The ROP model was used to study the effect of N-acetyl cysteine (NAC) on pathologic features of IVNV and avascular retinal area. NAC has reducing and antioxidant properties by acting as a direct scavenger of free radicals including OH−, H2O2, and O2− [116, 117]. It also restores the pool of intracellular reduced glutathione [118] and is an inhibitor of NF-kappa B and inßammatory cytokines [119, 120]. In the ROP model, NAC given intraperitoneally was found to signiÞcantly reduce retinal LHP [84] but did not affect features of severe ROP when administered at different dosing periods and at doses in the range used in other studies [121Ð123].

Several studies have looked at the effect of the NADPH oxidase inhibitor, apocynin, on both avascular retina and IVNV. In both the mouse OIR and rat ROP models, apocynin reduced avascular retina and apoptosis [84]. In a model of supplemental oxygen superimposed on the standard ROP model of ßuctuating oxygen, NADPH oxidase was activated to contribute to IVNV in a pathway that may appear to involve JAK/STAT3 signaling [97].

28.5Clinical Studies of Antioxidants on ROP

A meta-analysis of several clinical studies that tested vitamin E to reduce ROP in infants found a 52% overall reduction in the incidence of stage 3 ROP, i.e., the stage with IVNV. The study was not able to evaluate later visual development or complications of ROP [66].

A clinical trial testing NAC was performed in preterm infants. A low dose of NAC (16Ð32 mg/kg/day) given to premature infants under 1,000 g birthweight for the Þrst 6 days after birth showed no signiÞcant difference in survival, body weight gain, respiratory disease, or ROP [124]. Other studies have found discordance in the effects of NAC in in vitro and in vivo studies [125]. Although the reasons remain mostly unknown, NAC can act as an anti-inßammatory agent or antioxidant based on dose and cell type and may explain why beneÞcial effects in vitro are not always translated into the in vivo condition [125]. In addition, certain cells may be able to mount DNA repair responses when lipid peroxides are endogenously generated but not when exogenously administered [126].

28.6Genetics

Similar to other complex retinal and choroidal diseases characterized by abnormal growth of blood vessels (e.g., age-related macular degeneration, diabetic retinopathy and polypoidal choroidal vasculopathy), ROP is likely inßuenced by multiple genes, environmental factors and their interactions. Of particular interest pertaining to oxidation, is the potential to inherit susceptibility to DNA methylation, which can affect the expression of genes important in maintaining the integrity of the genome through DNA repair and quenching of ROS [127]. To date, only one study has investigated the degree that genetics inßuences risk of ROP in humans [128]. SpeciÞcally, Bizzarro et al. investigated both monozygotic twins (n = 63) and dizygotic twins

Besides discrepancies in phenotype, there may be diagnostic differences as many studies relied on descriptions of ROP rather than photographic evidence, the technology for which has only been available in the last decade. Also, studies may differ based on environmental exposures (nutrition, oxygen, prenatal care) in different populations. Further, there is evidence that genetics plays a role in ROP and additional variability may therefore depend on population differences. Also, oxidative signaling can affect numerous interacting cell types, and broad inhibition may have varying effects. Besides complexities in studying oxidative signaling pathways in ROP, there is also the concern of broad inhibition of oxidation in human preterm infants, who have reduced reserve to Þght infection.

References

1. Katz ML, Robison WG Jr (1988) Autoxidative damage to the retina: potential role in retinopathy of prematurity. Birth Defects Orig Artic Ser 24:237Ð248

2. Penn JS (1990) Oxygen-induced retinopathy in the rat: possible contribution of peroxidation reactions. Doc Ophthalmol 74:179Ð186

3. Phelps DL, Rosenbaum AL (1979) Vitamin E in kitten oxygen-induced retinopathy. II. Blockage of vitreal neovascularization. Arch Ophthalmol 97:1522Ð1526

4. Penn JS, Tolman BL, Lowery LA (1993) Variable oxygen exposure causes preretinal neovascularisation in the newborn rat. Invest Ophthalmol Vis Sci 34:576Ð585

5. Ward JPT (2008) Oxygen sensors in context. Biochim Biophys Acta 1777(1):1Ð14

6. OÕBrien JR, Usher RH, Maughan GB (1966) Causes of birth asphyxia and trauma. Can Med Assoc J 94(21):1077

7. Stiller R, Mering R, Kšnig V, Huch A, Huch R (2002) How well does reßectance pulse oximetry reßect intrapartum fetal acidosis? Am J Obstet Gynecol 186(6):1351Ð1357

