Skip to main content
SpringerLink
Log in

Therapeutic Effect of Liposomal Superoxide Dismutase in an Animal Model of Retinopathy of Prematurity

  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

A newborn rat model of retinopathy of prematurity was used to test the hypothesis that a lack of superoxide dismutase contributes to the retinal vaso-attenuation seen during exposure of the animals to hyperoxic conditions. To determine the endogenous superoxide dismutase activity of the retina under hyperoxic conditions, litters of albino rats were placed in either constant 80% ambient oxygen (constant hyperoxia), or placed in 21% oxygen (room air) immediately after birth. Every other day, for 14 days, several rat pups were sacrificed and their retinas removed for the determination of total superoxide dismutase (SOD) activity and manganese-associated SOD activity. An attempt was made to increase retinal SOD activity by intraperitoneal administration of exogenous SOD encapsulated in polyethylene glycol-modified liposomes. Additional litters were exposed to the same oxygen treatments and supplemented twice daily with either liposome-encapsulated superoxide dismutase in saline or liposomes containing saline without SOD. Animals were sacrificed at various time points for the determination of total superoxide dismutase activity and computer-assisted analysis of vessel density and avascular area. Animals raised in an atmosphere of constant 80% oxygen had significantly reduced levels of retinal superoxide dismutase activity through 6 days of life when compared to their room air-raised littermates. At 6 days of age, daily supplementation with liposome-encapsulated SOD had significantly increased retinal superoxide dismutase activity and reduced oxygen-induced vaso-attenuation as evidenced by increased vessel density and decreased avascular area, when compared to littermates exposed to constant hyperoxia that received control liposomes. Superoxide dismutase had no adverse effects on any of the animals regardless of treatment. Tracing experiments demonstrated that liposomes entered the retina and were found in cells morphologically resembling mi-croglia. Delivery of SOD to the retina via long-circulating liposomes proved beneficial, suggesting that restoration and/or supplementation of endogenous antioxidants in oxygen-damaged retinal tissue is a potentially valuable therapeutic strategy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. Flynn, T. J., Bancalari, E., Bawol, R., Goldberg, R., Cassady, J., Schiffman, J., Feuer, W., Roberts, J., Gillings, D., Sim, E., Burkley, E., and Bachynski, B. N. 1987. Retinopathy of prematurity. A randomized prospective trail of transcutaneous oxygen monitoring. Ophthalmol. 94:630–38.

    Google Scholar 

  2. Kendig, J. W., Notter, R. H., Cox, C., Aschner, J. L., Benn, S., Bernstein, R. A., Hendricks-Munoz, K., Maniscaixo, W. M., Metlay, L. A., Phelps, D. L., Sinkin, R. A., Woods, B. P., and Shapiro, D. L. 1988. Surfactant replacement therapy at birth: Final analysis of a clinical trial and comparisons with similar trials. Ped. 82:756–62.

    Google Scholar 

  3. Phelps, D. L. 1993. Retinopathy of prematurity. Ped. Ophthalmol. 40(4):705–14.

    Google Scholar 

  4. Kinsey, V. E. 1956. Retrolental fibroplasia: Cooperative study of retrolental fibroplasia and the use of oxygen. Arch. Ophthalmol. 56:481–543.

    Google Scholar 

  5. Ashton, N. 1966. Oxygen and the growth and development of retinal vessels: In vivo and in vitro studies. Am. J. Ophthalmol 62:412–35.

    Google Scholar 

  6. Daemen, F. J. M. 1973. Vertebrate rod outer segment membranes. Biochim. Biophys. Acta. 300:255–88.

    Google Scholar 

  7. Delmelle, M. 1979. Possible implication of photooxidation reactions in retinal photodamage. Photochem. Photobiol. 29:713–6.

    Google Scholar 

  8. Rodeick, R. W. 1973. The Vertebrate Retina: Principles of structure and function. Page 159, in Freeman, W. H., San Francisco, California, U.S.A.

  9. Stone, J., Itin, A., Alon, R., Pe'er, J., Gnessin, H., Chan-Ling, T., and Keshet, E. 1995. Development of retinal vasculature is mediated by hypoxia-induced vascular endothelial growth factor (VEGF) expression by neuroglia. J. Neurosci. 15:4738–47.

    Google Scholar 

  10. Nielsen, J., Naash, M., and Anderson, R. 1988. The regional distribution of vitamins E and C in mature and premature human retinas. Invest. Ophthalmol. Vis. Sci. 29:22–7.

    Google Scholar 

  11. Penn, J. 1990. Oxygen-induced retinopathy in the rat: Possible contribution of peroxidation reactions. Docum. Ophthalmol. 74:179–86.

    Google Scholar 

  12. Bougle, D., Vert, P., Reichart, E., Hartemann, D. and Heng, L. 1982. Retinal superoxide dismutase activity in newborn kittens exposed to normobaric hyperoxia effect of vitamin E. Ped. Res., 16:400–402.

