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Inhibition of Corneal Inflammation by an Acylated Superoxide Dismutase Derivative

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Inhibition of Corneal Inflammation by an Acylated Superoxide Dismutase Derivative Investigative Ophthalmology & Visual Science, Vol. 31, No. 10, October 1990 Copyright © Association for Research in Vision and Ophthalmology Inhibition of Corneal Inflammation by an Acylated Superoxide Dismutase Derivative Eiko Ando,* Yukio Ando,t Masayasu lnoue,t Yoshimasa Morino,t Ryuji Kamafa,* ond Ryoichi Okomuro" Superoxide radicals and their metabolite(s) have been postulated to play an important role in the pathogenesis of inflammation. Hence, superoxide dismutase (SOD) has been used to reduce tissue injury caused by reactive oxygens. However, protection of the cornea and other ocular tissues from oxygen toxicity could not be achieved by administering SOD presumably due to its unfavorable in vivo behavior. To scavenge superoxide radicals on the outer surface of corneal epithelial cells, the authors synthesized an acylated SOD derivative (AC-SOD) by linking capric acid. When instilled into rabbit eyes, a significant amount of AC-SOD remained bound to the corneal surface for a fairly long time. Intracorneal injection of lipopolysaccharide (LPS) triggered infiltration of polymorphonuclear leuko- cytes (PMNs) to the cornea and induced severe keratitis. Topical administration of AC-SOD to the LPS-treated cornea markedly inhibited the infiltration of PMNs and suppressed the occurrence of keratitis. Under identical conditions, topically administered SOD was rapidly removed by tears and, hence, did not inhibit LPS-induced keratitis. When the number of PMNs in the systemic circulation was reduced by intravenous administration of hydroxyurea, LPS-induced keratitis was inhibited mark- edly. These results indicate that superoxide radicals and circulating PMNs might play a critical role in LPS-induced keratitis. Invest Ophthalmol Vis Sci 31:1963-1967, 1990 Reactive oxygen species play an important role in Materials and Methods the pathogenesis of various ocular diseases, such as cataract,1 uveitis,2"5 and retinopathy of prematurity.6 Materials Keratitis caused by bacterial infection is often asso- Human erythrocyte-type SOD was purified by the 7 8 ciated with corneal abscess, ulcer, and erosion. ' method of Gartner et al." Capric acid was obtained Since a large number of polymorphonuclear leuko- from Wako Pure Chemical, Osaka, Japan. The LPS cytes (PMNs) migrate to the inflammatory cornea, ofSerratia marcescens came from Biological Labora- reactive oxygen species derived from PMNs may in- tory (Campbell). Hydroxyurea was from Sigma, St. crease tissue injury. To test a possible role of reactive Louis, MO. The l25I-labeled Bolton-Hunter reagent oxygen species in corneal inflammation, we tested the (2200 Ci/mmol) was from New England Nuclear, effect of superoxide dismutase (SOD) on endotoxin- Boston, MA. The AC-SOD was synthesized by link- induced keratitis, an animal model for aseptic cor- ing 5 mol of capric acid to the lysyl e-amino groups of 9 neal inflammation. Preliminary experiments re- SOD as described previously.10 Both SOD and AC- vealed that topically instilled SOD was rapidly re- SOD samples were labeled with the 125I-labeled Bol- moved by tears from the corneal surface and, hence, ton-Hunter reagent as described.12 The specific radio- did not have a protective action in situ. activity of the two enzyme samples was 200,000 To stabilize the enzyme on the corneal surface, we cpm/mg protein. synthesized an acylated SOD derivative (AC-SOD) that binds to cell surface membrane via its acyl Animals moiety.10 Topically instilled AC-SOD efficiently bound to the corneal surface and significantly sup- Male Japanese albino rabbits (2-2.5 kg) were fed pressed the lipopolysaccharide (LPS)-induced kera- laboratory chow and water ad libitum. Use of the titis in the rabbit, particularly in its early stages. animals conformed to the ARVO Resolution on the Use of Animals in Research. From the Departments of ""Ophthalmology and tBiochemistry, Kumamoto University Medical School, Kumamoto, Japan. LPS-induced Keratitis of the Rabbit Reprint requests: Dr. M. Inoue, The Department of Biochemis- try, Kumamoto University Medical School, 2-2-1 Honjo, Kuma- Under pentobarbital anesthesia (50 mg/kg), 10 ng moto 860, Japan. of LPS dissolved in 10 jul of saline solution was in- 1963 Downloaded from iovs.arvojournals.org on 09/29/2021 1964 INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / Ocrober 1990 Vol. 31 Table 1. LPS-induced keratitis Hinson et al.14 On day 5, the number of circulating PMNs decreased to less than 36% of the control Pathologic events Score* group. On day 6, LPS was injected into the cornea as Corneal edema described, and time-dependent changes in the inflam- Slight + 1 mation score (Table 1) were determined. Administra- Mild +2 Severe +3 tion of hydroxyurea was continued for another week Corneal