8. Strauss RG (2006) Controversies in the management of the anemia of prematurity using single-donor red blood cell transfusions and/or recombinant human erythropoietin. Transfus Med Rev 20(1):34Ð44

9.Saito Y, Uppal A, ByÞeld G, Budd S, Hartnett ME (2008) Activated NAD(P)H oxidase from supplemental oxygen induces neovascularization independent of VEGF in retinopathy of prematurity model. Invest Ophthalmol Vis Sci 49(4):1591Ð1598

10. 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(9):4351Ð4359

11. Berkowitz BA, Roberts R, Penn JS, Gradianu M (2007) High-resolution manganese-enhanced MRI of experimental retinopathy of prematurity. Invest Ophthalmol Vis Sci 48(10): 4733Ð4740

12. Askikainen TM, HeikkilŠ P, Kaarteenaho-Wiik R, Kinnula VL, Raivio KO (2001) CellspeciÞc expression of manganese superoxide dismutase protein in the lungs of patients with respiratory distress syndrome, chronic lung disease, or persistent pulmonary hypertension. Pediatr Pulmonol 32:193Ð200

13. Rodieck W (1973) Structure of the retinal epithelium and receptor inner segments. W.H. Freeman and Company, San Francisco

14. Daemen FJ (1973) Vertebrate rod outer segment membranes. Biochim Biophys Acta 300(3):255Ð288

15. Reynolds JD, Hardy RJ, Kennedy KA, Spencer R, van Heuven WAJ, Fielder AR (1998) Lack of efÞcacy of light reduction in preventing retinopathy of prematurity. N Engl J Med 338:1572Ð1576

16. Dennery PA (2004) Role of redox in fetal development and neonatal diseases. Antioxid Redox Signal 6(1):147Ð153

17. Gibson K, Halliday JL, Kirby DM, Yaplito-Lee J, Thorburn DR, Boneh A (2008) Mitochondrial oxidative phosphorylation disorders presenting in neonates: clinical manifestations and enzymatic and molecular diagnoses. Pediatrics 122(5):1003Ð1008

18. Fulton AB, Hansen RM, Peterson RA, Vanderveen DK (2001) The rod photoreceptors in retinopathy of prematurity: an electroretinographic study. Arch Ophthalmol 119:499Ð505

19. Gardiner TA, Gibson DS, de Gooyer TE, de la Cruz VF, McDonald DM, Stitt AW (2005) Inhibition of tumor necrosis factor-{alpha} improves physiological angiogenesis and reduces pathological neovascularization in ischemic retinopathy. Am J Pathol 166(2):637Ð644

20. Ernest JT, Goldstick TK (1984) Retinal oxygen tension and oxygen reactivity in retinopathy of prematurity in kittens. Invest Ophthalmol Vis Sci 25:1129Ð1134

21. Zeng G, Taylor SM, McColm JR, Kappas NC, Kearney JB, Williams LH et al (2007) Orientation of endothelial cell division is regulated by VEGF signaling during blood vessel formation. Blood 109(4):1345Ð1352

22. Beauchamp MH, Martinez-Bermudez AK, Gobeil F, Marrache AM, Hou X, Speranza G et al (2001) Role of thromboxane in retinal microvascular degeneration in oxygen-induced retinopathy. J Appl Physiol 90:2279Ð2288

23.Terry TL (1942) Extreme prematurity and Þbroblastic overgrowth of persistent vascular sheath behind each crystalline lens: (1) Preliminary report. Am J Ophthalmol 25:203Ð204

24. Palmer EA, Flynn JT, Hardy RJ, Phelps DL, Phillips CL, Schaffer DB et al (1991) Incidence and early course of retinopathy of prematurity. Ophthalmology 98:1628Ð1640

25. Semenza GL, Prabhakar NR (2007) HIF-1-dependent respiratory, cardiovascular, and redox responses to chronic intermittent hypoxia. Antioxid Redox Signal 9(9):1391Ð1396

26. Cunningham S, Fleck BW, Elton RA, Mclntosh N (1995) Transcutaneous oxygen levels in retinopathy of prematurity. Lancet 346:1464Ð1465