    Google Scholar 

  13. Yabe, H. 1985. Effects of vitamin E deficiency on oxygen induced retinopathy in rat. Nippon. Ganka. Gakkai Zasshi. 89:624.

    Google Scholar 

  14. Penn, J., Thum, L., and Nash, M. 1992. Oxygen-induced retinopathy in the rat: Vitamins C and E as potential therapies. Invest Ophthalmol Vis. Sci. 33:1836–45.

    Google Scholar 

  15. Phelps, D. and Rosenbaum, A. 1977. The role of tocopherol in oxygen-induced retinopathy: kitten model. Ped. 59:988–94.

    Google Scholar 

  16. Cotran, R., Kumar, V., and Robbins, S. 1994. Cellular injury and cellular death. Pages 11–12, in Robbins Pathologic Basis for Disease 5th edition. (Ed. Schoen, E.), W. B. Saunders Company, Pennsylvania, U.S.A.

    Google Scholar 

  17. Southorn, P. and Powis, G. 1988. Free radicals in medicine. I. Chemical nature and biologic reactions. Mayo. Clin. Proc. 63:381–89.

    Google Scholar 

  18. Freeman, B. 1983. Liposome-mediated augmentation of superoxide dismutase in endothelial cells prevents oxygen injury. J. Biol. Chem. 25:12534–42.

    Google Scholar 

  19. Nakae, D., Yoshiji, H., Amanuma, T., Kinugasa, T., Farber, J. L., and Konishi, Y. 1990. Endocytosis-independent uptake of lipo-some-encapsulated superoxide dismutase prevents the killing of cultured hepatocytes by tert-butyl hydroperoxide. Arch. Biochem. Biophys. 279:315–19.

    Google Scholar 

  20. Chan, P. H., Longar, S., and Fishman, R. A. 1987. Protective effects of liposome-entrapped superoxide dismutase on post-traumatic brain edema. Annals Neurol. 21(6):540–7.

    Google Scholar 

  21. Imaizumi, S., Woolworth, V., Fishman, R. A., and Chan, P. H. 1990. Liposome-entrapped superoxide dismutase reduces cerebral infarction in cerebral ischemia in rats. Stroke. 21(9):1312–7.

    Google Scholar 

  22. Chan, P. H., Fishman, R. A., Wesley, M. A., and Longar, S. 1990. Pathogenesis of vasogenic edema in focal cerebral ischemia. Role of superoxide radicals. Advances Neurol. 52:177–83.

    Google Scholar 

  23. Kinouchi, H., Epstein, C. J., Mizui, T., Carlson, E., Chen, S. F., and Chan, P. H. 1991. Attenuation of focal cerebral ischemic injury in transgenic mice overexpressing CuZn superoxide dismutase. Proc. Nat. Acad. Sci. USA 88(24):11158–62.

    Google Scholar 

  24. Chan, P. 1992. Antioxidant-dependent amelioration of brain injury: role of Cu-Zn-superoxide dismutase. J. Neurotrauma, 9:417–23.

    Google Scholar 

  25. Stanimirovic, D. B., Markovic, M., Micic, D. V., Spatz, M., and Mrsulj, A. 1994. Liposome-entrapped superoxide dismutase reduces ischemia/reperfusion oxidative stress in gerbil brain. Neurochem. Res. 12:1473–78.

    Google Scholar 

  26. Turrens, J., Crapo, J., and Freeman, B. 1984. Protection against oxygen toxicity by intravenous injection of liposome-entrapped catalase and superoxide dismutase. J. Clin. Invest. 73:87–95.

    Google Scholar 

  27. Beckman, J. S., Minor, R. L., Jr., and Freeman, B. A. 1986. Augmentation of antioxidant enzymes in vascular endothelium. J. Free Radicals Biol. Med. 2(5–6):359–65.

    Google Scholar 

  28. Senga, S., Onituka, H., Hirose, K., Yamamoto, K., and Niwa, K. 1990. Protective effect of liposomal encapsulated superoxide dismutase on ischemically injured liver in the rat. Transplant. Proc. 22(4):2025–26.

    Google Scholar 

  29. Bando, K., Schueler, S., Cameron, D. E., DeValeria, P. A., Hatanaka, M., Casale, A. S., Zebley, M. A., Hutchins, G. M., Reitz, B. A., and Baumgartner, W. A. 1991. Twelve-hour cardiopulmonary preservation using donor core cooling, leukocyte depletion, and liposomal superoxide dismutase. J. Heart Lung Transplant. 10:304–9.

    Google Scholar 

  30. Senior, J. H. 1987. Fate an behavior of liposomes in vivo: A review of controlling factors. Crit. Rev. Ther. Drug Carr. Sys. 3(2):123–93.

