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RESULTS
ADPase Histochemical Technique in Retinal Flatmounts The pattern of vascular development and neovascularization was seen readily in retinal flatmounts by ADPase histochemical technique. The retinal vascular patterns in the mice of control group were characterized by the neovascular tufts and avascular area,a typical pattern of pathological retinalneovascularization. The retinal vessels from the ArgGlntreated mice had reduced avascular area and neovascular tufts in a dosedependent manner compared with control group (Figure 1).
Tissue Slice of HE Staining Five days of treatment of mice with various doses of ArgGln (1.0, 3.0, and 5.0g/kg per day) resulted in a significant reduction in preretinal nuclei. At the highest dose tested, there was an about 75% reduction. All dipeptidetreated samples showed significant decreases in preretinal nuclei compared with control group(P＜0.01) (Figure 2).
Effect of ArgGln Administration on VEGF mRNA in OIR Mice There was a significant reduction in VEGF mRNA at the 17th day in ArgGln treated group in a dosedependent manner compared with control group (P＜0.01). At the dose of 5.0g/kg per day, there was about 68% reduction in the level of VEGF mRNA (Figure 3).
DISCUSSION
Many studies indicate that one of the proposed mechanisms for the pathogenesis of ROP includes overproduction of the angiogenic growth factors including VEGF[6,7], resulting invasoconstriction, poor blood flow, and ultimately retinal ischemia. Nutritional factors may play a major role in regulation of these mechanisms. Recent studies of retinal pigment epithelial cells in culture have demonstrated that glutamine deprivation results in a dramatic elevation of VEGF[8].In studies of mammary epithelium, glutamine deprivation increased both VEGF and IL8, a potent neutrophil chemoattractant, and these same changes were evident with arginine deprivation[9].In addition, several studies in animals suggest that glutamine supplementation reduces inflammation[10,11]. Premature infants undergoing intensive care are also frequently deprived of both arginine and glutamine[12,13] because of stress. They are unable to maintain endogenous synthesis of these conditionally essential amino acids, making these infants highly vulnerable to glutamine andarginine deprivation. Glutamine and arginine supplementation have both been shown to be safe in lowbirthweight infants[14,15].Recent studies indicated that arginine and glutamine (ArgGln) can improve blood flow to the microvasculature via increased local nitric oxide production through the Largininenitric oxide synthase pathway[16,17]. Supplementation of glutamine or arginine has resulted in beneficial effects in human neonates. This study is to demonstrate the beneficial effects of a nutraceutic agent, ArgGln dipeptide, in inhibiting retinal angiogenesis. The proposed mechanism is a reduction of VEGF expression in vivo. It may provide a safe way to prevent and treat some forms of proliferative retinopathies including ROP.
【参考文献】
1 Wang P, Tao LJ, Gao XR, Xie LH, Yang HL, Wang XL, Xiong S, Xiao ZG, Guo Y, Tang XR, Yang JF, Qi ZY. Clinical analysis of retinopathy of prematurity. Int J Ophthalmol(Guoji Yanke Zazhi)2007;7(6):17131715
2 Filho JB F , Barros CK, Eckert GU , Procianoy L, Procianoy RS. Retinopathy of prematurity in a tertiary center in south of Brazil. Int J Ophthalmol(Guoji Yanke Zazhi)2007;7(1):3135
3 Li SG, Zeng J. New development of retinopathy of prematurity. Int J
Ophthalmol(Guoji Yanke Zazhi) 2006;6(5):11171119
4 Smith LE, Wesolowski E, McLellan A, Kostyk SK, DAmato R, Sullivan R, DAmore PA. Oxygeninduced retinopathy in the mouse. Invest Ophthalmol Vis Sci1994;35:101111
5 Lutty GA, McLeod DS. A new technique for visualization of the human retinal vasculature. Arch Ophthalmol 1992;110:267276
6 Smith LE. Pathogenesis of retinopathy of prematurity. Growth Horm IGF Res2004;14(Suppl A):S140144
7 Zhang Q, Wei H. Recent advances in retinopathy of prematurity. Int JOphthalmol(Guoji Yanke Zazhi)2007;7(5):14031405
8 Abcouwer SF, Marjon PL, Loper RK, Vander Jagt DL. Response of VEGF expression to amino acid deprivation and inducers of endoplasmic reticulum stress. Invest Ophthalmol Vis Sci2002;43:27912798
9 Marjon PL, BobrovnikovaMarjon EV, Abcouwer SF. Expression of the proangiogenic factors vascular endothelial growth factor and interleukin8/CXCL8 by human breast carcinomas is responsive to nutrient deprivation and endoplasmic reticulum stress. Mol Cancer2004;3:4
10 Li N, Liboni K, Fang MZ, Samuelson D, Lewis P, Patel R, Neu J. Glutamine decreases lipopolysaccharideinduced intestinal inflammation in infant rats. Am J Physiol Gastrointest Liver Physiol2004;286:G914921
11 Liboni K, Li N, Neu J. Mechanism of glutaminemediated amelioration of lipopolysaccharideinduced IL8 production in Caco2 cells. Cytokine2004;26:5765
12 Neu J. Glutamine supplements in premature infants: why and how. J Pediatr Gastroenterol Nutr2003;37:533535
13 Wu G, Jaeger LA, Bazer FW, Rhoads JM. Arginine deficiency in preterm infants: biochemical mechanisms and nutritional implications. JNutr Biochem2004;15:442451
14 Poindexter BB, Ehrenkranz RA, Stoll BJ, Wright LL, Poole WK, Oh W, Bauer CR, Papile LA, Tyson JE, Carlo WA, Laptook AR, Narendran V, Stevenson DK, Fanaroff AA, Korones SB, Shankaran S, Finer NN, Lemons JA; National Institute of Child Health and Human Development Neonatal Research Network. Parenteral glutamine supplementation does not reduce the risk of mortality or lateonset sepsis in extremely low birth weight infants. Pediatrics2004;113:12091215
15 Vaughn P, Thomas P, Clark R, Neu J. Enteral glutamine supplementation and morbidity in low birth weight infants. J Pediatr2003;142:662668
16 Amin HJ, Zamora SA, McMillan DD, Fick GH, Butzner JD, Parsons HG, Scott RB. Arginine supplementation prevents necrotizing enterocolitis in the premature infant. J Pediatr2002;140:425431
17 Zhao Y, Ren B, Gao XW. Current research in mechanism and drug therapy of retinopathy of prematurity. Int J Ophthalmol(Guoji Yanke Zazhi)2006;6(6):13821385 上一页 [1] [2] |
