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BMC Pulmonary Medicine

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01-12-2020 | Sleep Apnea | Research article

Attenuation of intermittent hypoxia-induced apoptosis and fibrosis in pulmonary tissues via suppression of ER stress activation

Authors: Zhihui Shi, Linhao Xu, Hui Xie, Ruoyun Ouyang, Ya Ke, Rui Zhou, Wing-Ho Yung

Published in: BMC Pulmonary Medicine | Issue 1/2020

Abstract

Background

Obstructive sleep apnea (OSA) is associated with pulmonary fibrosis and endothelial apoptosis in pulmonary tissues. Chronic intermittent hypoxia (IH) is considered to be the primary player in OSA, but the mechanisms underlying its effect on pulmonary tissues are unknown. Endoplasmic reticulum (ER) stress induced by IH treatment plays an important role in accelerating the process of fibrosis and induction of apoptosis.

Methods

Mice were placed in IH chambers for 4 weeks with an oscillating oxygen (O₂) concentration between 5 and 21%, cycling every 90s for 8 h daily. Mice were randomly divided into four groups: control group (normal oxygen), tauroursodeoxycholic acid (TUDCA) group (normal oxygen intraperitoneally injected with TUDCA), IH group and IH + TUDCA group. After 4 weeks, the proteins in three branch signaling pathways of ER stress, including protein kinase RNA (PKR)-like/Pancreatic ER kinase (PERK), activating transcription factor 6 (ATF-6) and inositol-requiring enzyme 1 (IRE-1), were evaluated. The cleaved caspase-3, caspase-12 and TUNNEL staining was assessed. Furthermore, the expression of transforming growth factor-β1 (TGF-β1) and thrombospondin-1(TSP-1), two extracellular matrix proteins that play critical role in fibrosis, were examined. Finally, Masson’s trichrome staining was performed to detect the expression of collagen.

Results

After 4 weeks of IH treatment, the expressions of two ER stress markers, glucose regulated protein-78 (Grp78) and transcription factor C/EBP homologous protein (CHOP) were increased which was prevented by administration of the ER stress attenuator, TUDCA. The expressions of PERK, but not those of ATF-6 and IRE-1, were increased. The effects of IH were accompanied by an increased number of apoptotic cells and increased expressions of cleaved caspase-3 and caspase-12 in pulmonary tissues. In addition, histological examination suggested the presence of fibrosis after chronic IH treatment, indicated by increased expression of collagen, which was associated with the up-regulation of TGF-β1 and TSP-1 that are known to promote fibrosis. Similarly, TUDCA could reduce the extent of fibrotic area and the expression levels of these proteins.

Conclusions

It reveals the roles of ER stress, especially the PERK pathway, in IH induced apoptosis and fibrosis in pulmonary tissues that might underlie the pulmonary complications observed in OSA.

Appelberg J, Janson C, Lindberg E, Pavlenko T, Hedenstierna G. Lung aeration during sleep in patients with obstructive sleep apnoea. Clin Physiol Funct Imaging. 2010;30(4):301–7.PubMedCrossRef

Series F, Cormier Y, La Forge J. Role of lung volumes in sleep apnoea-related oxygen desaturation. Eur Respir J. 1989;2(1):26–30.PubMed

Zielinski J. Effects of intermittent hypoxia on pulmonary haemodynamics: animal models versus studies in humans. Eur Respir J. 2005;25(1):173–80.PubMedCrossRef

Isaiah A, Daher A, Sharma PB, Naqvi K, Mitchell RB. Predictors of sleep hypoxemia in children with cystic fibrosis. Pediatr Pulmonol. 2019;54(3):273–9.PubMedCrossRef

Reinke C, Bevans-Fonti S, Grigoryev DN, Drager LF, Myers AC, Wise RA, et al. Chronic intermittent hypoxia induces lung growth in adult mice. Am J Physiol Lung Cell Mol Physiol. 2011;300(2):L266–73.PubMedCrossRef

