Activation of the endoplasmic reticulum stress pathway involving CHOP in the lungs of rats with hyperoxia‑induced bronchopulmonary dysplasia

Lu,Hong‑Yan; Zhang,Jie; Wang,Qiu‑Xia; Tang,Wei; Zhang,Lu‑Jie

doi:10.3892/mmr.2015.3979

Activation of the endoplasmic reticulum stress pathway involving CHOP in the lungs of rats with hyperoxia‑induced bronchopulmonary dysplasia

Authors:
- Hong‑Yan Lu
- Jie Zhang
- Qiu‑Xia Wang
- Wei Tang
- Lu‑Jie Zhang
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Affiliations: Department of Pediatrics, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China
Published online on: June 22, 2015 https://doi.org/10.3892/mmr.2015.3979
Pages: 4494-4500

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Abstract

The molecular pathomechanisms underlying bronchopulmonary dysplasia (BPD) remain to be fully elucidated, however, lung injury is considered to be a key event. The present study was performed to determine the role of endoplasmic reticulum (ER) stress and investigate the apoptosis of alveolar epithelial cells in a BPD rat model. A total of 48 preterm Sprague‑Dawley rats were randomly divided into a control group and a hyperoxia group. The rats in the BPD group were exposed to 85% hyperoxia, while the rats in the control group were exposed to room air. A total of eight rats in each group were sacrificed 7, 14 or 21 days after exposure. The expression levels of 78‑kDa glucose‑regulated/binding immunoglobulin protein (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP) in the lung tissues were examined using immunohistochemistry, and the mRNA and protein levels of GRP78 and CHOP were detected using reverse transcription‑quantitative polymerase chain reaction and western blot analyses, respectively. In addition, the levels of apoptosis in the lung cells were evaluated suing terminal deoxynucleotidyl transferase‑mediated dUTP nick‑end labeling. It was demonstrated that the mRNA and protein levels of GRP78 and CHOP, and the levels of cell apoptosis in the hyperoxia group differed significantly from those in the control group (P<0.05) at different time‑points, and increased with extension of the duration of hyperoxic exposure. These data demonstrated that the ER stress pathway, involving CHOP, is activated and is important in the pathogenesis of BPD.

