Russian Pediatric OphthalmologyRussian Pediatric OphthalmologyРоссийская педиатрическая офтальмология1993-18592412-432XEco-Vector3955510.18821/1993-1859-2017-12-3-145-152ArticlesСтатьиReview ArticleTHE ROLE OF VARIOUS REGULATORY FACTORS IN PATHOLOGICAL VASOPROLIFERATION IN THE RETINOPATHY OF PREMATURITYРОЛЬ РАЗЛИЧНЫХ РЕГУЛЯТОРНЫХ ФАКТОРОВ В ПАТОЛОГИЧЕСКОЙ ВАЗОПРОЛИФЕРАЦИИ ПРИ РЕТИНОПАТИИ НЕДОНОШЕННЫХKatarginaL. AКатаргинаЛ. АOsipovaNatal’ya Anatol’evnaОсиповаНаталья Анатольевна

ophthalmologist for the Ophthalmological Department of Pediatric Surgery, The Helmholtz Moscow Research Institute of Eye Diseases, Russian Ministry of Health, Moscow, 105062, Russian Federation.

врач-офтальмолог офтальмологического отделения детской хирургии ФГБУ «Московский НИИ глазных болезней им. Гельмгольца» Минздрава России

natashamma@mail.ruThe Helmholtz Moscow Research Institute of Eye Diseases, Russian Ministry of HealthФГБУ «Московский НИИ глазных болезней им. Гельмгольца» Минздрава России15092017123VOL 12, NO3 (2017)ТОМ 12, №3 (2017)14515222072020Copyright ©; 2017, Eco-VectorCopyright ©; 2017, ООО "Эко-Вектор"2017Eco-VectorООО "Эко-Вектор"https://ruspoj.com/1993-1859/article/view/39555

Retinopathy of prematurity continues to occupy one of the leading positions in the structure of vision disability among the children. The problem of optimizing the prognosis of this condition, its early diagnostics, and adequate treatment remains a serious challenge and is inextricably connected with the better understanding of the pathogenesis of this disease. It is known that the mechanism underlying the development of retinopathy of prematurity involves the imbalance between the angiogenic factors controlling the process of growth and development of blood vessels in the immature retinal tissue in the combination with the biochemical and immunological disturbances of homeostasis in the prematurely born infants as a result of systemic somatic pathology and the unfavourable multifactorial influence of the environmental conditions, in the first place the effect of elevated oxygen concentrations used for the nursing the preterm babies. A large number of papers have been devoted to the study of various factors contributing to the development of retinopathy in preterm patients at the molecular level. For the purpose of the present review, the search for the relevant literature was carried out using the Medline database. The role of the vascular endothelial growth factor (VEGF-A) and insulin-like growth factor-1 (IGF-1) in the development of pathological vasoproliferation associated with retinopathy of prematurity has been most thoroughly explored. Information about the role of VEGF-A in the pathogenesis of the disease provided the basis for the use of anti-VEGF therapy in the clinical practice for the treatment of certain forms of retinopathy. However, the complicated and multifactorial character of the pathogenesis of this disease as well as the need for the enhancement of the effectiveness of its treatment and optimization of the screening procedure dictates the necessity of looking for additional approaches to the solution of this problem and of studying the relationships between various factors involved in the disturbance of retinal angiogenesis in the children presenting with retinopathy of prematurity.

Ретинопатия недоношенных на сегодняшний день продолжает занимать одну из лидирующих позиций в структуре детской инвалидности по зрению. Вопрос оптимизации прогнозирования ее течения, ранней диагностики и лечения остается крайне актуальным и неразрывно связан с углублением понимания патогенеза заболевания. Известно, что в основе развития ретинопатии недоношенных лежит нарушение баланса ростовых и иммунологических факторов, контролирующих процесс роста и развития сосудов незрелой ретинальной ткани при преждевременном рождении, которое является результатом многофакторного влияния, включающего как биохимические и иммунологические нарушения гомеостаза ребенка вследствие общесоматической патологии, так и факторы «внешней» среды, в частности воздействие повышенных концентраций кислорода, применяющихся при выхаживании недоношенных детей. Исследованию молекулярных участников патогенеза ретинопатии недоношенных посвящено большое количество работ во всем мире. Для составления данного обзора поиск литературы проводился по базе данных Medline. Наиболее изучена роль фактора роста эндотелия сосудов (VEGF-А) и инсулиноподобного фактора роста-1 (IGF-1) в развитии патологической вазопролиферации при ретинопатии недоношенных. Сведения о роли VEGF в патогенезе заболевания легли в основу применения анти-VEGF терапии в клинической практике в лечении определенных форм ретинопатии. Однако сложность и многофакторность патогенеза заболевания, а также необходимость повышения эффективности его лечения и оптимизации скрининга, делает очевидным необходимость поиска других агентов, а также изучения взаимодействия различных факторов в процессах нарушения ангиогенеза сетчатки при ретинопатии недоношенных.

