Disrupted intestinal structure in a rat model of intermittent hypoxia

Wu,Junping; Sun,Xin; Wu,Qi; Li,Hongwei; Li,Li; Feng,Jing; Zhang,Subei; Xu,Long; Li,Kuan; Li,Xue; Wang,Xing; Chen,Huaiyong

doi:10.3892/mmr.2016.5068

Disrupted intestinal structure in a rat model of intermittent hypoxia

Authors:
- Junping Wu
- Xin Sun
- Qi Wu
- Hongwei Li
- Li Li
- Jing Feng
- Subei Zhang
- Long Xu
- Kuan Li
- Xue Li
- Xing Wang
- Huaiyong Chen
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Affiliations: Department of Basic Medicine, Haihe Clinical College, Tianjin Medical University, Tianjin 300350, P.R. China, Department of Respiratory Medicine, Tianjin Haihe Hospital, Tianjin 300350, P.R. China, Respiratory Department, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
Published online on: March 30, 2016 https://doi.org/10.3892/mmr.2016.5068
Pages: 4407-4413

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Abstract

Obstructive sleep apnea (OSA) is a chronic condition characterized by chronic intermittent hypoxia (IH) and subsequent reoxygenation (ROX). The gastrointestinal system, which is particularly sensitive to tissue hypoxia and reduced perfusion, is likely to be affected by OSA. A rat model of IH was used to analyze oxidative stress-associated genes and tight junction proteins by reverse transcription‑quantitative polymerase chain reaction. Subsequently, altered morphology of the duodenal mucosa and elevated Chiu scores were observed in the IH‑exposed rats. In addition, IH exposure resulted in upregulation of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, NADPH oxidase 2 and p22phox, in the small intestine, and upregulation of transcription factors, including hypoxia‑inducible factor-1, nuclear factor‑κB and activator protein-1. Furthermore, the mRNA expression levels of intestinal tight junction (TJ)-related proteins, claudin-1 and claudin-4, were decreased in the IH‑exposed group, as compared with in the control group. In conclusion, the present study demonstrated that OSA, which is characterized by IH and ROX, may lead to disruption of the duodenum. The mechanism underlying the effects of OSA on duodenal morphology may be associated with increased oxidative stress and activation of transcription factors, subsequently inducing intestinal TJ disruption and intestinal injury.