27. Ushio-Fukai M, Alexander RW (2004) Reactive oxygen species as mediators of angiogenesis signaling. Role of NAD(P)H oxidase. Mol Cell Biochem V264(1):85Ð97

28. Bedard K, Krause KH (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87(1):245Ð313

29. Beauchamp MH, Marrache AM, Hou X, Gobeil F Jr, Bernier SG, Lachapelle P et al (2002) Platelet-activating factor in vasoobliteration of oxygen-induced retinopathy. Invest Ophthalmol Vis Sci 43(10):3327Ð3337

30. Saugstad OD, Ramji S, Soll RF, Vento M (2008) Resuscitation of newborn infants with 21% or 100% oxygen: an updated systematic review and meta-analysis. Neonatology 94(3):176Ð182 31. Najarian T, Hardy P, Hou X, Lachapelle J, Doke A, Gobeil F Jr et al (2000) Preservation of neural function in the perinate by high PGE2 levels acting via EP2 receptors. J Appl Physiol

89(2):777Ð784

32. Buhimschi IA, Buhimschi CS, Pupkin M, Weiner CP (2003) BeneÞcial impact of term labor: nonenzymatic antioxidant reserve in the human fetus. Am J Obstet Gynecol 189(1):181Ð188 33. Sanchez-Alvarez R, Almeida A, Medina JM (2002) Oxidative stress in preterm rat brain is

due to mitochondrial dysfunction (article). Pediatr Res 51(1):34Ð39

34. Birch EE, Birch DG, Hoffman DR, Uauy R (1992) Dietary essential fatty acid supply and visual acuity development. Invest Ophthalmol Vis Sci 33(11):3242Ð3253

35. Ates O, Alp HH, Caner I, Yildirim A, Tastekin A, Kocer I et al (2009) Oxidative DNA damage in retinopathy of prematurity. Eur J Ophthalmol 19(1):80Ð85

36. Weinberger B, Anwar M, Henien S, Sosnovsky A, Hiatt M, Jochnowitz N et al (2004) Association of lipid peroxidation with antenatal betamethasone and oxygen radial disorders in preterm infants. Biol Neonate 85(2):121Ð127

37. Tsukahara H, Jiang MZ, Ohta N, Sato S, Tamura S, Hiraoka M et al (2004) Oxidative stress in neonates: evaluation using speciÞc biomarkers. Life Sci 75(8):933Ð938

38. Vento M, Aguar M, Escobar J, Arduini A, Escrig R, Brugada M et al (2009) Antenatal steroids and antioxidant enzyme activity in preterm infants: inßuence of gender and timing. Antioxid Redox Signal 11(12):2945Ð2955

580 M.E. Hartnett and M.M. DeAngelis

39. Verhaeghe J, van Bree R, Van Herck E (2009) Oxidative stress after antenatal betamethasone: acute downregulation of glutathione peroxidase-3. Early Hum Dev 85(12):767Ð771

40. Cervantes-Mungu’a R, Espinosa-L—pez L, G—mez-Contreras P, Hern‡ndez-Flores G, Dom’nguez-Rodr’guez J, Bravo-CuŽllar A (2006) Retinopathy of prematurity and oxidative stress. An Pediatr (Barc) 64(2):126Ð131

41. Weinberger B, Nisar S, Anwar M, Ostfeld B, Hegyi T (2006) Lipid peroxidation in cord blood and neonatal outcome. Pediatr Int 48(5):479Ð483

42. Winterbourn CC, Chan T, Buss H, Inder TE, Mogridge N, Darlow BA (2000) Protein carbonyls and lipid peroxidation products as oxidation markers in preterm infant plasma: associations with chronic lung disease and retinopathy and effects of selenium supplementation. Pediatr Res 48(1):84Ð90

43. Buonocore G, Perrone S, Bracci R (2001) Free radicals and brain damage in the newborn. Biol Neonate 79(3Ð4):180Ð186

44. Papp A, NŽmeth I, Pelle Z (1993) Retrospective biochemical study of the preventive property of antioxidants in retinopathy of prematurity. Orv Hetil 134(19):1021Ð1026

45. Papp A, Nqmeth I, Karg E, Papp E (1999) Glutathione status in retinopathy of prematurity. Free Radic Biol Med 27(7Ð8):738Ð743

