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The development of the rat model of retinopathy of prematurity

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Abstract

Retinopathy of prematurity (ROP) is a potentially blinding disease affecting premature infants. ROP is characterized by pathological ocular angiogenesis or retinal neovascularization (NV). Models of ROP have yielded much of what is currently known about physiological and pathological blood vessel growth in the retina. The rat provides a particularly attractive and cost effective model of ROP. The rat model of ROP consistently produces a robust pattern of NV, similar to that seen in humans. This model has been used to study gross aspects of angiogenesis. More recently, it has been used to identify and therapeutically target specific genes and molecular mechanisms involved in the angiogenic cascade. As angiogenesis occurs as a complication of many diseases, knowledge gained from these studies has the potential to impact nonocular angiogenic conditions. This article provides historical perspective on the development and use of the rat model of ROP. Key findings generated through the use of this model are also summarized.

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References

  1. Terry TL (1942) Extreme prematurity and fibroblastic overgrowth of persistent vascular sheath behind each crystalline lens: I, preliminary report. Am J Ophthalmol 25:203–204

    Google Scholar 

  2. Campbell K (1951) Intensive oxygen therapy as a possible cause of retrolental fibroplasia; a clinical approach. Med J Aust 2:48–50

    PubMed  CAS  Google Scholar 

  3. Patz A, Hoech LE, Cruz ED (1953) Studies on the effect of high oxygen administration in retrolental fibroplasia. I. Nursery observations. Am J Ophthalmol 35:1245–1253

    Google Scholar 

  4. Kinsey VE (1956) Retrolental fibroplasia; cooperative study of retrolental fibroplasia and the use of oxygen. AMA Arch Ophthalmol 56:481–543

    PubMed  CAS  Google Scholar 

  5. Lucey JF, Dangman B (1984) A reexamination of the role of oxygen in retrolental fibroplasia. Pediatrics 73:82–96

    PubMed  CAS  Google Scholar 

  6. Patz A, Hoeck LE, De La Cruz E (1952) Studies on the effect of high oxygen administration in retrolental fibroplasia. I. Nursery observations. Am J Ophthalmol 35:1248–1253

    PubMed  CAS  Google Scholar 

  7. Gyllensten LJ, Hellstrom BE (1952) Retrolental fibroplasia; animal experiments: the effect of intermittingly administered oxygen on the postnatal development of the eyes of fullterm mice. Acta Paediatr 41:577–582

    Article  PubMed  CAS  Google Scholar 

  8. Ashton N, Ward B, Serpell G (1953) Role of oxygen in the genesis of retrolental fibroplasia: a preliminary report. Br J Ophthalmol 37:513–520

    Article  PubMed  CAS  Google Scholar 

  9. Forrester RM (1964) Oxygen, cerebral palsy and retrolental fibroplasia. Dev Med Child Neurol 6:648–650

    PubMed  CAS  Google Scholar 

  10. McDonald AD (1964) Oxygen treatment of premature babies and cerebral palsy. Dev Med Child Neurol 6:313–314

    Article  PubMed  CAS  Google Scholar 

  11. Hatfield EM (1972) Blindness in infants and young children. Sight Sav Rev 42:69–89

    PubMed  CAS  Google Scholar 

  12. Gibson DL, Sheps SB, Schechter MT, Wiggins S, McCormick AQ (1989) Retinopathy of prematurity: a new epidemic? Pediatrics 83:486–492

    PubMed  CAS  Google Scholar 

  13. Phelps DL (1981) Retinopathy of prematurity: an estimate of vision loss in the United States—1979. Pediatrics 67:924–925

    PubMed  CAS  Google Scholar 

  14. Curley MA, Thompson JE, Arnold JH (2000) The effects of early and repeated prone positioning in pediatric patients with acute lung injury. Chest 118:156–163

    Article  PubMed  CAS  Google Scholar 

  15. Calkovska A, Sun B, Curstedt T, Renheim G, Robertson B (1999) Combined effects of high-frequency ventilation and surfactant treatment in experimental meconium aspiration syndrome. Acta Anaesthesiol Scand 43:135–145