    Google Scholar 

  31. Allen, T. M., Hansen, C. B., and Guo, L. S. S. 1993. Subcutaneous administration of liposomes: A comparison with the intravenous and intraperitoneal routes of injection. Biochim. Biophys. Acta 1150:9–16.

    Google Scholar 

  32. McCord, J., and Fridovich, I. 1969. An enzymatic function for erythrocyprein (hemocuprein)*. J. Biol. Chem. 244:6049–55.

    Google Scholar 

  33. Iqbal, J., and Whitney, P. 1991. Use of cyanide and diethyldithiocarbamate in the assay of superoxide dismutases. Free Radic. Biol. Med. 10:69–77.

    Google Scholar 

  34. Allen, T. M., and Papahadjopoulos, D. 1993. Sterically stabilized (“stealth”) liposomes: Pharmacokinetic and therapeutic advantages. Pages 59–72, in Gregoriadis, G., Liposome Technology 2nd Edition Vol 111, Ed. CRC Press, Inc. Florida, U.S.A.

    Google Scholar 

  35. Mayer, L., Hope, M., Cullis, P., and Janoff, A. 1985. Solute distributions and trapping efficiencies observed in freeze thawed multilamellar vesicles. Biochim. Biophys. Acta. 817:193–6.

    Google Scholar 

  36. von Bartheld, C. S., Cunningham, D. E., and Rubel, E. W. 1990. Neuronal tracing with DiI: Decalcification, cryosectioning, and photoconversion for light and electron microscopic analysis. J. Histochem. Cytochem. 38(5):725–33.

    Google Scholar 

  37. Schmued, L. C., and Snavely, L. F. 1993. Photoconversion and electron microscopic localization of the fluorescent axon tracer fluoro-ruby (rhodamine-dextran-amine). J. Histochem. Cytochem. 41(5):777–82.

    Google Scholar 

  38. Penn, J., and Gay, C. 1992. Computerized digital image analysis of retinal vessel density: Application to normoxic and hyperoxic rearing of the newborn rat. Exp. Eye Res. 54:329–36.

    Google Scholar 

  39. Kingham, J. 1986. Classification of retinopathy of prematurity. Pages 32–33, in McPherson, A., Hittner, H., and Kretzer, F. (eds.), Retinopathy of prematurity, current concepts and controversies. B. C. Decker Inc., Ontario, Canada.

    Google Scholar 

  40. Penn, J., Tolman, B., and Henry, M. 1994. Oxygen-induced retinopathy in the rat: Relationship of retinal nonperfusion to subsequent neovascularization. Invest. Ophthalmol. Vis. Sci. 35:3429–35.

    Google Scholar 

  41. Palmer, E. A., Flynn, J. T., Hardy, R. J., Phelps, D. L., Phillips, C. L., Schaffer, D. B., and Tung, B. 1991. Incidence and early course of retinopathy of prematurity. Ophthalmol. 98:1628–40.

    Google Scholar 

  42. Schaffer, D., Palmer, E., Plotsky, D., Metz, H., Flynn, J., Tung, B., and Hardy, R. 1993. Prognostic factors in the natural course of retinopathy of prematurity. Ophthalmol. 100:230–37.

    Google Scholar 

  43. Nayak, M., Kita, M., and Marmor, M. 1993. Protection of rabbit retina from ischemic injury by superoxide dismutase and catalase. Invest. Ophthalmol. Vis. Sci. 34:2018–22.

    Google Scholar 

  44. Freeman, B. 1985. Modulation of oxidant lung injury by using liposome-entrapped superoxide dismutase and catalase. Fed. Proc. 44:2591–5.

    Google Scholar 

  45. Yusa, T., Crapo, J. D., and Freeman, B. A. 1984. Liposome-mediated augmentation of brain SOD and catalase inhibits CNS O2 toxicity. J. Applied Physiol.: Respiratory, Environmental and Exercise Physiol. 57(6):1674–81.

    Google Scholar 

  46. Tanswell, A. K., and Freeman, B. A. 1987. Liposome-entrapped antioxidant enzymes prevent lethal O2 toxicity in the newborn rat. J. Applied Physiol. 63(1):347–52.

    Google Scholar 

  47. Das, D. K., Russell, J. C., and Jones, R. M. 1991. Reduction of cold injury by superoxide dismutase and catalase. Free Radical Res. Commun. 12–13(2):653–62.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Arkansas Center for Eye Research, University of Arkansas for Medical Sciences, 4301 W. Markham, Slot 523, Little Rock, Arkansas, 72205

    Michael R. Niesman, Kelly A. Johnson & John S. Penn

Authors
  1. Michael R. Niesman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kelly A. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John S. Penn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John S. Penn.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Niesman, M.R., Johnson, K.A. & Penn, J.S. Therapeutic Effect of Liposomal Superoxide Dismutase in an Animal Model of Retinopathy of Prematurity. Neurochem Res 22, 597–605 (1997). https://doi.org/10.1023/A:1022474120512

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1022474120512

Search

Navigation