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Pierre Massion
Faculty Member
Last active: 1/11/2018

Hypoxia-inducible factor-1 signalling promotes goblet cell hyperplasia in airway epithelium.

Polosukhin VV, Cates JM, Lawson WE, Milstone AP, Matafonov AG, Massion PP, Lee JW, Randell SH, Blackwell TS
J Pathol. 2011 224 (2): 203-11

PMID: 21557221 · PMCID: PMC5901746 · DOI:10.1002/path.2863

Goblet cell hyperplasia is a common feature of chronic obstructive pulmonary disease (COPD) airways, but the mechanisms that underlie this epithelial remodelling in COPD are not understood. Based on our previous finding of hypoxia-inducible factor-1α (HIF-1α) nuclear localization in large airways from patients with COPD, we investigated whether hypoxia-inducible signalling could influence the development of goblet cell hyperplasia. We evaluated large airway samples obtained from 18 lifelong non-smokers and 13 former smokers without COPD, and 45 former smokers with COPD. In these specimens, HIF-1α nuclear staining occurred almost exclusively in COPD patients in areas of airway remodelling. In COPD patients, 93.2 ± 3.9% (range 65-100%) of goblet cells were HIF-1α positive in areas of goblet cell hyperplasia, whereas nuclear HIF-1α was not detected in individuals without COPD or in normal-appearing pseudostratified epithelium from COPD patients. To determine the direct effects of hypoxia-inducible signalling on epithelial cell differentiation in vitro, human bronchial epithelial cells (HBECs) were grown in air-liquid interface cultures under hypoxia (1% O(2)) or following treatment with a selective HIF-1α stabilizer, (2R)-[(4-biphenylylsulphonyl)amino]-N-hydroxy-3-phenyl-propionamide (BiPS). HBECs grown in hypoxia or with BiPS treatment were characterized by HIF-1α activation, carbonic anhydrase IX expression, mucus-producing cell hyperplasia and increased expression of MUC5AC. Analysis of signal transduction pathways in cells with HIF-1α activation showed increased ERK1/2 phosphorylation without activation of epidermal growth factor receptor, Ras, PI3K-Akt or STAT6. These data indicate an important effect of hypoxia-inducible signalling on airway epithelial cell differentiation and identify a new potential target to limit mucus production in COPD.

Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

MeSH Terms (24)

Adolescent Adult Aged Aged, 80 and over Airway Remodeling Bronchi Cell Differentiation Cell Hypoxia Cells, Cultured Enzyme Activation Female Goblet Cells Humans Hyperplasia Hypoxia-Inducible Factor 1 Male Middle Aged Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Mucin 5AC Pulmonary Disease, Chronic Obstructive Respiratory Mucosa Signal Transduction Young Adult

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