jun mRNA in the corneal epithelium after instillation of antiglaucoma eye drops. Thirty minutes to 1 hour after applying antiglaucoma medications, c-jun mRNA was detected in the corneal epithelium. Bar = 100 mm. E, epithelium. with hybridization buffer containing each probe (0.5–1.0 3 PBS, sections were incubated with biotinylated anti–rabbit 106 cpm/slide) for 16 hours at 37°C. After hybridization, immunoglobulin G (IgG) or anti–goat IgG (1:250; Vectastain sections were rinsed in 13 SSC at 55°Cfor43 15 minutes. ABC kit; Vector, Burlingame, CA) at room temperature for The sections were dehydrated and coated with Ilford G-5 1 hour and then with avidin-biotin peroxidase complex emulsion diluted 1:1 with water. The sections were dried in (Vectastain ABC kit; Vector) at room temperature for 1 hour. a level position for 30 minutes and exposed in tightly sealed Peroxidase reaction product in tissue sections was visualized dark boxes at 4°C for 8 weeks. After being developed in D-19 by using diaminobenzidine. After counterstaining with methyl (Kodak, Rochester, NY) developer, fixed with photographic green, sections were dehydrated and mounted in balsam. fixer, and washed with tap water, the sections were coun- Sections incubated with normal rabbit or goat serum (1:200) terstained with 1% neutral red (sodium acetate buffer). and processed in the same way as described above showed Incubation of sections with a mixture of each 35S- no immunostaining in the corneal epithelium. labeled probe and 100-fold excess of respective cold oligo- nucleotide resulted in no detectable signals. RESULTS Immunostaining for AP-1 Component Proteins Immunohistochemistry for c-Fos and COX-2 proteins In Situ Hybridization was carried out as previously reported.20–22 In brief, the eyes Expression of c-fos, c-jun, and COX-2 was minimally were fixed with 4% paraformaldehyde in 0.1 M phosphate observed in uninjured rat corneal epithelium (Figs. 1–3). buffer (pH 7.4) for 24 hours. Cryosections were incubated with Thirty minutes to 1 hour after applying antiglaucoma med- primary antibodies diluted (1:200; c-Fos; Oncogene Science, ications, signals for c-fos and c-jun mRNA were detected in Cambridge, MA; and 1:200; COX-2, Santa Cruz Biotechnol- the corneal epithelium (Figs.
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