May AM, Van Wagoner DR, Mehra R. OSA and cardiac Arrhythmogenesis: mechanistic insights. Chest. 2017;151(1):225–41.PubMedCrossRef

Ding W, Zhang X, Huang H, Ding N, Zhang S, Hutchinson SZ, et al. Adiponectin protects rat myocardium against chronic intermittent hypoxia-induced injury via inhibition of endoplasmic reticulum stress. PLoS One. 2014;9(4):e94545.PubMedPubMedCentralCrossRef

Xu LH, Xie H, Shi ZH, Du LD, Wing YK, Li AM, et al. Critical role of endoplasmic reticulum stress in chronic intermittent hypoxia-induced deficits in synaptic plasticity and long-term memory. Antioxid Redox Signal. 2015;23(9):695–710.PubMedPubMedCentralCrossRef

Chaudhari N, Talwar P, Parimisetty A, Lefebvre d'Hellencourt C, Ravanan P. A molecular web: endoplasmic reticulum stress, inflammation, and oxidative stress. Front Cell Neurosci. 2014;8:213.PubMedPubMedCentralCrossRef

10.

Prabhakar NR. Sensory plasticity of the carotid body: role of reactive oxygen species and physiological significance. Respir Physiol Neurobiol. 2011;178(3):375–80.PubMedPubMedCentralCrossRef

11.

Mello T, Zanieri F, Ceni E, Galli A. Oxidative stress in the healthy and wounded hepatocyte: a cellular organelles perspective. Oxidative Med Cell Longev. 2016;2016:8327410.CrossRef

12.

Gupta MK, Tahrir FG, Knezevic T, White MK, Gordon J, Cheung JY, et al. GRP78 interacting partner Bag5 responds to er stress and protects cardiomyocytes from er stress-induced apoptosis. J Cell Biochem. 2016;117(8):1813–21.PubMedPubMedCentralCrossRef

13.

Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2011;334(6059):1081–6.PubMedCrossRef

14.

Szegezdi E, Logue SE, Gorman AM, Samali A. Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep. 2006;7(9):880–5.PubMedPubMedCentralCrossRef

15.

Lee AH, Iwakoshi NN, Glimcher LH. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol. 2003;23(21):7448–59.PubMedPubMedCentralCrossRef

16.

Luo T, Kim JK, Chen B, Abdel-Latif A, Kitakaze M, Yan L. Attenuation of ER stress prevents post-infarction-induced cardiac rupture and remodeling by modulating both cardiac apoptosis and fibrosis. Chem Biol Interact. 2015;225:90–8.PubMedCrossRef

17.

Borok Z, Horie M, Flodby P, Wang H, Liu Y, Ganesh S, et al. Grp78 loss in epithelial progenitors reveals an age-linked role for endoplasmic reticulum stress in pulmonary fibrosis. Am J Respir Crit Care Med. 2020;201(2):198–211.PubMedCrossRefPubMedCentral

18.

Cardoso AV, Pereira N, Neves I, Santos V, Jesus JM, Melo N, et al. Obstructive sleep apnoea in patients with fibrotic diffuse parenchymal lung disease-characterization and treatment compliance assessment. Can J Respir Ther. 2018;54(2):35–40.PubMedCrossRef

19.

Ranga Rao S, Subbarayan R, Ajitkumar S, Murugan Girija D. 4PBA strongly attenuates endoplasmic reticulum stress, fibrosis, and mitochondrial apoptosis markers in cyclosporine treated human gingival fibroblasts. J Cell Physiol. 2018;233(1):60–6.PubMedCrossRef

20.

Carlucci A, Ceriana P, Mancini M, Cirio S, Pierucci P, D'Artavilla Lupo N, et al. Efficacy of Bilevel-auto treatment in patients with obstructive sleep apnea not responsive to or intolerant of continuous positive airway pressure ventilation. J Clin Sleep Med. 2015;11(9):981–5.PubMedPubMedCentralCrossRef

21.