46. Rogers S, Witz G, Anwar M, Hiatt M, Hegyi T (2000) Antioxidant capacity and oxygen radical diseases in the preterm newborn. Arch Pediatr Adolesc Med 154(6):544Ð548

47. Saugstad OD (2005) Oxidative stress in the newbornÑa 30-year perspective. Biol Neonate 88(3):228Ð236

48. Kermorvant-Duchemin E, Sapieha P, Sirinyan M, Beauchamp M, Checchin D, Hardy P et al (2010) Understanding ischemic retinopathies: emerging concepts from oxygen-induced retinopathy. Doc Ophthalmol 120(1):51Ð60

49. Sood BG, Madam A, Saha S, Schendel D, Thorsen P, Skogstrand K et al (2010) Perinatal systemic inßammatory response syndrome and retinopathy of prematurity (article). Pediatr Res 67(4):394Ð400

50. Sakurai E, Anand A, Ambati BK, van Rooijen N, Ambati J (2003) Macrophage depletion inhibits experimental choroidal neovascularization. Invest Ophthalmol Vis Sci 44(8):3578Ð3585

51. Barnett JM, McCollum GW, Penn JS (2010) Role of cytosolic phospholipase A2 in retinal neovascularization. Invest Ophthalmol Vis Sci 51(2):1136Ð1142

52. Hardy P, Beauchamp M, Sennlaub F, Gobeil J, Tremblay L, Mwaikambo B et al (2005) New insights into the retinal circulation: inßammatory lipid mediators in ischemic retinopathy. Prostaglandins Leukot Essent Fatty Acids 72(5):301Ð325

53. Lambert IH, Pedersen SF, Poulsen KA (2006) Activation of PLA2 isoforms by cell swelling and ischaemia/hypoxia. Acta Physiol (Oxf) 187(1Ð2):75Ð85

54. Dammann O, Phillips TM, Allred EN, OÕShea TM, Paneth N, Van Marter LJ et al (2001) Mediators of fetal inßammation in extremely low gestational age newborns. Cytokine 13(4):234Ð239

55. OÕDonovan DJ, Fernandes CJ (2000) Mitochondrial glutathione and oxidative stress: implications for pulmonary oxygen toxicity in premature infants. Mol Genet Metab 71(1Ð2): 352Ð358

56. Gilbert C, Rahi J, Eckstein M, OÕSullivan J, Foster A (1997) Retinopathy of prematurity in middle-income countries. Lancet 350:12Ð14

57. Saugstad OD (2006) Oxygen and retinopathy of prematurity. J Perinatol 26(Suppl 1): S46ÐS50

58. SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network (2010) Target ranges of oxygen saturation in extremely preterm infants. N Engl J Med 362(21):1959Ð1969

59. Tin W, Milligan DWA, Pennefather PM, Hey E (2001) Pulse oximetry, severe retinopathy, and outcome at one year in babies of less than 28 weeks gestation. Arch Dis Child Fetal Neonatal Ed 84:106Ð110

60. Chow LC, Wright KW, Sola A (2003) Can changes in clinical practice decrease the incidence of severe retinopathy of prematurity in very low birth weight infants? Pediatrics 111: 339Ð345

61. The STOP-ROP Multicenter Study Group (2000) Supplemental therapeutic oxygen for prethreshold retinopathy of prematurity (STOP-ROP), a randomized, controlled trial. I: primary outcomes. Pediatrics 105(2):295Ð310

62. Sears JE, Pietz J, Sonnie C, Dolcini D, Hoppe G (2009) A change in oxygen supplementation can decrease the incidence of retinopathy of prematurity. Ophthalmology 116(3):513Ð518

63. Wallace DK, Veness-Meehan KA, Miller WC (2007) Incidence of severe retinopathy of prematurity before and after a modest reduction in target oxygen saturation levels. J AAPOS 11(2):170Ð174

64.Vanderveen DK, MansÞeld TA, Eichenwald EC (2006) Lower oxygen saturation alarm limits decrease the severity of retinopathy of prematurity. J AAPOS 10(5):445Ð448

65. Phelps DL (1988) The role of vitamin E therapy in high-risk neonates. Clin Perinatol 15(4):955Ð963

66. Raju TNK, Langenberg P, Bhutani V, Quinn GE (1997) Vitamin E prophylaxis to reduce retinopathy of prematurity: a reappraisal of published trials. J Pediatr 131(6):844Ð850