    Article  PubMed  CAS  Google Scholar 

  16. Tang SF, Sherwood MC, Miller OI (1998) Randomised trial of three doses of inhaled nitric oxide in acute respiratory distress syndrome. Arch Dis Child 79:415–418

    Article  PubMed  CAS  Google Scholar 

  17. Gibson DL, Sheps SB, Uh SH, Schechter MT, McCormick AQ (1990) Retinopathy of prematurity-induced blindness: birth weight-specific survival and the new epidemic. Pediatrics 86:405–412

    PubMed  CAS  Google Scholar 

  18. Payne JW, Patz A (1977) Fluorescein angiography in retrolental fibroplasia. Int Ophthalmol Clin 17:121–135

    Article  PubMed  CAS  Google Scholar 

  19. Chan-Ling T, Stone J (1993) Retinopathy of prematurity: origins of the architecture of the retina. Prog Retin Eye Res 12:155–178

    Google Scholar 

  20. Hardy P, Dumont I, Bhattacharya M, Hou X, Lachapelle P, Varma DR, Chemtob S (2000) Oxidants, nitric oxide and prostanoids in the developing ocular vasculature: a basis for ischemic retinopathy. Cardiovasc Res 47:489–509

    Article  PubMed  CAS  Google Scholar 

  21. Schaffer DB, Palmer EA, Plotsky DF, Metz HS, Flynn JT, Tung B, Hardy RJ (1993) Prognostic factors in the natural course of retinopathy of prematurity. The Cryotherapy for Retinopathy of Prematurity Cooperative Group. Ophthalmology 100:230–237

    PubMed  CAS  Google Scholar 

  22. Foos RY (1985) Chronic retinopathy of prematurity. Ophthalmology 92:563–574

    PubMed  CAS  Google Scholar 

  23. Patz A (1954) Oxygen studies in retrolental fibroplasia. IV. Clinical and experimental observations. Am J Ophthalmol 38:291–308

    PubMed  CAS  Google Scholar 

  24. Coats DK, Paysse EA, Steinkuller PG (2000) Threshold retinopathy of prematurity in neonates less than 25 weeks’ estimated gestational age. J AAPOS 4:183–185

    PubMed  CAS  Google Scholar 

  25. Fruttiger M (2002) Development of the mouse retinal vasculature: angiogenesis versus vasculogenesis. Invest Ophthalmol Vis Sci 43:522–527

    PubMed  Google Scholar 

  26. Brands KH, Hofmann H, Klees E (1958) Die retrolentale fibroplasie. Geburtshilfe Frauenheilkd 18:805–814

    PubMed  CAS  Google Scholar 

  27. Ashton N, Blach R (1961) Studies on developing retinal vessels Viii. Effect of oxygen on the retinal vessels of the ratling. Br J Ophthalmol 45:321–340

    Article  PubMed  CAS  Google Scholar 

  28. Ricci B, Calogero G (1988) Oxygen-induced retinopathy in newborn rats: effects of prolonged normobaric and hyperbaric oxygen supplementation. Pediatrics 82:193–198

    PubMed  CAS  Google Scholar 

  29. Penn JS, Tolman BL, Lowery LA, Koutz CA (1992) Oxygen-induced retinopathy in the rat: hemorrhages and dysplasias may lead to retinal detachment. Curr Eye Res 11:939–953

    Article  PubMed  CAS  Google Scholar 

  30. Ventresca MR, Gonder JR, Tanswell AK (1990) Oxygen-induced proliferative retinopathy in the newborn rat. Can J Ophthalmol 25:186–189

    PubMed  CAS  Google Scholar 

  31. Reynaud X, Vallat M, Vincent D, Dorey CK (1991) Protective effect of the ginkgo biloba extract in the rat model of retinopathy of prematurity. Invest Ophthalmol Vis Sci 32(suppl):1147

    Google Scholar 

  32. Flower RW, McLeod DS, Lutty GA, Goldberg B, Wajer SD (1985) Postnatal retinal vascular development of the puppy. Invest Ophthalmol Vis Sci 26:957–968

    PubMed  CAS  Google Scholar 

  33. Biglan AW, Brown DR, Reynolds JD, Milley JR (1984) Risk factors associated with retrolental fibroplasia. Ophthalmology 91:1504–1511