literature reviewretinopathy of prematuritypathogenesisgrowth factorsbeta-adrenoreceptorsобзорретинопатия недоношенныхпатогенезфакторы ростацитокиныβ-адренорецепторыКатаргина Л. А. Ретинопатия недоношенных, современное состояние проблемы и задачи организации офтальмологической помощи недоношенным детям в РФ. Рос. педиатр. офтальмол. 2012; (1): 5-7.Gilbert C. Retinopathy of prematurity as of blindness worldwide and babies at risk. In: III World Retinopathy of Prematurity Congress: Abstract Book. Shanghai; 2012: 36.Катаргина Л.А., Слепова О.С., Демченко Е.Н., Осипова Н.А. Новые аспекты иммунопатогенеза ретинопатии недоношенных: роль TGF-β1 и IGF-II в нарушениях процесса васкуляризации сетчатки. Росс. офтальмол. журнал. 2017; (1): 20-6.Коголева Л.В. Клинико-функциональное состояние глаз у глубоко недоношенных детей в отдаленный период. Рос. педиатр. офтальмол. 2014; 9(3): 14-20.Matta N., Young D., Boulton R., Mactier H. Survival of extremely preterm infants. Arch. Dis. Child. Fetal. Neonat. Ed. 2010; 95(2): 151-2.Hartnett M.E., Penn J.S. Mechanisms and management of retinopathy of prematurity. N. Engl. J. Med. 2012; 367(26): 2515-26.Smith L. E. Pathogenesis of retinopathy of prematurity. Growth Horm. IGF Res. 2004; 14(Suppl. 6): 140-4.Катаргина Л.А., Слепова О.С., Демченко Е.Н., Осипова Н.А. Роль системного дисбаланса цитокинов в патогенезе ретинопатии недоношенных. Рос. педиатр. офтальмол. 2015; (4): 16-20.Chen J., Stahl A., Hellstrom A., Smith L.E. Current update on retinopathy of prematurity: screening and treatment. Curr. Opin. Pediatr. 2011; 23(2): 173-178.Mutlu F.M., Sarici S.U. Treatment of retinopathy of prematurity: a review of conventional and promising new therapeutic options. Int. J. Ophthalmol. 2013; 6(2): 228-36.Langford K., Nicolaides K., Miell J.P. Maternal and fetal insulin-like growth factors and their binding proteins in the second and third trimesters of human pregnancy. Hum. Reprod. 1998; 13(5): 1389-93.Hellström A., Engström E., Hаrd A.L., Albertsson-Wikland K., Carlsson B., Niklasson A. et al. Postnatal serum insulin-like growth factor I deficiency is associated with retinopathy of prematurity and other complications of premature birth. Pediatrics. 2003; 112(5): 1016-20.Hellstrom A., Perruzzi C., Ju M., Engstrom E., Hard A.L., Liu J.L. et al. Low IGF-I suppresses VEGF-survival signaling in retinal endothelial cells: direct correlation with clinical retinopathy of prematurity. Proc. Natl. Acad. Sci. USA. 2001; 98(10): 5804-8.Hellström A., Carlsson B., Niklasson A., Segnestam K., Boguszewski M., de Lacerda L. et al. IGF-I is critical for normal vascularization of the human retina. J. Clin. Endocrinol. Metab. 2002; 87 (7): 3413-6.Vanhaesebrouck S., Daniels H., Moons L. et al. Oxygen-induced retinopathy in mice: amplification by neonatal IGF-I deficit and attenuation by IGF-I administration. Pediatr. Res. 2009; 65: 307-10.Capoluongo E., Vento G., Ameglio F., Lulli P., Matassa P.G., Carrozza C. et al. Increased levels of IGF-1 and beta2-microglobulin in epithelial lining fluid of preterm newborns developing chronic lung disease, effects of rhG-CSF. Int. J. Immunopathol. Pharmacol. 2006; 19(1): 57-66.Bhola R., Purkiss T., Hunter S., Stewart D., Rychwalski P.J. Effect of granulocyte colony-stimulating factor on the incidence of threshold retinopathy of prematurity. J. AAPOS. 2009; 13(5): 450-3.Niranjan H.S., Benakappa N., Reddy K.B., Nanda S., Kamath M.V. Retinopathy of prematurity-promising newer modalities of treatment. Indian Pediatr. 