Skip to main content
Top
Published in: Sleep and Breathing 2/2021

01-06-2021 | Sleep Apnea | Sleep Breathing Physiology and Disorders • Original Article

Intermittent hypoxia induces turbinate mucosal hypertrophy via upregulating the gene expression related to inflammation and EMT in rats

Authors: Yo-ichiro Kuma, Jun Hosomichi, Hideyuki Maeda, Shuji Oishi, Risa Usumi-Fujita, Yasuhiro Shimizu, Sawa Kaneko, Jun-ichi Suzuki, Ken-ichi Yoshida, Takashi Ono

Published in: Sleep and Breathing | Issue 2/2021

Login to get access

Abstract

Purpose

Chronic intermittent hypoxia (IH) plays a pivotal role in the consequences of obstructive sleep apnea (OSA). It has been demonstrated that IH impairs nasomaxillary complex growth to reduce nasal airway cavity size in rodent models. Although turbinate dysfunction with inflammatory mucosal hypertrophy is related to OSA, the role of IH in turbinate hypertrophy with inflammation-driven fibrosis is unknown. Here, we aimed to clarify the pathogenesis of inflammatory mucosal hypertrophy and epithelial-mesenchymal transition (EMT) in the nasal turbinate under IH.

Methods

Seven-week-old male Sprague-Dawley rats were exposed to IH (4% O2 to 21% O2 with 0% CO2) at a rate of 20 cycles/h.

Results

Hypertrophy of the turbinate mucosa occurred after 3 weeks, with the turbinate mucosa of the experimental group becoming significantly thicker than in the control group. Immunostaining showed that IH increased the expression of TGFβ and N-cadherin and decreased E-cadherin expression in the turbinate mucosa. Quantitative PCR analysis demonstrated that IH enhanced the expression of not only the inflammatory markers Tnf-a, Il-1b, and Nos2 but also the EMT markers Tgf-b1, Col1a1, and Postn.