    PubMed  CAS  Google Scholar 

  34. Brown BA, Thach AB, Song JC, Marx JL, Kwun RC, Frambach DA (1998) Retinopathy of prematurity: evaluation of risk factors. Int Ophthalmol 22:279–283

    Article  PubMed  Google Scholar 

  35. Gunn TR, Easdown J, Outerbridge EW, Aranda JV (1980) Risk factors in retrolental fibroplasia. Pediatrics 65:1096–1100

    PubMed  CAS  Google Scholar 

  36. Holmstrom G (1993) Retinopathy of prematurity. BMJ 307:694–695

    Article  PubMed  CAS  Google Scholar 

  37. Hammer ME, Mullen PW, Ferguson JG, Pai S, Cosby C, Jackson KL (1986) Logistic analysis of risk factors in acute retinopathy of prematurity. Am J Ophthalmol 102:1–6

    PubMed  CAS  Google Scholar 

  38. Purohit DM, Ellison RC, Zierler S, Miettinen OS, Nadas AS (1985) Risk factors for retrolental fibroplasia: experience with 3,025 premature infants. National Collaborative Study on Patent Ductus Arteriosus in Premature Infants. Pediatrics 76:339–344

    PubMed  CAS  Google Scholar 

  39. York JR, Landers S, Kirby RS, Arbogast PG, Penn JS (2004) Arterial oxygen fluctuation and retinopathy of prematurity in very-low-birth-weight infants. J Perinatol 24:82–87

    Article  PubMed  Google Scholar 

  40. Penn JS, Thum LA (1989) The rat as an animal model for retinopathy of prematurity. Prog Clin Biol Res 314:623–642

    PubMed  CAS  Google Scholar 

  41. Penn JS, Thum LA, Naash MI (1992) Oxygen-induced retinopathy in the rat. Vitamins C and E as potential therapies. Invest Ophthalmol Vis Sci 33:1836–1845

    PubMed  CAS  Google Scholar 

  42. Cunningham S, Fleck BW, Elton RA, McIntosh N (1995) Transcutaneous oxygen levels in retinopathy of prematurity. Lancet 346:1464–1465

    Article  PubMed  CAS  Google Scholar 

  43. Gaynon MW, Stevenson DK (2000) What can we learn from STOP-ROP and earlier studies? Pediatrics 105:420–421

    Article  PubMed  CAS  Google Scholar 

  44. Saito Y, Omoto T, Cho Y, Hatsukawa Y, Fujimura M, Takeuchi T (1993) The progression of retinopathy of prematurity and fluctuation in blood gas tension. Graefes Arch Clin Exp Ophthalmol 231:151–156

    Article  PubMed  CAS  Google Scholar 

  45. Penn JS, Tolman BL, Lowery LA (1993) Variable oxygen exposure causes preretinal neovascularization in the newborn rat. Invest Ophthalmol Vis Sci 34:576–585

    PubMed  CAS  Google Scholar 

  46. Penn JS, Henry MM, Tolman BL (1994) Exposure to alternating hypoxia and hyperoxia causes severe proliferative retinopathy in the newborn rat. Pediatr Res 36:724–731

    Article  PubMed  CAS  Google Scholar 

  47. Penn JS, Henry MM, Wall PT, Tolman BL (1995) The range of PaO2 variation determines the severity of oxygen-induced retinopathy in newborn rats. Invest Ophthalmol Vis Sci 36:2063–2070

    PubMed  CAS  Google Scholar 

  48. Shahinian L Jr, Malachowski N (1978) Retrolental fibroplasia: a new analysis of risk factors based on recent cases. Arch Ophthalmol 96:70–74

    PubMed  Google Scholar 

  49. Askie LM, Henderson-Smart DJ, Irwig L, Simpson JM (2003) Oxygen-saturation targets and outcomes in extremely preterm infants. N Engl J Med 349:959–967