Epstein LJ, Kristo D, Strollo PJ Jr, Friedman N, Malhotra A, Patil SP, et al. Clinical guideline for the evaluation, management and long-term care of obstructive sleep apnea in adults. J Clin Sleep Med. 2009;5(3):263–76.PubMedCrossRef

22.

Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 2006;313(5790):1137–40.PubMedPubMedCentralCrossRef

23.

Goldbart A, Row BW, Kheirandish L, Schurr A, Gozal E, Guo SZ, et al. Intermittent hypoxic exposure during light phase induces changes in cAMP response element binding protein activity in the rat CA1 hippocampal region: water maze performance correlates. Neuroscience. 2003;122(3):585–90.PubMedCrossRef

24.

Gozal D, Row BW, Kheirandish L, Liu R, Guo SZ, Qiang F, et al. Increased susceptibility to intermittent hypoxia in aging rats: changes in proteasomal activity, neuronal apoptosis and spatial function. J Neurochem. 2003;86(6):1545–52.PubMedCrossRef

25.

Xie H, Leung KL, Chen L, Chan YS, Ng PC, Fok TF, et al. Brain-derived neurotrophic factor rescues and prevents chronic intermittent hypoxia-induced impairment of hippocampal long-term synaptic plasticity. Neurobiol Dis. 2010;40(1):155–62.PubMedCrossRef

26.

Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol. 2012;13(2):89–102.PubMedCrossRef

27.

Lin JH, Li H, Yasumura D, Cohen HR, Zhang C, Panning B, et al. IRE1 signaling affects cell fate during the unfolded protein response. Science. 2007;318(5852):944–9.PubMedPubMedCentralCrossRef

28.

Lin JH, Li H, Zhang Y, Ron D, Walter P. Divergent effects of PERK and IRE1 signaling on cell viability. PLoS One. 2009;4(1):e4170.PubMedPubMedCentralCrossRef

29.

Chang JC, Hu WF, Lee WS, Lin JH, Ting PC, Chang HR, et al. Intermittent hypoxia induces autophagy to protect Cardiomyocytes from endoplasmic reticulum stress and apoptosis. Front Physiol. 2019;10:995.PubMedPubMedCentralCrossRef

30.

Song S, Tan J, Miao Y, Sun Z, Zhang Q. Intermittent-hypoxia-induced autophagy activation through the er-stress-related PERK/elf2α/ATF4 pathway is a protective response to pancreatic β-cell apoptosis. Cell Physiol Biochem. 2018;51(6):2955–71.PubMedCrossRef

31.

Shiraishi H, Okamoto H, Yoshimura A, Yoshida H. ER stress-induced apoptosis and caspase-12 activation occurs downstream of mitochondrial apoptosis involving Apaf-1. J Cell Sci. 2006;119(Pt 19):3958–66.PubMedCrossRef

32.

Zhang Y, Liu Y, Zhang J. Saturated hydrogen saline attenuates endotoxin-induced lung dysfunction. J Surg Res. 2015;198(1):41–9.PubMedCrossRef

33.

Bauça JM, Yañez A, Fueyo L, de la Peña M, Pierola J, Sánchez-de-la-Torre A, et al. Cell death biomarkers and obstructive sleep apnea: implications in the acute coronary syndrome. Sleep. 2017;40(5).

34.

Tanjore H, Blackwell TS, Lawson WE. Emerging evidence for endoplasmic reticulum stress in the pathogenesis of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2012;302(8):L721–9.PubMedPubMedCentralCrossRef

35.

Wang YC, Dong J, Nie J, Zhu JX, Wang H, Chen Q, et al. Amelioration of bleomycin-induced pulmonary fibrosis by chlorogenic acid through endoplasmic reticulum stress inhibition. Apoptosis. 2017;22(9):1147–56.PubMedCrossRef

36.

Briones AM, Arribas SM, Salaices M. Role of extracellular matrix in vascular remodeling of hypertension. Curr Opin Nephrol Hypertens. 2010;19(2):187–94.PubMedCrossRef

37.

