4 research outputs found
Hypoxia-mediated mechanism of MUC5AC production in human nasal epithelial and its implication in rhinosinusitis
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-1ฮฑ, is induced during hypoxia, and transfection of a mammalian expression vector encoding HIF-1ฮฑ results in increased MUC5AC mRNA levels under normoxic conditions. Moreover, hypoxia-induced expression of MUC5AC mRNA is down-regulated by transfected HIF-1ฮฑ 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-1ฮฑ 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-1ฮฑ is higher than in control mucosa.
CONCLUSION:
The results indicate that anoxia up-regulates MUC5AC by the HIF-1ฮฑ signaling pathway in human nasal epithelia and suggest that hypoxia might be a pathogenic mechanism of mucus hypersecretion in sinusitis.ope
Delphi study on public company policies for SMEs' supports
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ผ๋ฌธ (์์ฌ)-- ์์ธ๋ํ๊ต ๋ํ์ : ๊ณต๊ธฐ์
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ํ๊ณผ, 2011.8. ๋ฐ์ ํ.Maste