abscess after LPS injection; the number of circulating PMNs Slender ring (<l/2 circle) + 1 further decreased to less than 10% of the control Slender ring (> 1/2 circle) +2 Wide ring (<l/2 circle) +3 group after 1 week. Disc +4 Corneal ulcer Results <l/2 area of corneal abscess + 1 > 1 /2 area of corneal abscess +2 Fate of Topically Instilled SOD and AC-SOD Disc +3 To assess the binding of enzyme samples to the * Inflammation score was expressed as the sum of these values. corneal surface, 125I-labeled SOD or AC-SOD was topically instilled onto the intact cornea. As shown in jected into both sides of the central stroma of the Figure 1A, the amount of AC-SOD remained asso- rabbit cornea by using a microsyringe (30-G needle). ciated with the cornea was significantly larger than After injection of LPS, the right side of the cornea was that of SOD. Binding of the two SOD samples was topically instilled with 640 /xg of either SOD or AC- also determined in inflamed corneas pretreated with SOD dissolved in 80 JX\ of saline six times a day (every LPS (Fig. IB). Interestingly, binding of SOD and 4 hr). The left side of the eye received the same vol- ume of saline. At the indicated times after LPS ad- ministration, the grade of corneal inflammation was determined according to the inflammation score (Table 1). Microinjection of LPS was done at approx- imately 1:00 PM. Binding of SOD and AC-SOD to the Cornea 3.0 D) Six days after injection of LPS, 320 ng of 125I-la- beled SOD or AC-SOD was topically instilled onto the intact and inflamed corneas. Under pentobarbital anesthesia, the central part of the cornea (10 mm in V) diameter) was excised with a trephine after 30 min of CD instillation. After washing the excised cornea with 3 ml of ice-cold saline, tissue-associated radioactivity was determined in a Packard autogamma-scintilla- tion spectrophotometer model-5130 (IL). Q O CO Thiobarbituric Acid-Reactive Metabolites • in LPS-Injected Cornea I • The LPS-induced keratitis consists of four stages: 0 early, active (ring abscess), late (disciform ulcer and B neovascularization), and scarring stages. At each Fig. 1. Fate of topically instilled enzymes on the corneal surface. stage, the cornea was excised with a trephine (7 mm (A) Under pentobarbital anesthesia (50 mg/kg), l25I-labeled SOD or in diameter) without being contaminated by the area AC-SOD was topically instilled to the cornea of the intact rabbit with neovascularization. Thiobarbituric acid-reactive (160 /xg/cornea). Thirty minutes after instillation, the cornea was excised, washed with 3 ml of ice-cold saline, and studied for tissue- metabolite (TBAR) levels in the inflamed corneas associated radioactivity. (B) Six days after intracorneal injection of 13 were determined by the method of Uchiyama et al. LPS (jug/cornea), radioactive SOD samples were instilled to the inflammatory cornea. The cornea was excised, washed in 3 ml of Depletion of the Circulating PMNs ice-cold saline, and tested for tissue-associated radioactivity. De- tailed conditions are described in the text. The data show the mean Rabbits were intravenously injected with hydrox- ± SEM derived from three eyes. Open columns = SOD-treated yurea (100 mg/kg/day) for 5 days by the method of groups; spotted columns = AC-SOD-treated groups. *P < 0.05. Downloaded from iovs.arvojournals.org on 09/29/2021 No. 10 INHIDITION OF CORNEAL INJURY DY ACYLATED SOD / Ando er ol 1965 Fig. 2. Effect of SOD and AC-SOD on corneal inflam- mation. Under pentobarbi- tal anesthesia, 10 ng of LPS was injected into the cor- neal stroma of the rabbit. After 30 min, 80 ^1 of saline or 640 jig of AC-SOD or SOD was topically instilled to the cornea six times a day. Photographs were taken 6 days after LPS in- jection. (A, left) saline- treated group; (B, right) AC-SOD-treated group. AC-SOD to the LPS-injected cornea increased mark- markedly inhibited the increase in TBAR levels of edly compared with that in the intact cornea. Again, LPS-treated cornea (Fig. 5). significantly larger amounts of AC-SOD bound to the injured cornea than did SOD. The amounts of AC- Effect of Depleting PMNs in the Circulation SOD associated with the conjunctiva and sclera were also higher than those of SOD (data not shown). To understand the role of PMNs in the propaga- tion of the inflammatory process occurring in the Effect of AC-SOD on Corneal Inflammation avascular cornea, circulating PMNs were depleted by hydroxyurea. Interestingly, the inflammatory score To examine the effect of SOD samples on corneal markedly decreased in PMN-depleted animals espe- inflammation, the enzyme samples were topically in- cially at an early stage of keratitis (Fig. 6). stilled onto the LPS-treated cornea. As shown in Fig- ure 2, AC-SOD significantly suppressed corneal in- Discussion flammation while SOD had no appreciable effect. The protective effect of AC-SOD was remarkable par- Our study shows that AC-SOD binds to the mem- ticularly at early stages of inflammation (Fig.
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