67. Lofqvist C, Andersson E, Sigurdsson J, Engstrom E, Hard AL, Niklasson A et al (2006) Longitudinal postnatal weight and insulin-like growth factor I measurements in the prediction of retinopathy of prematurity. Arch Ophthalmol 124(12):1711Ð1718

68. Hellstrom A, Hard AL, Engstrom E, Niklasson A, Andersson E, Smith L et al (2009) Early weight gain predicts retinopathy in preterm infants: new, simple, efÞcient approach to screening. Pediatrics 123(4):e638Ðe645

69. Smith LEH, Wesolowski E, McLellan A, Kostyk SK, DÕAmato R, Sullivan R et al (1994) Oxygen induced retinopathy in the mouse. Invest Ophthalmol Vis Sci 35(1):101Ð111

70. Hirano K, Morinobu T, Kim H, Hiroi M, Ban R, Ogawa S et al (2001) Blood transfusion increases radical promoting non-transferrin bound iron in preterm infants. Arch Dis Child Fetal Neonatal Ed 84(3):F188ÐF193

71. Bell EF, Strauss RG, Widness JA, Mahoney LT, Mock DM, Seward VJ et al (2005) Randomized trial of liberal versus restrictive guidelines for red blood cell transfusion in preterm infants. Pediatrics 115(6):1685Ð1691

72. Kirpalani H, Whyte RK, Andersen C, Asztalos EV, Heddle N, Blajchman MA et al (2006) The premature infants in need of transfusion (pint) study: a randomized, controlled trial of a restrictive (LOW) versus liberal (HIGH) transfusion threshold for extremely low birth weight infants. J Pediatr 149(3):301

73. Bracci R, Perrone S, Buonocore G (2001) Red blood cell involvement in fetal/neonatal hypoxia. Biol Neonate 79(3Ð4):210Ð212

74. Lubetzky R, Stolovitch C, Dollberg S, Mimouni FB, Salomon M, Mandel D (2005) Nucleated red blood cells in preterm infants with retinopathy of prematurity. Pediatrics 116(5): e619Ðe622

75. Aher SM, Ohlsson A (2006) Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev CD004865(3):1Ð21

76. Ohlsson A, Aher SM (2006) Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev 3:CD004863

77. Suk KK, Dunbar JA, Liu A, Daher NS, Leng CK, Leng JK et al (2008) Human recombinant erythropoietin and the incidence of retinopathy of prematurity: a multiple regression model. J AAPOS 12(3):233Ð238

78. Brown MS, Baron AE, France EK, Hamman RF (2006) Association between higher cumulative doses of recombinant erythropoietin and risk for retinopathy of prematurity. J AAPOS 10(2):143Ð149

79. Gao G, Li Y, Zhang D, Gee S, Crosson C, Ma J (2001) Unbalanced expression of VEGF and PEDF in ischemia-induced retinal neovascularization. FEBS Lett 489(2Ð3):270Ð276

80. McLeod DS, Brownstein R, Lutty GA (1996) Vaso-obliteration in the canine model of oxygen-induced retinopathy. Invest Ophthalmol Vis Sci 37:300Ð311

81. McLeod DS, Crone SN, Lutty GA (1996) Vasoproliferation in the neonatal dog model of oxygen-induced retinopathy. Invest Ophthalmol Vis Sci 37(7):1322Ð1333

82. Phelps DL (1990) Oxygen and developmental retinal capillary remodelling in the kitten. Invest Ophthalmol Vis Sci 31:2194Ð2200

83. Penn JS, Henry MM, Tolman BL (1994) Exposure to alternating hypoxia and hyperoxia causes severe proliferative retinopathy in the newborn rat. Pediatr Res 36:724Ð731

84. Saito Y, Geisen P, Uppal A, Hartnett ME (2007) Inhibition of NAD(P)H oxidase reduces apoptosis and avascular retina in an animal model of retinopathy of prematurity. Mol Vis 13:840Ð853

85. Sapieha P, Sirinyan M, Hamel D, Zaniolo K, Joyal JS, Cho JH et al (2008) The succinate receptor GPR91 in neurons has a major role in retinal angiogenesis. Nat Med 14(10): 1067Ð1076

86. Armstrong D, Ueda T, Aljeda A, Browne R, Fukuda S, Spengler R et al (1998) Lipid hydroperoxide stimulates retinal neovascularization in rabbit retina through expression of TNF-alpha, VEGF, and PDGF. Angiogenesis 2:93Ð104

