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Rationale: Nasal polyposis implies a refractory clinical course in case of chronic rhinosinusitis (CRS). Although hypoxia is believed to be associated with nasal polyposis, little is known about the mechanism underlying polypogenesis.
Objectives: To determine if hypoxia drives nasal polyposis by epithelial-to-mesenchymal transition (EMT).
Methods: Immunoblotting, immunofluorescence, flow cytometry, andreal-timepolymerase chain reactionwereperformedto evaluate EMTandhypoxic markersinhumannasal epithelial cells(hNECs)and in sinonasal tissues from patients with CRS with or without polyps. In addition, the effects of hypoxia-inducible factor (HIF)-1a inhibitors on nasal polypogenesis were investigated in a murine model.
Measurements and Main Results: E-cadherin and a-smooth muscle actin (a-SMA) were down-regulated and up-regulated, respectively, in patients with polyps as compared with patients without polyps. Under hypoxia, hNECs transformed to a mesenchymal shape, and demonstrated representative changes in EMT markers; that is, mesenchymal markers (a-SMA, vimentin, and twist) increased but epithelial markers (E-cadherin and b-catenin) decreased. Mechanistically, E-cadherin level was recovered in hypoxia by silencing HIF-1a and decreased in normoxia by expressing HIF-1a. Furthermore, hypoxia was found to down-regulate PP2Ac phosphatase and upregulate pSmad3, which led to a-SMA induction. In CRS sinonasal specimens, HIF-1aexpressionwasfoundto correlate with E-cadherin loss and a-SMA expression. Finally, HIF-1a inhibitors suppressed nasal polypogenesis in a murine model.
Conclusions: hNECs undergo EMT during hypoxia and this process is critically mediated by HIF-1a and pSmad3. This study shows that hypoxia-induced EMT is likely to contribute to nasal polyposis in CRS, and suggests that HIF-1a be viewed as a therapeutic target for nasal polyposis.
Keywords: nasal polyposis; epithelial-to-mesenchymal transition; hypoxia; hypoxia-inducible factor 1; Smad3
Chronic rhinosinusitis (CRS) is a common chronic disease that includes a broad spectrum of disease entities (1). Nasal polyps (NPs) are frequently present in conjunction with CRS, and their presence indicates a greater burden of illness with recalcitrant and refractory clinical features (2, 3). NP is characterized by epithelial thickening and denudation, thickening of the basement membrane, glandular hyperplasia, edematous stroma, and immune cell infiltration (4).
Polypogenesis, the formation of NP, is generally believed to be the result of sustained inflammation in sinonasal cavities. This inflammation is caused by various etiologies, and blocks mucus drainage from sinuses, which leads to mucus retention and hypoxia. In addition, it promotes the infiltration of inflammatory cells and mucosal hyperplasia, potentially leading to the development of NPs....