Can IL-33 and Endocan be New Markers for Retinopathy of Prematurity?

Author(s): Ufuk Cakir*, Cuneyt Tayman, Cigdem Yucel, Ozdemir Ozdemir

Journal Name: Combinatorial Chemistry & High Throughput Screening
Accelerated Technologies for Biotechnology, Bioassays, Medicinal Chemistry and Natural Products Research

Volume 22 , Issue 1 , 2019

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Background: Retinopathy of Prematurity (ROP) is a pathophysiologic condition of the retina due to abnormal proliferation of retinal vessels.

Objective: The study aimed too ascertain the importance of vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), interleukin-33 (IL-33) and endocan in the diagnosis and follow-up of ROP.

Methods: This prospective cohort study was conducted in the neonatal intensive care unit (NICU) of Health Science University, Zekai Tahir Burak Maternity Teaching Hospital, Ankara, Turkey, between February 2017 and August 2018. Preterm infants (gestational age (GA) of ≤32 weeks and birth weight of ≤1500 gr), diagnosed ROP were included in the study. VEGF, IGF-1, IL-33 and endocan levels were evaluated in the cord blood and in the serum before and after treatment of infants in the ROP and control groups.

Results: A final number of 146 infants were included in the study. During the study period, 73 infants were identified as the ROP group, and 73 infants were allocated as the control group. In the ROP group, the cord blood VEGF value was higher than the control group (p <0.05). However, IGF-1 levels in the cord blood were lower in the ROP group than control (P<0.05). IL-33 and endocan values in the cord blood were similar in both control and ROP groups (p>0.05). Although serum levels of IL-33, VEGF and endocan were higher before laser treatment, these biomarkers decreased significantly after laser treatment (p <0.05).

Conclusion: We determined that serum IL-33 and endocan levels might be suggested as sensitive novel markers for the prediction of severe ROP.

Keywords: Insulin-like growth factor-1, interleukin-33, retinopathy of prematurity, vascular endothelial growth factor, retina, laser treatment.