Conclusions

Collectively, these results suggest that IH induced turbinate hypertrophy via upregulation of gene expression related to inflammation and EMT in the nasal mucosa.
Literature
1.
go back to reference Vicente E, Marin JM, Carrizo SJ, Osuna CS, González R, Marin-Oto M, Forner M, Vicente P, Cubero P, Gil AV, Soler X (2016) Upper airway and systemic inflammation in obstructive sleep apnoea. Eur Respir J 48:1108–1117CrossRef Vicente E, Marin JM, Carrizo SJ, Osuna CS, González R, Marin-Oto M, Forner M, Vicente P, Cubero P, Gil AV, Soler X (2016) Upper airway and systemic inflammation in obstructive sleep apnoea. Eur Respir J 48:1108–1117CrossRef
2.
go back to reference Huang YS, Guilleminault C (2013) Pediatric obstructive sleep apnea and the critical role of oral-facial growth: evidences. Front Neurol 3:184CrossRef Huang YS, Guilleminault C (2013) Pediatric obstructive sleep apnea and the critical role of oral-facial growth: evidences. Front Neurol 3:184CrossRef
3.
go back to reference Kuma Y, Usumi-Fujita R, Hosomichi J, Oishi S, Maeda H, Nagai H, Shimizu Y, Kaneko S, Shitano C, Suzuki JI, Yoshida KI, Ono T (2014) Impairment of nasal airway under intermittent hypoxia during growth period in rats. Arch Oral Biol 59:1139–1145CrossRef Kuma Y, Usumi-Fujita R, Hosomichi J, Oishi S, Maeda H, Nagai H, Shimizu Y, Kaneko S, Shitano C, Suzuki JI, Yoshida KI, Ono T (2014) Impairment of nasal airway under intermittent hypoxia during growth period in rats. Arch Oral Biol 59:1139–1145CrossRef
4.
go back to reference Patino M, Sadhasivam S, Mahmoud M (2013) Obstructive sleep apnoea in children: perioperative considerations. Br J Anaesth 111:i83–i95CrossRef Patino M, Sadhasivam S, Mahmoud M (2013) Obstructive sleep apnoea in children: perioperative considerations. Br J Anaesth 111:i83–i95CrossRef
5.
go back to reference Paulsen FP, Steven P, Tsokos M, Jungmann K, Müller A, Verse T, Pirsig W (2002) Upper airway epithelial structural changes in obstructive sleep-disordered breathing. Am J Respir Crit Care Med 166:501–509CrossRef Paulsen FP, Steven P, Tsokos M, Jungmann K, Müller A, Verse T, Pirsig W (2002) Upper airway epithelial structural changes in obstructive sleep-disordered breathing. Am J Respir Crit Care Med 166:501–509CrossRef
6.
go back to reference Woodson BT, Garancis JC, Toohill RJ (1991) Histopathologic changes in snoring and obstructive sleep apnoea syndrome. Laryngoscope 101:1318–1322CrossRef Woodson BT, Garancis JC, Toohill RJ (1991) Histopathologic changes in snoring and obstructive sleep apnoea syndrome. Laryngoscope 101:1318–1322CrossRef
7.
go back to reference Inamoto S, Yoshioka T, Yamashita C, Miyamura M, Mori T, Ukimura A, Matsumoto C, Matsumura Y, Kitaura Y, Hayashi T (2010) Pitavastatin reduces oxidative stress and attenuates intermittent hypoxia-induced left ventricular remodeling in lean mice. Hypertens Res 33:579–586CrossRef Inamoto S, Yoshioka T, Yamashita C, Miyamura M, Mori T, Ukimura A, Matsumoto C, Matsumura Y, Kitaura Y, Hayashi T (2010) Pitavastatin reduces oxidative stress and attenuates intermittent hypoxia-induced left ventricular remodeling in lean mice. Hypertens Res 33:579–586CrossRef
8.
go back to reference Reinke C, Bevans-Fonti S, Grigoryev DN, Drager LF, Myers AC, Wise RA, Schwartz AR, Mitzner W, Polotsky VY (2011) Chronic intermittent hypoxia induces lung growth in adult mice. Am J Physiol Lung Cell Mol Physiol 300:L266–L273CrossRef Reinke C, Bevans-Fonti S, Grigoryev DN, Drager LF, Myers AC, Wise RA, Schwartz AR, Mitzner W, Polotsky VY (2011) Chronic intermittent hypoxia induces lung growth in adult mice. Am J Physiol Lung Cell Mol Physiol 300:L266–L273CrossRef
9.
go back to reference Dewan NA, Nieto FJ, Somers VK (2015) Intermittent hypoxemia and OSA. Chest 147:266–274CrossRef Dewan NA, Nieto FJ, Somers VK (2015) Intermittent hypoxemia and OSA. Chest 147:266–274CrossRef
10.
go back to reference Scott A, Khan KM, Roberts CR, Cook JL, Duronio V (2004) What do we mean by the term “inflammation”? A contemporary basic science update for sports medicine. Br J Sports Med 38(3):372–380CrossRef Scott A, Khan KM, Roberts CR, Cook JL, Duronio V (2004) What do we mean by the term “inflammation”? A contemporary basic science update for sports medicine. Br J Sports Med 38(3):372–380CrossRef
