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Mechanism of hypoxia-induced hypersecretion in paranasal sinusitis

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Dept. of Medical Science/석사
Excessive mucus production and hypersecretion characterize various upper airway diseases. In sinusitis, the expression of major respiratory mucin genes, such as MUC5AC, MUC5B is increased. However, the primary mechanisms leading to mucus hypersecretion in sinusitis are not well known. Hypoxia due to occlusion of sinus ostium is known to be one of the major pathologic mechanisms of the sinusitis. However, there has been no report about the mechanism of hypoxia-induced hypersecretion of mucus in sinusitis. This study is aimed to identify whether induces mucus hypersecretion in upper airway epithelia and to elucidate the mechanism of hypoxia-induced hypersecretion in upper airway epithelia.Here we show that expression of mRNA of MUC5AC is a function of time under hypoxia in normal human nasal epithelial cells. Our results also show that the expression of MUC5AC mRNA was increased by transfection of mammalian expression vector encoding HIF-1α, a major transcription factor for hypoxia, even under normoxic condition in human lung mucoepidermoid carcinoma cell lines (NCI-H292 cells). Moreover, the induced expression of MUC5AC mRNA by hypoxia was down-regulated by transfection of siRNA for HIF-1. The luciferase assay for MUC5AC promoter demonstrated increased reporter activity under hypoxic condition, however the mutation of the putative HRE in MUC5AC promoter attenuated the reporter activity. We also confirmed the binding of over-expressed HIF-1 and hypoxia-response element (HRE) in the promoter of MUC5AC by electromobility shift assay. In human sinusitis mucosa, we found the overexpression of HIF-1 and MUC5AC compared to normal sinus mucosa.Hypoxia upregulates MUC5AC expression by binding of HIF-1α to HRE in the promoter of MUC5AC. In conclusion, hypoxia upregulates mucin gene expression and secretion by signaling using HIF-1α in the airway epithelia and hypoxia might be a pathophysiologic mechanism of hypersecretion in airway disease such as sinusitis.
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