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Hypoxia-mediated mechanism of MUC5AC production in human nasal epithelial and its implication in rhinosinusitis

Authors
 Yoon-Ju Kim  ;  Hyung-Ju Cho  ;  Woo-Chul Shin  ;  Hyun-Ah Song  ;  Joo-Heon Yoon  ;  Chang-Hoon Kim 
Citation
 PLOS ONE, Vol.9(5) : e98136, 2014 
Journal Title
 PLOS ONE 
Issue Date
2014
MeSH
Blotting, Western ; Cell Line, Tumor ; Chromatin Immunoprecipitation ; Electrophoretic Mobility Shift Assay ; Humans ; Hypoxia/etiology ; Hypoxia/metabolism* ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Luciferases ; Mucin 5AC/metabolism* ; Mucus/secretion* ; Nasal Mucosa/secretion* ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/genetics ; Signal Transduction/physiology* ; Sinusitis/complications ; Sinusitis/metabolism*
Abstract
BACKGROUND: Excessive mucus production is typical in various upper airway diseases. In sinusitis, the expression of MUC5AC, a major respiratory mucin gene, increases. However, the mechanisms leading to mucus hypersecretion in sinusitis have not been characterized. Hypoxia due to occlusion of the sinus ostium is one of the major pathologic mechanisms of sinusitis, but there have been no reports regarding the mechanism of hypoxia-induced mucus hypersecretion. METHODS AND FINDINGS: This study aims to identify whether hypoxia may induce mucus hypersecretion and elucidate its mechanism. Normal human nasal epithelial (NHNE) cells and human lung mucoepidermoid carcinoma cell line (NCI-H292) were used. Sinus mucosa from patients was also tested. Anoxic condition was in an anaerobic chamber with a 95% N2/5% CO2 atmosphere. The regulatory mechanism of MUC5AC by anoxia was investigated using RT-PCR, real-time PCR, western blot, ChIP, electrophoretic mobility shift, and luciferase assay. We show that levels of MUC5AC mRNA and the corresponding secreted protein increase in anoxic cultured NHNE cells. The major transcription factor for hypoxia-related signaling, HIF-1α, is induced during hypoxia, and transfection of a mammalian expression vector encoding HIF-1α results in increased MUC5AC mRNA levels under normoxic conditions. Moreover, hypoxia-induced expression of MUC5AC mRNA is down-regulated by transfected HIF-1α siRNA. We found increased MUC5AC promoter activity under anoxic conditions, as indicated by a luciferase reporter assay, and mutation of the putative hypoxia-response element in MUC5AC promoter attenuated this activity. Binding of over-expressed HIF-1α to the hypoxia-response element in the MUC5AC promoter was confirmed. In human sinusitis mucosa, which is supposed to be hypoxic, expression of MUC5AC and HIF-1α is higher than in control mucosa. CONCLUSION: The results indicate that anoxia up-regulates MUC5AC by the HIF-1α signaling pathway in human nasal epithelia and suggest that hypoxia might be a pathogenic mechanism of mucus hypersecretion in sinusitis.
Files in This Item:
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DOI
10.1371/journal.pone.0098136
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Medical Research Center (임상의학연구센터) > 1. Journal Papers
Yonsei Authors
Kim, Chang Hoon(김창훈) ORCID logo https://orcid.org/0000-0003-1238-6396
Song, Hyun Ah(송현아)
Yoon, Joo Heon(윤주헌)
Cho, Hyung Ju(조형주) ORCID logo https://orcid.org/0000-0002-2851-3225
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/98754
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