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1	Lurie A: Obstructive sleep apnea in adults: Epidemiology, clinical presentation, and treatment options. Adv Cardiol. 46:1–42. 2011. View Article : Google Scholar : PubMed/NCBI
2	Dempsey JA, Veasey SC, Morgan BJ and O'Donnell CP: Pathophysiology of sleep apnea. Physiol Rev. 90:47–112. 2010. View Article : Google Scholar : PubMed/NCBI
3	Punjabi NM: The epidemiology of adult obstructive sleep apnea. Proc Am Thorac Soc. 5:136–143. 2008. View Article : Google Scholar : PubMed/NCBI
4	Kendzerska T, Mollayeva T, Gershon AS, Leung RS, Hawker G and Tomlinson G: Untreated obstructive sleep apnea and the risk for serious long-term adverse outcomes: A systematic review. Sleep Med Rev. 18:49–59. 2014. View Article : Google Scholar
5	Shiao TH, Liu CJ, Luo JC, Su KC, Chen YM, Chen TJ, Chou KT, Shiao GM and Lee YC: Sleep apnea and risk of peptic ulcer bleeding: A nationwide population-based study. Am J Med. 126:249–255.e1. 2013. View Article : Google Scholar : PubMed/NCBI
6	Tsukita S, Furuse M and Itoh M: Multifunctional strands in tight junctions. Nat Rev Mol Cell Biol. 2:285–293. 2001. View Article : Google Scholar : PubMed/NCBI
7	Zahraoui A, Louvard D and Galli T: Tight junction, a platform for trafficking and signaling protein complexes. J Cell Biol. 151:F31–F36. 2000. View Article : Google Scholar : PubMed/NCBI
8	Mitic LL, Van Itallie CM and Anderson JM: Molecular physiology and pathophysiology of tight junctions I. Tight junction structure and function: Lessons from mutant animals and proteins. Am J Physiol Gastrointest Liver Physiol. 279:G250–G254. 2000.PubMed/NCBI
9	Lurie A: Inflammation, oxidative stress, and procoagulant and thrombotic activity in adults with obstructive sleep apnea. Adv Cardiol. 46:43–66. 2011. View Article : Google Scholar : PubMed/NCBI
10	Prabhakar NR: Oxygen sensing during intermittent hypoxia: cellular and molecular mechanisms. J Appl Physiol (1985). 90:1986–1994. 2001.
11	Bonsignore MR and Eckel J: ERS Meeting Report. Metabolic aspects of obstructive sleep apnoea syndrome. Eur Respir Rev. 18:113–124. 2009. View Article : Google Scholar : PubMed/NCBI
12	González-Mariscal L, Tapia R and Chamorro D: Crosstalk of tight junction components with signaling pathways. Biochim Biophys Acta. 1778:729–756. 2008. View Article : Google Scholar
13	Feng J, Wang QS, Chiang A and Chen BY: The effects of sleep hypoxia on coagulant factors and hepatic inflammation in emphysematous rats. PLoS One. 5:e132012010. View Article : Google Scholar : PubMed/NCBI
14	Chiu CJ, McArdle AH, Brown R, Scott HJ and Gurd FN: Intestinal mucosal lesion in low-flow states. I A morphological, hemodynamic, and metabolic reappraisal. Arch Surg. 101:478–483. 1970. View Article : Google Scholar : PubMed/NCBI
15	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
16	Lavie L: Obstructive sleep apnoea syndrome - an oxidative stress disorder. Sleep Med Rev. 7:35–51. 2003. View Article : Google Scholar : PubMed/NCBI
17	Zheng X, Mao Y, Cai J, Li Y, Liu W, Sun P, Zhang JH, Sun X and Yuan H: Hydrogen-rich saline protects against intestinal ischemia/reperfusion injury in rats. Free Radic Res. 43:478–484. 2009. View Article : Google Scholar : PubMed/NCBI
18	Yang R, Gallo DJ, Baust JJ, Watkins SK, Delude RL and Fink MP: Effect of hemorrhagic shock on gut barrier function and expression of stress-related genes in normal and gnotobiotic mice. Am J Physiol Regul Integr Comp Physiol. 283:R1263–R1274. 2002. View Article : Google Scholar : PubMed/NCBI
19	Ban K, Peng Z and Kozar RA: Inhibition of ERK1/2 worsens intestinal ischemia/reperfusion injury. PLoS One. 8:e767902013. View Article : Google Scholar : PubMed/NCBI
20	Zhou W, Li S, Wan N, Zhang Z, Guo R and Chen B: Effects of various degrees of oxidative stress induced by intermittent hypoxia in rat myocardial tissues. Respirology. 17:821–829. 2012. View Article : Google Scholar : PubMed/NCBI
21	Yuan G, Khan SA, Luo W, Nanduri J, Semenza GL and Prabhakar NR: Hypoxia-inducible factor 1 mediates increased expression of NADPH oxidase-2 in response to intermittent hypoxia. J Cell Physiol. 226:2925–2933. 2011. View Article : Google Scholar : PubMed/NCBI
22	Nanduri J, Vaddi DR, Khan SA, Wang N, Makarenko V, Semenza GL and Prabhakar NR: HIF-1α activation by intermittent hypoxia requires NADPH oxidase stimulation by xanthine oxidase. PLoS One. 10:e01197622015. View Article : Google Scholar
23	Yuan G, Nanduri J, Khan S, Semenza GL and Prabhakar NR: Induction of HIF-1alpha expression by intermittent hypoxia: Involvement of NADPH oxidase, Ca²⁺ signaling, prolyl hydroxylases, and mTOR. J Cell Physiol. 217:674–685. 2008. View Article : Google Scholar : PubMed/NCBI