87. Gardiner TA, Gibson DS, de Gooyer TE, de la Cruz VF, McDonald DM, Stitt AW (2005) Inhibition of tumor necrosis factor-alpha improves physiological angiogenesis and reduces pathological neovascularization in ischemic retinopathy. Am J Pathol 166(2):637Ð644

88. Armstrong D, Ueda T, Ueda T, Aljada A, Browne R, Fukuda S et al (1998) Lipid hydroperoxide stimulates retinal neovascularization in rabbit retina through expression of tumor necrosis factor-alpha, vascular endothelial growth factor and platelet-derived growth factor. Angiogenesis 2(1):93Ð104

89. Iruela-Arispe ML, Davis GE (2009) Cellular and molecular mechanisms of vascular lumen formation. Dev Cell 16(2):222Ð231

90. Guaiquil V, Swendeman S, Yoshida T, Chavala S, Campochiaro P, Blobel CP (2009) ADAM9 is involved in pathological retinal neovascularization. Mol Cell Biol 29(10):2694Ð2703

91. Rey S, Semenza GL (2010) Hypoxia-inducible factor-1-dependent mechanisms of vascularization and vascular remodelling. Cardiovasc Res 86(2):236Ð242

92.Brafman A, Mett I, ShaÞr M, Gottlieb H, Damari G, Gozlan-Kelner S et al (2004) Inhibition of oxygen-induced retinopathy in RTP801-deÞcient mice. Invest Ophthalmol Vis Sci 45(10):3796Ð3805

93. Garrett TA, Van Buul JD, Burridge K (2007) VEGF-induced Rac1 activation in endothelial cells is regulated by the guanine nucleotide exchange factor Vav2. Exp Cell Res 313(15): 3285Ð3297

94. Monaghan-Benson E, Hartmann J, Vendrov AE, Budd S, ByÞeld G, Parker A et al (2010) The role of VEGF-induced activation of NADPH oxidase in choroidal endothelial cells and choroidal neovascularization. Am J Pathol 177(4):2091Ð2102

95. Mettu P, Agron E, Samtani S, Chew EY, Wong WT (2010) Genotype-phenotype correlation in ocular von Hippel-Lindau (VHL) disease: the effect of missense mutation position on ocular VHL phenotype. Invest Ophthalmol Vis Sci 51(9):4464Ð4470

96. Sears JE, Hoppe G, Ebrahem Q, Anand-Apte B (2008) Prolyl hydroxylase inhibition during hyperoxia prevents oxygen-induced retinopathy. Proc Natl Acad Sci 105(50):19898Ð19903

97.ByÞeld GE, Budd S, Hartnett ME (2009) Supplemental oxygen can cause intravitreous neovascularization through JAK/STAT pathways in a model of retinopathy of prematurity. Invest

Ophthalmol Vis Sci 50(7):3360Ð3365

98. Al Shabrawey M, Bartoli M, El Remessy AB, Platt DH, Matragoon S, Behzadian MA et al (2005) Inhibition of NAD(P)H oxidase activity blocks vascular endothelial growth factor overexpression and neovascularization during ischemic retinopathy. Am J Pathol 167(2):599Ð607

99.TawÞk A, Sanders T, Kahook K, Akeel S, Elmarakby A, Al Shabrawey M (2009) Suppression of retinal peroxisome proliferator-activated receptor gamma in experimental diabetes and oxygen-induced retinopathy: role of NADPH oxidase. Invest Ophthalmol Vis Sci 50(2): 878Ð884

100. Tang Y, Scheef EA, Wang S, Sorenson CM, Marcus CB, Jefcoate CR et al (2009) CYP1B1 expression promotes the proangiogenic phenotype of endothelium through decreased intracellular oxidative stress and thrombospondin-2 expression. Blood 113(3):744Ð754

101. Caro AA, Cederbaum AI (2006) Role of cytochrome P450 in phospholipase A2and arachidonic acid-mediated cytotoxicity. Free Radic Biol Med 40(3):364Ð375

102. Lee JJ, Natsuizaka M, Ohashi S, Wong GS, Takaoka M, Michaylira CZ et al (2010) Hypoxia activates the cyclooxygenase-2-prostaglandin E synthase axis. Carcinogenesis 31(3): 427Ð434