    Article  PubMed  CAS  Google Scholar 

  50. Leach CL, Greenspan JS, Rubenstein SD, Shaffer TH, Wolfson MR, Jackson JC, DeLemos R, Fuhrman BP (1996) Partial liquid ventilation with perflubron in premature infants with severe respiratory distress syndrome. The LiquiVent Study Group. N Engl J Med 335:761–767

    Article  PubMed  CAS  Google Scholar 

  51. Courtney SE, Durand DJ, Asselin JM, Hudak ML, Aschner JL, Shoemaker CT (2002) High-frequency oscillatory ventilation versus conventional mechanical ventilation for very-low-birth-weight infants. N Engl J Med 347:643–652

    Article  PubMed  Google Scholar 

  52. Werdich XQ, McCollum GW, Rajaratnam VS, Penn JS (2004) Variable oxygen and retinal VEGF levels: correlation with incidence and severity of pathology in a rat model of oxygen-induced retinopathy. Exp Eye Res 79:623–630

    Article  PubMed  CAS  Google Scholar 

  53. Liu K, Akula JD, Falk C, Hansen RM, Fulton AB (2006) The retinal vasculature and function of the neural retina in a rat model of retinopathy of prematurity. Invest Ophthalmol Vis Sci 47:2639–2647

    Article  PubMed  Google Scholar 

  54. Akula JD, Hansen RM, Martinez-Perez ME, Fulton AB (2007) Rod photoreceptor function predicts blood vessel abnormality in retinopathy of prematurity. Invest Ophthalmol Vis Sci 48:4351–4359

    Article  PubMed  Google Scholar 

  55. Fulton AB, Akula JD, Mocko JA, Hansen RM, Benador IY, Beck SC, Fahl E, Seeliger MW, Moskowitz A, Harris ME (2009) Retinal degenerative and hypoxic ischemic disease. Doc Ophthalmol 118:55–61

    Article  PubMed  Google Scholar 

  56. Cunningham S, McColm JR, Wade J, Sedowofia K, McIntosh N, Fleck B (2000) A novel model of retinopathy of prematurity simulating preterm oxygen variability in the rat. Invest Ophthalmol Vis Sci 41:4275–4280

    PubMed  CAS  Google Scholar 

  57. McColm JR, Cunningham S, Wade J, Sedowofia K, Gellen B, Sharma T, McIntosh N, Fleck BW (2004) Hypoxic oxygen fluctuations produce less severe retinopathy than hyperoxic fluctuations in a rat model of retinopathy of prematurity. Pediatr Res 55:107–113

    Article  PubMed  CAS  Google Scholar 

  58. Roberto KA, Tolman BL, Penn JS (1996) Long-term retinal vascular abnormalities in an animal model of retinopathy of prematurity. Curr Eye Res 15:932–937

    Article  PubMed  CAS  Google Scholar 

  59. Mintz-Hittner HA, Prager TC, Kretzer FL (1992) Visual acuity correlates with severity of retinopathy of prematurity in untreated infants weighing 750 g or less at birth. Arch Ophthalmol 110:1087–1091

    PubMed  CAS  Google Scholar 

  60. Zhang S, Leske DA, Holmes JM (2000) Neovascularization grading methods in a rat model of retinopathy of prematurity. Invest Ophthalmol Vis Sci 41:887–891

    PubMed  CAS  Google Scholar 

  61. Larrazabal LI, Penn JS (1989) Study of ocular vasculature in the newborn rat by fluorescein angiography. J Ophthal Phot 11:49–52

    Google Scholar 

  62. Larrazabal LI, Penn JS (1990) Fluorescein angiography of the newborn rat. Implications in oxygen-induced retinopathy. Invest Ophthalmol Vis Sci 31:810–818

    PubMed  CAS  Google Scholar 

  63. Penn JS, Johnson BD (1993) Fluorescein angiography as a means of assessing retinal vascular pathology in oxygen-exposed newborn rats. Curr Eye Res 12:561–570

    Article  PubMed  CAS  Google Scholar 

  64. Penn JS, Henry MM (1996) Assessing retinal neovascularization in an animal model of proliferative retinopathy. Microvasc Res 51:126–130

    Article  PubMed  CAS  Google Scholar 

  65. Holmes JM, Duffner LA (1996) The effect of postnatal growth retardation on abnormal neovascularization in the oxygen exposed neonatal rat. Curr Eye Res 15:403–409