24	Nanduri J, Yuan G, Kumar GK, Semenza GL and Prabhakar NR: Transcriptional responses to intermittent hypoxia. Respir Physiol Neurobiol. 164:277–281. 2008. View Article : Google Scholar : PubMed/NCBI
25	Peng YJ, Yuan G, Ramakrishnan D, Sharma SD, Bosch-Marce M, Kumar GK, Semenza GL and Prabhakar NR: Heterozygous HIF-1alpha deficiency impairs carotid body-mediated systemic responses and reactive oxygen species generation in mice exposed to intermittent hypoxia. J Physiol. 577:705–716. 2006. View Article : Google Scholar : PubMed/NCBI
26	Ryan S, Taylor CT and McNicholas WT: Systemic inflammation: A key factor in the pathogenesis of cardiovascular complications in obstructive sleep apnoea syndrome? Thorax. 64:631–636. 2009.PubMed/NCBI
27	Ryan S, McNicholas WT and Taylor CT: A critical role for p38 map kinase in NF-kappaB signaling during intermittent hypoxia/reoxygenation. Biochem Biophys Res Commun. 355:728–733. 2007. View Article : Google Scholar : PubMed/NCBI
28	Greenberg HE, Sica AL, Scharf SM and Ruggiero DA: Expression of c-fos in the rat brainstem after chronic intermittent hypoxia. Brain Res. 816:638–645. 1999. View Article : Google Scholar : PubMed/NCBI
29	Peterson LW and Artis D: Intestinal epithelial cells: Regulators of barrier function and immune homeostasis. Nat Rev Immunol. 14:141–153. 2014. View Article : Google Scholar : PubMed/NCBI
30	Hering NA, Fromm M and Schulzke JD: Determinants of colonic barrier function in inflammatory bowel disease and potential therapeutics. J Physiol. 590:1035–1044. 2012. View Article : Google Scholar : PubMed/NCBI
31	Saeedi B, Kendrick A, Schwisow K, Bayless A, Colgan S and Glover L: A role for hypoxia inducible factor in the junctional integrity and barrier function of intestinal epithelial cells (60.1). FASEB J. 28:S60.12014.
32	Furuta GT, Turner JR, Taylor CT, Hershberg RM, Comerford K, Narravula S, Podolsky DK and Colgan SP: Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia. J Exp Med. 193:1027–1034. 2001. View Article : Google Scholar : PubMed/NCBI
33	Guma M, Stepniak D, Shaked H, Spehlmann ME, Shenouda S, Cheroutre H, Vicente-Suarez I, Eckmann L, Kagnoff MF and Karin M: Constitutive intestinal NF-κB does not trigger destructive inflammation unless accompanied by MAPK activation. J Exp Med. 208:1889–1900. 2011. View Article : Google Scholar : PubMed/NCBI
34	Fischer A, Gluth M, Pape UF, Wiedenmann B, Theuring F and Baumgart DC: Adalimumab prevents barrier dysfunction and antagonizes distinct effects of TNF-α on tight junction proteins and signaling pathways in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol. 304:G970–G979. 2013. View Article : Google Scholar : PubMed/NCBI
35	Ye D, Ma I and Ma TY: Molecular mechanism of tumor necrosis factor-alpha modulation of intestinal epithelial tight junction barrier. Am J Physiol Gastrointest Liver Physiol. 290:G496–G504. 2006. View Article : Google Scholar : PubMed/NCBI
36	Tang Y, Clayburgh DR, Mittal N, Goretsky T, Dirisina R, Zhang Z, Kron M, Ivancic D, Katzman RB, Grimm G, et al: Epithelial NF-kappaB enhances transmucosal fluid movement by altering tight junction protein composition after T cell activation. Am J Pathol. 176:158–167. 2010. View Article : Google Scholar :
37	Chen ML, Ge Z, Fox JG and Schauer DB: Disruption of tight junctions and induction of proinflammatory cytokine responses in colonic epithelial cells by Campylobacter jejuni. Infect Immun. 74:6581–6589. 2006. View Article : Google Scholar : PubMed/NCBI
38	Al-Sadi R, Ye D, Boivin M, Guo S, Hashimi M, Ereifej L and Ma TY: Interleukin-6 modulation of intestinal epithelial tight junction permeability is mediated by JNK pathway activation of claudin-2 gene. PLoS One. 9:e853452014. View Article : Google Scholar : PubMed/NCBI
39	Taylor CT and Colgan SP: Hypoxia and gastrointestinal disease. J Mol Med Berl. 85:1295–1300. 2007. View Article : Google Scholar : PubMed/NCBI
40	Colgan SP and Taylor CT: Hypoxia: An alarm signal during intestinal inflammation. Nat Rev Gastroenterol Hepatol. 7:281–287. 2010. View Article : Google Scholar : PubMed/NCBI
41	Eltzschig HK and Carmeliet P and Carmeliet P: Hypoxia and inflammation. N Engl J Med. 364:656–665. 2011. View Article : Google Scholar : PubMed/NCBI
42	Sitkovsky M and Lukashev D: Regulation of immune cells by local-tissue oxygen tension: HIF1 α and adenosine receptors. Nat Rev Immunol. 5:712–721. 2005. View Article : Google Scholar : PubMed/NCBI