11.
go back to reference Westergren-Thorsson G, Larsen K, Nihlberg K, Andersson-Sjöland A, Hallgren O, Marko-Varga G, Bjermer L (2010) Pathological airway remodelling in inflammation. Clin Respir J 4:1–8CrossRef Westergren-Thorsson G, Larsen K, Nihlberg K, Andersson-Sjöland A, Hallgren O, Marko-Varga G, Bjermer L (2010) Pathological airway remodelling in inflammation. Clin Respir J 4:1–8CrossRef
12.
go back to reference Zhang D, Xiao Y, Luo JA et al (2019) Measurement of fractional exhaled nitric oxide and nasal nitric oxide in male patients with obstructive sleep apnea. Sleep Breath 23:785–793CrossRef Zhang D, Xiao Y, Luo JA et al (2019) Measurement of fractional exhaled nitric oxide and nasal nitric oxide in male patients with obstructive sleep apnea. Sleep Breath 23:785–793CrossRef
13.
go back to reference Ijaz T, Pazdrak K, Kalita M, Konig R, Choudhary S, Tian B, Boldogh I, Brasier AR (2014) Systems biology approaches to understanding epithelial mesenchymal transition (EMT) in mucosal remodeling and signaling in asthma. World Allergy Organ J 7:13CrossRef Ijaz T, Pazdrak K, Kalita M, Konig R, Choudhary S, Tian B, Boldogh I, Brasier AR (2014) Systems biology approaches to understanding epithelial mesenchymal transition (EMT) in mucosal remodeling and signaling in asthma. World Allergy Organ J 7:13CrossRef
14.
go back to reference Yang HW, Lee SA, Shin JM, Park IH, Lee HM (2017) Glucocorticoids ameliorate TGF-β1-mediated epithelial-to-mesenchymal transition of airway epithelium through MAPK and Snail/Slug signaling pathways. Sci Rep 7:3486CrossRef Yang HW, Lee SA, Shin JM, Park IH, Lee HM (2017) Glucocorticoids ameliorate TGF-β1-mediated epithelial-to-mesenchymal transition of airway epithelium through MAPK and Snail/Slug signaling pathways. Sci Rep 7:3486CrossRef
15.
go back to reference Nagai H, Kuwahira I, Schwenke DO, Tsuchimochi H, Nara A, Ogura S, Sonobe T, Inagaki T, Fujii Y, Yamaguchi R, Wingenfeld L, Umetani K, Shimosawa T, Yoshida KI, Uemura K, Pearson JT, Shirai M (2015) Pulmonary macrophages attenuate hypoxic pulmonary vasoconstriction via β3AR/iNOS pathway in rats exposed to chronic intermittent hypoxia. PLoS One 10:e0131923CrossRef Nagai H, Kuwahira I, Schwenke DO, Tsuchimochi H, Nara A, Ogura S, Sonobe T, Inagaki T, Fujii Y, Yamaguchi R, Wingenfeld L, Umetani K, Shimosawa T, Yoshida KI, Uemura K, Pearson JT, Shirai M (2015) Pulmonary macrophages attenuate hypoxic pulmonary vasoconstriction via β3AR/iNOS pathway in rats exposed to chronic intermittent hypoxia. PLoS One 10:e0131923CrossRef
16.
go back to reference Maeda H, Nagai H, Takemura G, Shintani-Ishida K, Komatsu M, Ogura S, Aki T, Shirai M, Kuwahira I, Yoshida KI (2013) Intermittent-hypoxia induced autophagy attenuates contractile dysfunction and myocardial injury in rat heart. Biochim Biophys Acta - Mol Basis Dis 1832:1159–1166CrossRef Maeda H, Nagai H, Takemura G, Shintani-Ishida K, Komatsu M, Ogura S, Aki T, Shirai M, Kuwahira I, Yoshida KI (2013) Intermittent-hypoxia induced autophagy attenuates contractile dysfunction and myocardial injury in rat heart. Biochim Biophys Acta - Mol Basis Dis 1832:1159–1166CrossRef
17.
go back to reference Nagai H, Shirai M, Tsuchimochi H, Yoshida K, Kuwahira I (2014) A novel system including an N 2 gas generator and an air compressor for inducing intermittent or chronic hypoxia. Int J Clin Exp Physiol 1:307CrossRef Nagai H, Shirai M, Tsuchimochi H, Yoshida K, Kuwahira I (2014) A novel system including an N 2 gas generator and an air compressor for inducing intermittent or chronic hypoxia. Int J Clin Exp Physiol 1:307CrossRef
19.
go back to reference Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta C(T)) method. Methods 25:402–408CrossRef Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta C(T)) method. Methods 25:402–408CrossRef
20.
go back to reference Aihara K, Oga T, Chihara Y et al (2013) Analysis of systemic and airway inflammation in obstructive sleep apnea. Sleep Breath 17:5CrossRef Aihara K, Oga T, Chihara Y et al (2013) Analysis of systemic and airway inflammation in obstructive sleep apnea. Sleep Breath 17:5CrossRef