2012; 49(2): 139-43.Takahashi T., Kalka C., Masuda H., Chen D., Silver M., Kearney M. et al. Ischemia and cytokine-induced mobilization of bone marrow derived endothelial progenitor cells for neovascularization. Nat. Med. 1999; 5(4): 434-8.Ozaki H., Yu A.Y., Della N. et al. Hypoxia-inducible factor 1a is increased in ischemic retina: Temporal and spatial correlation with VEGF expression. Invest. Ophthalmol. Vis. Sci. 1999; 40: 182-9.Kim J.H., Kim J.H., Yu Y.S. et al. Deguelin inhibits retinal neovascularization by down-regulation of HIF-1alpha in oxygeninduced retinopathy. J. Cell Mol. Med. 2008; 12: 2407-15.Xia Y., Choi H.K., Lee K. Recent advances in hypoxia-inducible factor (HIF)-1 inhibitors. Eur. J. Med. Chem. 2012; 49: 24-40.Blobe G.C., Schiemann W.P., Lodish H.F. Role of transforming growth factor beta in human disease. N. Engl. J. Med. 2000; 342: 1350-8.Kim K.S., Park J.M., Kong T. et al. Retinal angiogenesis effects of TGF-β1 and paracrine factors secreted from human placental stem cells in response to a pathological environment. Cell. Transplant. 2016; 25 (6): 1145-57.Zorena K., Malinowska E., Raczyńska D. et al. Serum concentrations of transforming growth factor-beta 1 in predicting the occurrence of diabetic retinopathy in juvenile patients with type 1 diabetes mellitus. J. Diabet. Res. 2013; Article ID 614908.Rakic J.M., Lambert V., Devy L. et al. Placental growth factor, a member of the VEGF family, contributes to the development of choroidal neovascularization. Invest. Ophthalmol. Vis. Sci. 2003; 44: 3186-93.Luttun A., Tjwa M., Carmeliet P. Placental growth factor (PlGF) and its receptor Flt-1 (VEGFR-1): novel therapeutic targets for angiogenic disorders. Ann. N. Y. Acad. Sci. 2002; 979: 80-93.Nagy J.A., Dvorak A.M., Dvorak H.F. VEGF-A164 ⁄ 165 and PlGF. Roles in angiogenesis and arteriogenesis. Trends Cardiovasc. Med. 2003; 13: 169-75.Michels S., Schmidt-Erfurth U., Rosenfeld P.J. Promising new treatments for neovascular age-related macular degeneration. Expert Opin. Invest. Drugs. 2006; 15: 779-93.Cao Y. Positive and negative modulation of angiogenesis by VEGFR1 ligands. Sci. Signal. 2009; 2: 1-11.Cao Y., Chen H., Zhou L. et al. Heterodimers of placenta growth factor ⁄ vascular endothelial growth factor: endothelial activity, tumor cell expression, and high affinity binding to Flk-1 ⁄ KDR. J. Biol. Chem. 1996; 271: 3154-62.Cunningham S.A., Tran T.M., Arrate M.P. et al. Characterization of vascular endothelial cell growth factor interactions with the kinase insert domain-containing receptor tyrosine kinase: a real time kinetic study. J. Biol. Chem. 1999; 274: 18421-7.Park J.E., Chen H.H., Winer J. et al. Placenta growth factor: potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flt-1 ⁄ KDR. J. Biol. Chem. 1994; 269: 25646-54.Carmeliet P., Moons L., Luttun A. et al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat. Med. 2001; 7: 575-83.Khaliq A., Foreman D., Ahmed A. et al. Increased expression of placenta growth factor in proliferative diabetic retinopathy. Lab. Invest. 1998; 78: 109-16.Shih S.C., Ju M., Liu N. et al. Selective stimulation of VEGFR-1 prevents oxygeninduced retinal vascular degeneration in retinopathy of prematurity. J. Clin. Invest. 2003; 112: 50-7.Akrami H., Soheili Z.S., Sadeghizadeh M. et al. PlGF gene knockdown in human retinal pigment epithelial cells. Graefes Arch. Clin. Exp. Ophthalmol. 2011; 249: 537-46.Watanabe D., Suzuma K., Matsui S. et al. Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy. N. Engl. J. Med. 2005; 353: 782-92.Heeschen C., Aicher A., Lehmann R. et al. Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization. Blood. 2003; 102: 1340-6.Beleslin-Cokic B.B., Cokic V.P., Yu X. et al. Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells. Blood. 2004; 104: 2073-80.Westenbrink B.D., Lipsic E., van der Meer P. et al. Erythropoietin improves cardiac function through endothelial progenitor cell and vascular endothelial growth factor mediated neovascularization. Eur. Heart J. 2007; 28: 2018-27.Chen J., Connor K.M., Aderman C.M. et al. Erythropoietin deficiency decreases vascular stability in mice. J. Clin. Invest. 