Erythropoietin attenuates hyperoxia-induced lung injury by upregulating epidermal growth factor-like domain 7 in newborn rats

Cui,Huanjin; He,Jiayu; Chen,Hongwu; Chen,Jinwen; Qian,Xinhua; Huang,Weimin

doi:10.3892/br.2016.820

Erythropoietin attenuates hyperoxia-induced lung injury by upregulating epidermal growth factor-like domain 7 in newborn rats

Authors:
- Huanjin Cui
- Jiayu He
- Hongwu Chen
- Jinwen Chen
- Xinhua Qian
- Weimin Huang
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Affiliations: Department of Neonatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
Published online on: November 29, 2016 https://doi.org/10.3892/br.2016.820
Pages: 32-38
Copyright: © Cui et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The aim of the present study was to observe the effects of recombinant human erythropoietin (rhEPO) on the expression of epidermal growth factor‑like domain 7 (EGFL7) and cell apoptosis in lung tissue following hyperoxic lung injury in newborn rats. The 96 Sprague-Dawley newborn rats were randomly divided into 4 groups (n=24) as follows: Room air‑exposed control group, room air-exposed rhEPO-treated group, hyperoxia‑exposed group and the hyperoxia-exposed rhEPO-treated group. Pups (n=8) from each group were sacrificed on postnatal days 3, 7 and 14. The pulmonary morphometric and microvessel density changes were observed. In addition, the mRNA and protein expression levels of EGFL7, B-cell lymphoma 2 (Bcl-2) and Bcl-2-like protein 4 (Bax) in lung tissue samples were measured. The rats in the hyperoxia-exposed group exhibited alveolar and pulmonary vascular dysplasia, as well as low mRNA and protein expression levels of EGFL7 and Bcl‑2, in addition to high level of Bax in the lung tissue samples when compared with the room air‑exposed control group (P<0.05). However, in the hyperoxia‑exposed rhEPO‑treated group the lung histopathology was improved, and the protein and mRNA expression levels of EGFL7 and Bcl‑2 were increased compared with the hyperoxia‑exposed group (P<0.05). Furthermore, the expression level of Bax was lower than that of the hyperoxia‑exposed group (P<0.05). The present study demonstrated that rhEPO promotes alveolar development and increases pulmonary vascular density by upregulating the expression level of EGFL7 in hyperoxia‑induced lung injury of newborn rats.