103. Chemtob S, Hardy P, Abran D, Li DY, Peri K, Cuzzani O et al (1995) Peroxide-cyclooxygenase interactions in postasphyxial changes in retinal and choroidal hemodynamics. J Appl Physiol 78(6):2039Ð2046

104. Wilkinson-Berka JL, Alousis NS, Kelly DJ, Gilbert RE (2003) COX-2 inhibition and retinal angiogenesis in a mouse model of retinopathy of prematurity. Invest Ophthalmol Vis Sci 44(3):974Ð979

105. Yanni SE, Barnett JM, Clark ML, Penn JS (2009) The role of PGE2 receptor EP4 in pathologic ocular angiogenesis. Invest Ophthalmol Vis Sci 50(11):5479Ð5486

106. Beauchamp MH, Sennlaub F, Speranza G, Gobeil J, Checchin D, Kermorvant-Duchemin E et al (2004) Redox-dependent effects of nitric oxide on microvascular integrity in oxygeninduced retinopathy. Free Radic Biol Med 37(11):1885Ð1894

107. Brooks SE, Gu X, Samuel S, Marcus DM, Bartoli M, Huang PL et al (2001) Reduced severity of oxygen-induced retinopathy in eNOS-deÞcient mice. Invest Ophthalmol Vis Sci 42: 222Ð228

108. Gu X, El Remessy AB, Brooks SE, Al Shabrawey M, Tsai NT, Caldwell RB (2003) Hyperoxia induces retinal vascular endothelial cell apoptosis through formation of peroxynitrite. Am J Physiol Cell Physiol 285(3):C546ÐC554

109. Geisen P, Peterson L, Martiniuk D, Uppal A, Saito Y, Hartnett M (2008) Neutralizing antibody to VEGF reduces intravitreous neovascularization and does not interfere with vascularization of avascular retina in an ROP model. Mol Vis 14:345Ð357

110.Hartnett ME, Martiniuk DJ, ByÞeld GE, Geisen P, Zeng G, Bautch VL (2008) Neutralizing VEGF decreases tortuosity and alters endothelial cell division orientation in arterioles and veins in rat model of ROP: relevance to plus disease. Invest Ophthalmol Vis Sci 49(7):

3107Ð3114

111. Goldenberg-Cohen N, Dadon-Bar-El S, Hasanreisoglu M, Avraham-Lubin BC, DratvimanStorobinsky O, Cohen Y et al (2009) Possible neuroprotective effect of brimonidine in a mouse model of ischaemic optic neuropathy. Clin Experiment Ophthalmol 37(7):718Ð729

112. Penn JS (1992) Oxygen-induced retinopathy in the rat. Vitamins C and E as potential therapies. Invest Ophthalmol Vis Sci 33:1836Ð1845

113. Penn JS, Tolman BL, Bullard LE (1997) Effect of a water-soluble vitamin E analog, Trolox C, on retinal vascular development in an animal model of retinopathy of prematurity. Free Radic Biol Med 22(6):977Ð984

114. Niesman MR, Johnson KA, Penn JS (1997) Therapeutic effect of liposomal superoxide dismutase in an animal model of retinopathy of prematurity. Neurochem Res 22(5):597Ð605

115. Flynn JT (1987) Retinopathy of prematurity. Pediatr Clin North Am 34(6):1487Ð1516

116. Aruoma OI, Halliwell B, Hoey BM, Butler J (1989) The antioxidant action of N-acetylcysteineÑits reaction with hydrogen-peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic Biol Med 6(6):593Ð597

117. Benrahmoune M, Therond P, Abedinzadeh Z (2000) The reaction of superoxide radical with N-acetylcysteine. Free Radic Biol Med 29(8):775Ð782

118. Grinberg L, Fibach E, Amer J, Atlas D (2005) N-acetylcysteine amide, a novel cell-permeat- ing thiol, restores cellular glutathione and protects human red blood cells from oxidative stress. Free Radic Biol Med 38(1):136Ð145

119. Fox ES, Brower JS, Bellezzo JM, Leingang KA (1997) N-acetylcysteine and alpha-tocoph- erol reverse the inßammatory response in activated rat Kupffer cells. J Immunol 158(11): 5418Ð5423