Hartnett, M.E.; Penn, J.S. Mechanisms and management of retinopathy of prematurity. N. Engl. J. Med., 2012, 367(26), 2515-2526.
Liegl, R. Hellström. A.; Smith, L.E. Retinopathy of prematurity: The need for prevention. Eye Brain, 2016, 8, 91-102.
Kong, L.; Bhatt, A.R.; Demny, A.B.; Coats, D.K.; Li, A.; Rahman, E.Z.; Smith, O.E.; Steinkuller, P.G. Pharmacokinetics of bevacizumab and its effects on serum VEGF and IGF-1 in infants with retinopathy of prematurity. Invest. Ophthalmol. Vis. Sci., 2015, 56(2), 956-961.
Hellström, A.; Engström, E.; Hård, A.L.; Albertsson-Wikland, K.; Carlsson, B.; Niklasson, A.; Löfqvist, C.; Svensson, E.; Holm, S.; Ewald, U.; Holmström, G.; Smith, L.E. Postnatal serum insulin-like growth factor I deficiency is associated with retinopathy of prematurity and other complications of premature birth. Pediatrics, 2003, 112(5), 1016-1020.
Hellstrom, A.; Perruzzi, C.; Ju, M.; Engstrom, E.; Hard, A.L.; Liu, J.L.; Albertsson-Wikland, K.; Carlsson, B.; Niklasson, A.; Sjodell, L.; LeRoith, D.; Senger, D.R.; Smith, L.E. 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), 5804-5808.
Matano, F.; Yoshida, D.; Ishii, Y.; Tahara, S.; Teramoto, A.; Morita, A. Endocan, a new invasion and angiogenesis marker of pituitary adenomas. J. Neurooncol., 2014, 117(3), 485-491.
Abu El-Asrar, A.M.; Nawaz, M.I.; De Hertogh, G.; Al-Kharashi, A.S.; Van den Eynde, K.; Mohammad, G.; Geboes, K. The angiogenic biomarker endocan is upregulated in proliferative diabetic retinopathy and correlates with vascular endothelial growth factor. Curr. Eye Res., 2015, 40(3), 321-331.
Theodoropoulou, S.; Copland, D.A.; Liu, J.; Wu, J.; Gardner, P.J.; Ozaki, E.; Doyle, S.L.; Campbell, M.; Dick, A.D. Interleukin-33 regulates tissue remodelling and inhibits angiogenesis in the eye. J. Pathol., 2017, 241, 45-56.
Kliegman, R.M.; Walsh, M.C. Neonatal necrotizing enterocolitis: pathogenesis, classification, and spectrum of illness. Curr. Probl. Pediatr., 1987, 17(4), 213-288.
Walsh, M.C.; Wilson-Costello, D.; Zadell, A.; Newman, N.; Fanaroff, A. Safety, reliability, and validity of a physiologic definition of bronchopulmonary dysplasia. J. Perinatol., 2003, 23(6), 451-456.
Papile, L.A.; Burstein, J.; Burstein, R.; Koffler, H. Incidence and evolution of subependymal and intraventricular hemorrhage: A study of infants with birth weights less than 1,500 gm. J. Pediatr., 1978, 92(4), 529-534.
International Committee for the Classification of Retinopathy of Prematurity.The international classification of retinopathy of prematurity revisited. Arch. Ophthalmol., 2005, 123(7), 991-999.
Ezz-Eldin, Z.M.; Hamid, T.A.; Youssef, M.R. Nabil, Hel-D. Clinical risk index for babies (CRIB II) scoring system in prediction of mortality in premature babies. J. Clin. Diagn. Res., 2015, 9(6), SC08-SC11.
Shah, P.K.; Prabhu, V.; Karandikar, S.S.; Ranjan, R.; Narendran, V.; Kalpana, N. Retinopathy of prematurity: Past, present and future. World J. Clin. Pediatr., 2016, 5(1), 35-46.
Multicenter trial of cryotherapy for retinopathy of prematurity. Preliminary results. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Arch. Ophthalmol., 1988, 106(4), 471-479.
Early Treatment For Retinopathy Of Prematurity Cooperative Group.Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial. Arch. Ophthalmol., 2003, 121(12), 1684-1694.
Heidary, G.; Vanderveen, D.; Smith, L.E. Retinopathy of prematurity: Current concepts in molecular pathogenesis. Semin. Ophthalmol., 2009, 24(2), 77-81.
Hellström, A.; Ley, D.; Hansen-Pupp, I.; Hallberg, B.; Ramenghi, L.A.; Lofqvist, C.; Smith, L.E.; Hard, A.L. Role of insulinlike growth factor 1 in fetal development and in the early postnatal life of premature infants. Am. J. Perinatol., 2016, 33(11), 1067-1071.
Hellström, A.; Ley, D.; Hansen-Pupp, I.; Hallberg, B.; Ramenghi, L.A.; Löfqvist, C.; Smith, L.E.; Hård, A.L. IGF-I in the clinics: Use in retinopathy of prematurity. Growth Horm. IGF Res., 2016, •••, 75-80.
Pérez-Muñuzuri, A.; Fernández-Lorenzo, J.R.; Couce-Pico, M.L.; Blanco-Teijeiro, M.J.; Fraga-Bermúdez, J.M. Serum levels of IGF1 are a useful predictor of retinopathy of prematurity. Acta Paediatr., 2010, 99(4), 519-525.
Kandasamy, Y.; Hartley, L.; Rudd, D.; Smith, R. The association between systemic vascular endothelial growth factor and retinopathy of prematurity in premature infants: A systematic review. Br. J. Ophthalmol., 2017, 101(1), 21-24.
Rennel, E.; Mellberg, S.; Dimberg, A.; Petersson, L.; Botling, J.; Ameur, A.; Westholm, J.O.; Komorowski, J.; Lassalle, P.; Cross, M.J.; Gerwins, P. Endocan is a VEGF-A and PI3K regulated gene with increased expression in human renal cancer. Exp. Cell Res., 2007, 313(7), 1285-1294.
Chen, L.Y.; Liu, X.; Wang, S.L.; Qin, C.Y. Over-expression of the Endocan gene in endothelial cells from hepatocellular carcinoma is associated with angiogenesis and tumour invasion. J. Int. Med. Res., 2010, 38(2), 498-510.
Roudnicky, F.; Poyet, C.; Wild, P.; Krampitz, S.; Negrini, F.; Huggenberger, R.; Rogler, A.; Stöhr, R.; Hartmann, A.; Provenzano, M.; Otto, V.I.; Detmar, M. Endocan is upregulated on tumor vessels in invasive bladder cancer where it mediates VEGF-A-induced angiogenesis. Cancer Res., 2013, 73(3), 1097-1106.
Su, T.; Zhong, Y.; Demetriades, A.M.; Shen, J.; Sui, A.; Yao, Y.; Gao, Y.; Zhu, Y.; Shen, X.; Xie, B. Endocan blockade suppresses experimental ocular neovascularization in mice. Invest. Ophthalmol. Vis. Sci., 2018, 59(2), 930-939.
Liu, X.C.; Liu, X.F.; Jian, C.X.; Li, C.J.; He, S.Z. IL-33 is induced by amyloid-β stimulation and regulates inflammatory cytokine production in retinal pigment epithelium cells. Inflammation, 2012, 35(2), 776-784.
Halil, H.; Tayman, C.; Buyuktiryaki, M.; Okur, N.; Cakir, U.; Serkant, U. Serum interleukin-33 as a biomarker in predicting neonatal sepsis in very low birth weight infants. Comb. Chem. High Throughput Screen., 2018, 21, 510-515.
Choi, Y.S.; Choi, H.J.; Min, J.K.; Pyun, B.J.; Maeng, Y.S.; Park, H.; Kim, J.; Kim, Y.M.; Kwon, Y.G. Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide production. Blood, 2009, 114(14), 3117-3126.
Milosavljevic, M.Z.; Jovanovic, I.P.; Pejnovic, N.N.; Mitrovic, S.L.; Arsenijevic, N.N. Simovic, Markovic, B.J.; Lukic, M.L. Deletion of IL-33R attenuates VEGF expression and enhances necrosis in mammary carcinoma. Oncotarget, 2016, 7(14), 18106-18115.
Yalin, Imamoglu,. E.; Gunay, M.; Gursoy, T.; Imamoglu, S.; Balci, Ekmekci.; Celik, G.; Karatekin, G.; Ovali, F. Effect of laser photocoagulation on plasma levels of VEGF-A, VEGFR-2, and Tie2 in infants with retinopathy of prematurity. J. AAPOS, 2014, 18(5), 466-470.

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Year: 2019
Page: [41 - 48]
Pages: 8
DOI: 10.2174/1386207322666190325120244
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