Tanaka Y, Ishitsuka Y, Hayasaka M, Yamada Y, Miyata K, Endo M, et al. The exacerbating roles of CCAAT/enhancer-binding protein homologous protein (CHOP) in the development of bleomycin-induced pulmonary fibrosis and the preventive effects of tauroursodeoxycholic acid (TUDCA) against pulmonary fibrosis in mice. Pharmacol Res. 2015;99:52–62.PubMedCrossRef

38.

Samarakoon R, Overstreet JM, Higgins PJ. TGF-beta signaling in tissue fibrosis: redox controls, target genes and therapeutic opportunities. Cell Signal. 2013;25(1):264–8.PubMedCrossRef

39.

Poczatek MH, Hugo C, Darley-Usmar V, Murphy-Ullrich JE. Glucose stimulation of transforming growth factor-beta bioactivity in mesangial cells is mediated by thrombospondin-1. Am J Pathol. 2000;157(4):1353–63.PubMedPubMedCentralCrossRef

40.

Zhang M, Guo Y, Fu H, Hu S, Pan J, Wang Y, et al. CHOP deficiency prevents UUO-induced renal fibrosis by attenuating fibrotic signals originated from Hmgb1/TLR4/NFκB/IL-1β signaling. Cell Death Dis. 2015;6:e1847.PubMedPubMedCentralCrossRef

41.

Kato M, Wang M, Chen Z, Bhatt K, Oh HJ, Lanting L, et al. An endoplasmic reticulum stress-regulated lncRNA hosting a microRNA megacluster induces early features of diabetic nephropathy. Nat Commun. 2016;7:12864.PubMedPubMedCentralCrossRef

42.

Zhang Y, Huang W. Transforming growth factor β1 (tgf-β1)-stimulated integrin-linked kinase (ilk) regulates migration and epithelial-mesenchymal transition (emt) of human lens epithelial cells via nuclear factor κB (NF-κB). Med Sci Monit. 2018;24:7424–30.PubMedPubMedCentralCrossRef

43.

Xing T, Wang Y, Ding WJ, Li YL, Hu XD, Wang C, et al. Thrombospondin-1 production regulates the inflammatory cytokine secretion in THP-1 cells through NF-κB signaling pathway. Inflammation. 2017;40(5):1606–21.PubMedCrossRef

44.

Lu D, Abulimiti A, Wu T, Abudureyim A, Li N. Pulmonary surfactant-associated proteins and inflammatory factors in obstructive sleep apnea. Sleep Breath. 2018;22(1):99–107.PubMedCrossRef

45.

de Lima FF, Mazzotti DR, Tufik S, Bittencourt L. The role inflammatory response genes in obstructive sleep apnea syndrome: a review. Sleep Breath. 2016;20(1):331–8.PubMedCrossRef

46.

Lee EJ, Heo W, Kim JY, Kim H, Kang MJ, Kim BR, et al. Alteration of inflammatory mediators in the upper and lower airways under chronic intermittent hypoxia: preliminary animal study. Mediat Inflamm. 2017;2017:4327237.

47.

Bhandary B, Marahatta A, Kim HR, Chae HJ. An involvement of oxidative stress in endoplasmic reticulum stress and its associated diseases. Int J Mol Sci. 2012;14(1):434–56.PubMedPubMedCentralCrossRef

Title: Attenuation of intermittent hypoxia-induced apoptosis and fibrosis in pulmonary tissues via suppression of ER stress activation
Authors: Zhihui Shi
Linhao Xu
Hui Xie
Ruoyun Ouyang
Ya Ke
Rui Zhou
Wing-Ho Yung
Publication date: 01-12-2020
Publisher: BioMed Central
Keyword: Sleep Apnea
Published in: BMC Pulmonary Medicine / Issue 1/2020
Electronic ISSN: 1471-2466
DOI: https://doi.org/10.1186/s12890-020-1123-0

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