120. Wuyts WA, Vanaudenaerde BM, Dupont LJ, Demedts MG, Verleden GM (2003) N-acetylcysteine reduces chemokine release via inhibition of p38 MAPK in human airway smooth muscle cells. Eur Respir J 22(1):43Ð49

121. Rocksen D, Lilliehook B, Larsson R, Johansson T, Bucht A (2000) Differential anti-inßam- matory and anti-oxidative effects of dexamethasone and N-acetylcysteine in endotoxininduced lung inßammation. Clin Exp Immunol 122(2):249Ð256

122. Koch T, Heller S, Heissler S, Breil I, Schiefer HG, VanAckern K et al (1996) Effects of N-acetylcysteine on bacterial clearance. Eur J Clin Invest 26(10):884Ð892

123. Blackwell TS, Blackwell TR, Holden EP, Christman BW, Christman JW (1996) In vivo antioxidant treatment suppresses nuclear factor-kappa B activation and neutrophilic lung inßammation. J Immunol 157(4):1630Ð1637

124. Soghier LM, Brion LP (2006) Cysteine, cystine or N-acetylcysteine supplementation in parenterally fed neonates. Cochrane Database Syst Rev (4):CD004869

125. Sadowska AM, Keenoy B, De Backer WA (2007) Antioxidant and anti-inßammatory efÞcacy of NAC in the treatment of COPD: discordant in vitro and in vivo dose-effects: a review. Pulm Pharmacol Ther 20(1):9Ð22

126. Halligan EP, Lowes D, Mistry N, Dove R, Cooke M, Evans M et al (2007) A comparison of the gene expression proÞles of CRL-1807 colonocytes exposed to endogenous AAPHgenerated peroxides and exogenous peroxides from heated oil. Redox Rep 12(1):86Ð90

127. Yildiz M, Karkucak M, Yakut T, Gorukmez O, Ozmen A (2010) Lack of association of genetic polymorphisms of angiotensin-converting enzyme gene I/D and glutathione-S-trans- ferase enzyme T1 and M1 with retinopathy of prematures. Genet Mol Res 94(4):2131Ð2139 128. Bizzarro MJ, Hussain N, Jonsson B, Feng R, Ment LR, Gruen JR et al (2006) Genetic suscep-

tibility to retinopathy of prematurity. Pediatrics 118(5):1858Ð1863

129. van Wijngaarden P, Coster DJ, Brereton HM, Gibbins IL, Williams KA (2005) Straindependent differences in oxygen-induced retinopathy in the inbred rat. Invest Ophthalmol Vis Sci 46(4):1445Ð1452

130. Hutcheson KA, Paluru PC, Bernstein SL, Koh J, Rappaport EF, Leach RA et al (2005) Norrie disease gene sequence variants in an ethnically diverse population with retinopathy of prematurity. Mol Vis 11:501Ð508

131. Dickinson JL, Sale MM, Passmore A, FitzGerald LM, Wheatley CM, Burdon KP et al (2006) Mutations in the NDP gene: contribution to Norrie disease, familial exudative vitreoretinopathy and retinopathy of prematurity. Clin Experiment Ophthalmol 34(7):682Ð688

132. Shastry BS (2007) Assessment of the contribution of insulin-like growth factor I receptor 3174 GÐ > A polymorphism to the progression of advanced retinopathy of prematurity. Eur J Ophthalmol 17(6):950Ð953

133. Mohamed S, Schaa K, Cooper ME, Ahrens E, Alvarado A, Colaizy T et al (2009) Genetic contributions to the development of retinopathy of prematurity. Pediatr Res 65(2):193Ð197

134. Vannay A, Dunai G, Banyansz I, Szabo M, Vamos R, Trezl A et al (2005) Association of genetic polymorphisms of vascular endothelial growth factor and risk for proliferative retinopathy of prematurity. Pediatr Res 57(3):396Ð398

135. MacDonald MLE, Goldberg YP, MacFarlane J, Samuels ME, Trese MT, Shastry BS (2005) Genetic variants of frizzled-4 gene in familial exudative vitreoretinopathy and advanced retinopathy of prematurity. Clin Genet 67(4):363Ð366

136. Ahola T, Lapatto R, Raivio KO, Selander B, Stigson L, Jonsson B et al (2003) N-acetylcysteine does not prevent bronchopulmonary dysplasia in immature infants: a randomized controlled trial. J Pediatr 143(6):713Ð719