21.
go back to reference He Q, Yang QC, Zhou Q, Zhu H, Niu WY, Feng J, Wang Y, Cao J, Chen BY (2014) Effects of varying degrees of intermittent hypoxia on proinflammatory cytokines and adipokines in rats and 3T3-L1 adipocytes. PLoS One 9:e86326CrossRef He Q, Yang QC, Zhou Q, Zhu H, Niu WY, Feng J, Wang Y, Cao J, Chen BY (2014) Effects of varying degrees of intermittent hypoxia on proinflammatory cytokines and adipokines in rats and 3T3-L1 adipocytes. PLoS One 9:e86326CrossRef
22.
go back to reference Hua-Huy T, Le-Dong NN, Duong-Quy S, Luchon L, Rouhani S, Dinh-Xuan AT (2015) Increased alveolar nitric oxide concentration is related to nocturnal oxygen desaturation in obstructive sleep apnoea. Nitric Oxide 45:27–34CrossRef Hua-Huy T, Le-Dong NN, Duong-Quy S, Luchon L, Rouhani S, Dinh-Xuan AT (2015) Increased alveolar nitric oxide concentration is related to nocturnal oxygen desaturation in obstructive sleep apnoea. Nitric Oxide 45:27–34CrossRef
23.
go back to reference Branton MH, Kopp JB (1999) TGF-beta and fibrosis. Microbes Infect 1:1349–1365CrossRef Branton MH, Kopp JB (1999) TGF-beta and fibrosis. Microbes Infect 1:1349–1365CrossRef
24.
go back to reference Eifan AO, Orban NT, Jacobson MR, Durham SR (2015) Severe persistent allergic rhinitis. Inflammation but no histologic features of structural upper airway remodeling. Am J Respir Crit Care Med 192:1431–1439CrossRef Eifan AO, Orban NT, Jacobson MR, Durham SR (2015) Severe persistent allergic rhinitis. Inflammation but no histologic features of structural upper airway remodeling. Am J Respir Crit Care Med 192:1431–1439CrossRef
25.
go back to reference Câmara J, Jarai G (2010) Epithelial-mesenchymal transition in primary human bronchial epithelial cells is Smad-dependent and enhanced by fibronectin and TNF-alpha. Fibrogenesis Tissue Repair 3:2CrossRef Câmara J, Jarai G (2010) Epithelial-mesenchymal transition in primary human bronchial epithelial cells is Smad-dependent and enhanced by fibronectin and TNF-alpha. Fibrogenesis Tissue Repair 3:2CrossRef
26.
go back to reference Kang HH, Kim IK, Lee HI et al (2017) Chronic intermittent hypoxia induces liver fibrosis in mice with diet-induced obesity via TLR4/MyD88/MAPK/NF-kB signaling pathways. Biochem Biophys Res Commun 490:349–355CrossRef Kang HH, Kim IK, Lee HI et al (2017) Chronic intermittent hypoxia induces liver fibrosis in mice with diet-induced obesity via TLR4/MyD88/MAPK/NF-kB signaling pathways. Biochem Biophys Res Commun 490:349–355CrossRef
27.
go back to reference Hoshino M, Nakamura Y, Sim J, Shimojo J, Isogai S (1998) Bronchial subepithelial fibrosis and expression of matrix metalloproteinase-9 in asthmatic airway inflammation. J Allergy Clin Immunol 102:783–788CrossRef Hoshino M, Nakamura Y, Sim J, Shimojo J, Isogai S (1998) Bronchial subepithelial fibrosis and expression of matrix metalloproteinase-9 in asthmatic airway inflammation. J Allergy Clin Immunol 102:783–788CrossRef
28.
go back to reference Strutz F, Zeisberg M, Ziyadeh FN, Yang CQ, Kalluri R, Müller GA, Neilson EG (2002) Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney Int 61:1714–1728CrossRef Strutz F, Zeisberg M, Ziyadeh FN, Yang CQ, Kalluri R, Müller GA, Neilson EG (2002) Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney Int 61:1714–1728CrossRef
Metadata
Title
Intermittent hypoxia induces turbinate mucosal hypertrophy via upregulating the gene expression related to inflammation and EMT in rats
Authors
Yo-ichiro Kuma
Jun Hosomichi
Hideyuki Maeda
Shuji Oishi
Risa Usumi-Fujita
Yasuhiro Shimizu
Sawa Kaneko
Jun-ichi Suzuki
Ken-ichi Yoshida
Takashi Ono
Publication date
01-06-2021
Publisher
Springer International Publishing
Keyword
Sleep Apnea
Published in
Sleep and Breathing / Issue 2/2021
Print ISSN: 1520-9512
Electronic ISSN: 1522-1709
DOI
https://doi.org/10.1007/s11325-020-02162-6

Other articles of this Issue 2/2021

Sleep and Breathing 2/2021 Go to the issue

Sleep Breathing Physiology and Disorders • Original Article

Renalase and hypertension—demographic and clinical correlates in obstructive sleep apnea