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1	Li C, Fu J, Liu H, Yang H, Yao L, You K and Xue X: Hyperoxia arrests pulmonary development in newborn rats via disruption of endothelial tight junctions and downregulation of Cx40. Mol Med Rep. 10:61–67. 2014.PubMed/NCBI
2	Trembath A and Laughon MM: Predictors of bronchopulmonary dysplasia. Clin Perinatol. 39:585–601. 2012. View Article : Google Scholar : PubMed/NCBI
3	Lal CV and Ambalavanan N: Genetic predisposition to bronchopulmonary dysplasia. Semin Perinatol. 39:584–591. 2015. View Article : Google Scholar : PubMed/NCBI
4	Northway WH Jr, Rosan RC and Porter DY: Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl J Med. 276:357–368. 1967. View Article : Google Scholar : PubMed/NCBI
5	Shivanna B, Zhang S, Patel A, Jiang W, Wang L, Welty SE and Moorthy B: Omeprazole attenuates pulmonary aryl hydrocarbon receptor activation and potentiates hyperoxia-induced developmental lung injury in newborn mice. Toxicol Sci. 148:276–287. 2015. View Article : Google Scholar : PubMed/NCBI
6	Jakkula M, Le Cras TD, Gebb S, Hirth KP, Tuder RM, Voelkel NF and Abman SH: Inhibition of angiogenesis decreases alveolarization in the developing rat lung. Am J Physiol Lung Cell Mol Physiol. 279:L600–L607. 2000.PubMed/NCBI
7	Remesal A, Pedraz C, San Feliciano L and Ludeña D: Pulmonary expression of vascular endothelial growth factor (VEGF) and alveolar septation in a newborn rat model exposed to acute hypoxia and recovered under conditions of air or hyperoxia. Histol Histopathol. 24:325–330. 2009.PubMed/NCBI
8	Chang M, Bany-Mohammed F, Kenney MC and Beharry KD: Effects of a superoxide dismutase mimetic on biomarkers of lung angiogenesis and alveolarization during hyperoxia with intermittent hypoxia. Am J Transl Res. 5:594–607. 2013.PubMed/NCBI
9	Xu D, Perez RE, Ekekezie II, Navarro A and Truog WE: Epidermal growth factor-like domain 7 protects endothelial cells from hyperoxia-induced cell death. Am J Physiol Lung Cell Mol Physiol. 294:L17–L23. 2008. View Article : Google Scholar : PubMed/NCBI
10	Wang XH and Huang WM: Astragalus polysaccharides exert protective effects in newborn rats with bronchopulmonary dysplasia by upregulating the expression of EGFL7 in lung tissue. Int J Mol Med. 34:1529–1536. 2014.PubMed/NCBI
11	Ozer EA, Kumral A, Ozer E, Yilmaz O, Duman N, Ozkal S, Koroglu T and Ozkan H: Effects of erythropoietin on hyperoxic lung injury in neonatal rats. Pediatr Res. 58:38–41. 2005. View Article : Google Scholar : PubMed/NCBI
12	Luo W, Hu L and Wang F: The protective effect of erythropoietin on the retina. Ophthalmic Res. 53:74–81. 2015.PubMed/NCBI
13	Wang XL, Fu JH and Xue XD: Effects of hyperoxia on erythropoietin receptor expression in lung development of neonatal rats. Zhonghua Er Ke Za Zhi. 49:361–366. 2011.(In Chinese). PubMed/NCBI
14	Lee JH, Sung DK, Koo SH, Shin BK, Hong YS, Son CS, Lee JW, Chang YS and Park WS: Erythropoietin attenuates hyperoxia-induced lung injury by down-modulating inflammation in neonatal rats. J Korean Med Sci. 22:1042–1047. 2007. View Article : Google Scholar : PubMed/NCBI
15	Martin CR, Zaman MM, Gilkey C, Salguero MV, Hasturk H, Kantarci A, Van Dyke TE and Freedman SD: Resolvin D1 and lipoxin A4 improve alveolarization and normalize septal wall thickness in a neonatal murine model of hyperoxia-induced lung injury. PLoS One. 9:e987732014. View Article : Google Scholar : PubMed/NCBI
16	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
17	Carrera P, Di Resta C, Volonteri C, Castiglioni E, Bonfiglio S, Lazarevic D, Cittaro D, Stupka E, Ferrari M and Somaschini M: BPD and Genetics Study Group: Exome sequencing and pathway analysis for identification of genetic variability relevant for bronchopulmonary dysplasia (BPD) in preterm newborns: A pilot study. Clin Chim Acta 451 (Pt A). 39–45. 2015. View Article : Google Scholar
18	Spiteller G: The important role of lipid peroxidation processes in aging and age dependent diseases. Mol Biotechnol. 37:5–12. 2007. View Article : Google Scholar : PubMed/NCBI
19	Dang H, Wang S, Yang L, Fang F and Xu F: Upregulation of Shh and Ptc1 in hyperoxia induced acute lung injury in neonatal rats. Mol Med Rep. 6:297–302. 2012.PubMed/NCBI
20	D'Angio CT and Maniscalco WM: The role of vascular growth factors in hyperoxia-induced injury to the developing lung. Front Biosci. 7:d1609–d1623. 2002. View Article : Google Scholar : PubMed/NCBI
21	Asikainen TM, Ahmad A, Schneider BK, Ho WB, Arend M, Brenner M, Günzler V and White CW: Stimulation of HIF-1alpha, HIF-2alpha, and VEGF by prolyl 4-hydroxylase inhibition in human lung endothelial and epithelial cells. Free Radic Biol Med. 38:1002–1013. 2005. View Article : Google Scholar : PubMed/NCBI
22	Bany-Mohammed FM, Slivka S and Hallman M: Recombinant human erythropoietin: Possible role as an antioxidant in premature rabbits. Pediatr Res. 40:381–387. 1996. View Article : Google Scholar : PubMed/NCBI
23	Ding L, Wu BQ, Huang JJ, Liu ZP and Chen L: Effect of erythropoietin on apoptosis following hyperoxic lung injury in neonatal rats. Zhongguo Dang Dai Er Ke Za Zhi. 12:576–579. 2010.(In Chinese). PubMed/NCBI
24	Piedboeuf B, Gamache M, Frenette J, Horowitz S, Baldwin HS and Petrov P: Increased endothelial cell expression of platelet-endothelial cell adhesion molecule-1 during hyperoxic lung injury. Am J Respir Cell Mol Biol. 19:543–553. 1998. View Article : Google Scholar : PubMed/NCBI
25	Privratsky JR and Newman PJ: PECAM-1: Regulator of endothelial junctional integrity. Cell Tissue Res. 355:607–619. 2014. View Article : Google Scholar : PubMed/NCBI
26	Matsuda Y, Hagio M and Ishiwata T: Nestin: A novel angiogenesis marker and possible target for tumor angiogenesis. World J Gastroenterol. 19:42–48. 2013. View Article : Google Scholar : PubMed/NCBI
27	Oltvai ZN, Milliman CL and Korsmeyer SJ: Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 74:609–619. 1993. View Article : Google Scholar : PubMed/NCBI