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1	Jobe AH and Bancalari E: Bronchopulmonary dysplasia. Am J Respir Crit Care Med. 163:1723–1729. 2001. View Article : Google Scholar : PubMed/NCBI
2	Chen Y, Martinez MA and Frank L: Prenatal dexamethasone administration to premature rats exposed to prolonged hyperoxia: A new rat model of pulmonary fibrosis (bronchopulmonary dysplasia). J Pediatr. 130:409–416. 1997. View Article : Google Scholar : PubMed/NCBI
3	Zhang X, Shan P, Sasidhar M, Chupp GL, Flavell RA, Choi AM and Lee PJ: Reactive oxygen species and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase mediate hyperoxia-induced cell death in lung epithelium. Am J Respir Cell Mol Biol. 28:305–315. 2003. View Article : Google Scholar : PubMed/NCBI
4	Szegezdi E, Logue SE, Gorman AM and Samali A: Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep. 7:880–885. 2006. View Article : Google Scholar : PubMed/NCBI
5	Malhotra JD and Kaufman RJ: The endoplasmic reticulum and the unfolded protein response. Semin Cell Dev Biol. 18:716–731. 2007. View Article : Google Scholar : PubMed/NCBI
6	Ron D and Walter P: Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 8:519–529. 2007. View Article : Google Scholar : PubMed/NCBI
7	Lai E, Teodoro T and Volchuk A: Endoplasmic reticulum stress: Signaling the unfolded protein response. Physiology (Bethesda). 22:193–201. 2007. View Article : Google Scholar
8	Zhang K and Kaufman RJ: Signaling the unfolded protein response from the endoplasmic reticulum. J Biol Chem. 279:25935–25938. 2004. View Article : Google Scholar : PubMed/NCBI
9	Marciniak SJ, Yun CY, Oyadomari S, Novoa I, Zhang Y, Jungreis R, Nagata K, Harding HP and Ron D: CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev. 18:3066–3077. 2004. View Article : Google Scholar : PubMed/NCBI
10	Zinszner H, Kuroda M, Wang X, Batchvarova N, Lightfoot RT, Remotti H, Stevens JL and Ron D: CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev. 12:982–995. 1998. View Article : Google Scholar : PubMed/NCBI
11	Oyadomari S and Mori M: Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. 11:381–389. 2004. View Article : Google Scholar
12	Song B, Scheuner D, Ron D, Pennathur S and Kaufman RJ: Chop deletion reduces oxidative stress, improves beta cell function, and promotes cell survival in multiple mouse models of diabetes. J Clin Invest. 118:3378–3389. 2008. View Article : Google Scholar : PubMed/NCBI
13	Tessitore A, del P Martin M, Sano R, Ma Y, Mann L, Ingrassia A, Laywell ED, Steindler DA, Hendershot LM and d'Azzo A: GM1-ganglioside-mediated activation of the unfolded protein response causes neuronal death in a neurodegenerative gangliosidosis. Mol Cell. 15:753–766. 2004. View Article : Google Scholar : PubMed/NCBI
14	Yuan Y, Guo Q, Ye Z, Pingping X, Wang N and Song Z: Ischemic postconditioning protects brain from ischemia/reperfusion injury by attenuating endoplasmic reticulum stress-induced apoptosis through PI3K-Akt pathway. Brain Res. 1367:85–93. 2011. View Article : Google Scholar
15	Miyazaki Y, Kaikita K, Endo M, Horio E, Miura M, Tsujita K, Hokimoto S, Yamamuro M, Iwawaki T, Gotoh T, et al: C/EBP homologous protein deficiency attenuates myocardial reperfusion injury by inhibiting myocardial apoptosis and inflammation. Arterioscler Thromb Vasc Biol. 31:1124–1132. 2011. View Article : Google Scholar : PubMed/NCBI
16	Emery JL and Mithal A: The number of alveoli in the terminal respiratory unit of man during late intrauterine life and childhood. Arch Dis Child. 35:544–547. 1960. View Article : Google Scholar : PubMed/NCBI
17	Coalson JJ: Pathology of new bronchopulmonary dysplasia. Semin Neonatal. 8:73–81. 2003. View Article : Google Scholar
18	Merritt TA, Deming DD and Boynton BR: The 'new' broncho-pulmonary dysplasia: Challenges and commentary. Semin Fetal Neonatal Med. 14:345–357. 2009. View Article : Google Scholar : PubMed/NCBI
19	Saugstad OD: Oxygen and oxidative stress in bronchopulmonary dysplasia. J Perinat Med. 38:571–577. 2010.PubMed/NCBI
20	Malhotra JD and Kaufman RJ: Endoplasmic reticulum stress and oxidative stress: A vicious cycle or a double-edged sword? Antioxid Redox Signal. 9:2277–2293. 2007. View Article : Google Scholar : PubMed/NCBI
21	Tabas I and Ron D: Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol. 13:184–190. 2011. View Article : Google Scholar : PubMed/NCBI
22	Shore GC, Papa FR and Oakes SA: Signaling cell death from the endoplasmic reticulum stress response. Curr Opin Cell Biol. 23:143–149. 2011. View Article : Google Scholar :
23	Jäger R, Bertrand MJ, Gorman AM, Vandenabeele P and Samali A: The unfolded protein response at the crossroads of cellular life and death during endoplasmic reticulum stress. Biol Cell. 104:259–270. 2012. View Article : Google Scholar : PubMed/NCBI
24	Endo M, Oyadomari S, Suga M, Mori M and Gotoh T: The ER stress pathway involving CHOP is activated in the lungs of LPS-treated mice. J Biochem. 138:501–507. 2005. View Article : Google Scholar : PubMed/NCBI
25	Greene CM and McElvaney NG: Protein misfolding and obstructive lung disease. Proc Am Thorac Soc. 7:346–355. 2010. View Article : Google Scholar : PubMed/NCBI
26	Korfei M, Ruppert C, Mahavadi P, Henneke I, Markart P, Koch M, Lang G, Fink L, Bohle RM, Seeger W, et al: Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 178:838–846. 2008. View Article : Google Scholar : PubMed/NCBI
27	Nakayama Y, Endo M, Tsukano H, Mori M, Oike Y and Gotoh T: Molecular mechanisms of the LPS-induced non-apoptotic ER stress-CHOP pathway. J Biochem. 147:471–483. 2010. View Article : Google Scholar
28	Rao RV, Peel A, Logvinova A, del Rio G, Hermel E, Yokota T, Goldsmith PC, Ellerby LM, Ellerby HM and Bredesen DE: Coupling endoplasmic reticulum stress to the cell death program: Role of the ER chaperone GRP78. FEBS Lett. 514:122–128. 2002. View Article : Google Scholar : PubMed/NCBI
29	Lee AS: The ER chaperone and signaling regulator GRP78/BiP as a monitor of endoplasmic reticulum stress. Methods. 35:373–381. 2005. View Article : Google Scholar : PubMed/NCBI
30	O'Reilly MA, Staversky RJ, Watkins RH, Maniscalco WM and Keng PC: p53-independent induction of GADD45 and GADD153 in mouse lungs exposed to hyperoxia. Am J Physiol Lung Cell Mol Physiol. 278:L552–L559. 2000.PubMed/NCBI
31	Lozon TI, Eastman AJ, Matute-Bello G, Chen P, Hallstrand TS and Altemeier WA: PKR-dependent CHOP induction limits hyperoxia-induced lung injury. Am J Physiol Lung Cell Mol Physiol. 300:L422–L429. 2011. View Article : Google Scholar :
32	Sung B, Ravindran J, Prasad S, Pandey MK and Aggarwal BB: Gossypol induces death receptor-5 through activation of the ROS-ERK-CHOP pathway and sensitizes colon cancer cells to TRAIL. J Biol Chem. 285:35418–35427. 2010. View Article : Google Scholar : PubMed/NCBI