Faculty Johns Hopkins University School of Medicine/Dept Otolaryngology Head and Neck Surgery/Division of Rhinology Baltimore, Maryland
Epithelial cell hyperplasia is a key feature of nasal polyps in chronic rhinosinusitis with nasal polyposis (CRSwNP). We have previously shown that overexpression of growth factor VEGF promotes autocrine driven hyperplastic growth of primary nasal epithelial cells (PNEC) in vitro. Therefore, we sought to examine the upstream mechanisms involved in this process. We hypothesize that HIF1α (hypoxia inducible factor-1), a known master regulator of VEGF, promotes this process. We now report that both HIF1α and HIF2α protein and mRNA are highly expressed in PNEC as measured by flow cytometry and realtime PCR. Immunohistochemical analysis shows that HIF1α is induced in the epithelium of polyps in CRSwNP patients as compared to control patients. Specific inhibition of HIF1α by siRNA knockdown results in inhibition of VEGF mRNA and protein expression, which subsequently results in inhibition and normalization of hyperplastic growth of PNEC from CRSwNP patients, as measured by DNA binding assay. This was specific for HIF1α and not observed for knockdown of HIF2α. Additionally, downstream inhibition of HIF1α pathway by MAP kinase pathway inhibitors results in inhibition of PNEC cell growth. Exposure of whole human nasal polyps in ex vivo culture to HIF1α inhibitor digoxin results in induction of PNEC apoptosis as assessed by TUNEL assay. Collectively, these data indicate that in human PNEC and nasal polyp tissue, HIF1α regulates VEGF in promoting hyperplastic nasal epithelial cell growth and survival in CRSwNP and implicate a critical role for hypoxia in the development of hyperplastic polyp growth.