    Article  PubMed  CAS  Google Scholar 

  66. Shohat M, Reisner SH, Krikler R, Nissenkorn I, Yassur Y, Ben-Sira I (1983) Retinopathy of prematurity: incidence and risk factors. Pediatrics 72:159–163

    PubMed  CAS  Google Scholar 

  67. Smith LE, Wesolowski E, McLellan A, Kostyk SK, D’Amato R, Sullivan R, D’Amore PA (1994) Oxygen-induced retinopathy in the mouse. Invest Ophthalmol Vis Sci 35:101–111

    PubMed  CAS  Google Scholar 

  68. Gao G, Li Y, Fant J, Crosson CE, Becerra SP, Ma JX (2002) Difference in ischemic regulation of vascular endothelial growth factor and pigment epithelium-derived factor in brown norway and sprague dawley rats contributing to different susceptibilities to retinal neovascularization. Diabetes 51:1218–1225

    Article  PubMed  CAS  Google Scholar 

  69. Zhang SX, Ma JX, Sima J, Chen Y, Hu MS, Ottlecz A, Lambrou GN (2005) Genetic difference in susceptibility to the blood-retina barrier breakdown in diabetes and oxygen-induced retinopathy. Am J Pathol 166:313–321

    PubMed  Google Scholar 

  70. van Wijngaarden P, Coster DJ, Brereton HM, Gibbins IL, Williams KA (2005) Strain-dependent differences in oxygen-induced retinopathy in the inbred rat. Invest Ophthalmol Vis Sci 46:1445–1452

    Article  PubMed  Google Scholar 

  71. Chan CK, Pham LN, Zhou J, Spee C, Ryan SJ, Hinton DR (2005) Differential expression of pro- and antiangiogenic factors in mouse strain-dependent hypoxia-induced retinal neovascularization. Lab Invest 85:721–733

    Article  PubMed  CAS  Google Scholar 

  72. Floyd BN, Leske DA, Wren SM, Mookadam M, Fautsch MP, Holmes JM (2005) Differences between rat strains in models of retinopathy of prematurity. Mol Vis 11:524–530

    PubMed  CAS  Google Scholar 

  73. Kitzmann A, Leske D, Chen Y, Kendall A, Lanier W, Holmes J (2002) Incidence and severity of neovascularization in oxygen- and metabolic acidosis-induced retinopathy depend on rat source. Curr Eye Res 25:215–220

    Article  PubMed  Google Scholar 

  74. Yanni SE, McCollum GW, Penn JS (2008) Rodent models of oxygen-induced retinopathy. In: Penn JS (ed) Retinal and choroidal angiogenesis. Springer, Dordrecht, pp 57–80

  75. Penn JS, Rajaratnam VS (2003) Inhibition of retinal neovascularization by intravitreal injection of human rPAI-1 in a rat model of retinopathy of prematurity. Invest Ophthalmol Vis Sci 44:5423–5429

    Article  PubMed  Google Scholar 

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Acknowledgments

This study was supported by NIH EY07533, NIH EY01826, NIH AG031036, and an Unrestricted Grant from Research to Prevent Blindness, Inc., and a Research to Prevent Blindness Senior Scientific Investigator Award to JSP.

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Authors and Affiliations

  1. Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA

    Joshua M. Barnett & John S. Penn

  2. Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA

    Susan E. Yanni & John S. Penn

  3. Department of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA

    John S. Penn

  4. Vanderbilt Eye Institute, Vanderbilt University School of Medicine, 8000 Medical Center East, Nashville, TN, 37232-8808, USA

    John S. Penn

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  1. Joshua M. Barnett
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  2. Susan E. Yanni
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  3. John S. Penn
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Correspondence to John S. Penn.

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Joshua M. Barnett and Susan E. Yanni have contributed equally to this study.

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Barnett, J.M., Yanni, S.E. & Penn, J.S. The development of the rat model of retinopathy of prematurity. Doc Ophthalmol 120, 3–12 (2010). https://doi.org/10.1007/s10633-009-9180-y

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