title: Hypoxia-inducible factor-1 signalling promotes goblet cell hyperplasia in airway epithelium.
abstract: 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.
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-2650, USA. vasiliy.v.polosukhin@vanderbilt.edu
authors.forename: Vasiliy V
authors.initials: VV
authors.lastname: Polosukhin
authors.forename: Justin M
authors.initials: JM
authors.lastname: Cates
authors.forename: William E
authors.initials: WE
authors.lastname: Lawson
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Milstone
authors.forename: Anton G
authors.initials: AG
authors.lastname: Matafonov
authors.forename: Pierre P
authors.initials: PP
authors.lastname: Massion
authors.forename: Jae Woo
authors.initials: JW
authors.lastname: Lee
authors.forename: Scott H
authors.initials: SH
authors.lastname: Randell
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D056151:Airway Remodeling / Q000502:physiology; D001980:Bronchi / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D020397:Goblet Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology; D051793:Hypoxia-Inducible Factor 1 / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D055271:Mucin 5AC / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism / Q000473:pathology*; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology; D055815:Young Adult
chemical_list: D051793:Hypoxia-Inducible Factor 1; C524678:MUC5AC protein, human; D055271:Mucin 5AC; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3