2008; 118: 526-33.Aher S.M., Ohlsson A. Early versus late erythropoietin for preventing red blood cell transfusion in preterm and ⁄ or low birth weight infants. Cochrane Database Syst. Rev. 2006; (3): CD004865.Figueras-Aloy J., Alvarez-Dominguez E., Morales-Ballus M. et al. Early administration of erythropoietin in the extreme premature, a risk factor for retinopathy of prematurity? An. Pediatr. (Barc.). 2010; 73: 327-33.Guimaraes S., Moura D. Vascular adrenoceptors: an update. Pharmacol. Rev. 2001; 53: 319-56.Guo K., Ma Q., Wang L. et al. Norepinephrine-induced invasion by pancreatic cancer cells is inhibited by propranolol. Oncol. Rep. 2009; 22: 825-30.Yang E.V., Kim S.J., Donovan E.L. et al. Norepinephrine upregulates VEGF, IL-8, and IL-6 expression in human melanoma tumor cell lines: implications for stressrelated enhancement of tumor progression. Brain Behav. Immun. 2009; 23: 267-75.Filippi L., Cavallaro G., Fiorini P. et al. Study protocol: safety and efficacy of propranolol in newborns with Retinopathy of Prematurity (PROP-ROP): ISRCTN18523491. BMC Pediatr. 2010; 10: 83.Steinle J.J., Cappocia F.C. Jr., Jiang Y. Beta-adrenergic receptor regulation of growth factor protein levels in human choroidal endothelial cells. Growth Factors. 2008; 26(6): 325-30.Jiang Y., Walker R.J., Kern T.S. et al. Application of isoproterenol inhibits diabetic-like changes in the rat retina. Exp. Eye Res. 2010; 91: 171-9.Dal Monte M., Martini D., Latina V. et al. Beta-adrenoreceptor (b-AR) agonism influences retinal responses to hypoxia in a mouse model of retinopathy of prematurity. Invest. Ophthalmol. Vis. Sci. 2012; 53: 2181-92.Zheng Z., Chen H., Xu X. et al. Effects of angiotensin-converting enzyme inhibitors and beta-adrenergic blockers on retinal vascular endothelial growth factor expression in rat diabetic retinopathy. Exp. Eye Res. 2007; 84: 745-52.Ricci B., Ricci F., Maggiano N. Oxygen-induced retinopathy in the newborn rat: morphological and immunohistological findings in animals treated with topical timolol maleate. Ophthalmologica. 2000; 214: 136-9.Катаргина Л.А., Осипова Н.А. Основные принципы экспе-риментального моделирования ретинопатии недоношенных на животных. Рос. педиатр. офтальмол. 2014; (1): 56-60.Dammann O., Leviton A. Inflammation, brain damage and visual dysfunction in preterm infants. Semin. Fetal Neonat. Med. 2006; 11: 363-8.Chen M., Citil A., McCabe F., Leicht K.M., Fiascone J., Dammann C.E. et al. Infection, oxygen, and immaturity: interacting risk factors for retinopathy of prematurity. Neonatology. 2010; 99: 125-32.Silveira R.C., Fortes Filho J.B., Procianoy R.S. Assessment of the contribution of cytokine plasma levels to detect retinopathy of prematurity in very low birth weight infants. Invest. Ophthalmol. Vis. Sci. 2011; 52(3): 1297-301.Sood B.G., Madan A., Saha Sh., Schendel D., Thorsen P., Skogstrand K. et al. Perinatal systemic inflammatory response syndrome and retinopathy of prematurity. Pediatr. Res. 2010; 67(4): 394-400.Sato T., Kusaka S., Shimojo H., Fujikado T. Simultaneous analyses of vitreous levels of 27 cytokines in eyes with retinopathy of prematurity. Ophthalmology. 2009; 116: 2165-9.Kurtul B.E., Kabatas E.U., Zenciroglu A., Ozer P.A., Ertugrul G.T., Beken S. et al. Serum neutrophil-to-lymphocyte ratio in retinopathy of prematurity. J. AAPOS. 2015; 19(4): 327-31.Катаpгина Л. А., Слепова О. С., Скpипец П. П., Дементьева Г. М., Чеpноног И. Н., Каламкаpов Г. P. Гумоpальный иммунный ответ на S-антиген сетчатки у недоношенных детей и его pоль в pазвитии и течении pетинопатии недоношенных. Вестн. офтальмол. 2003; 119(1): 20-2.