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% O2) 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.

Hypoxia and the hypoxia-regulated transcription factor HIF-1α suppress the host defence of airway epithelial cells

“…However, to our knowledge all available literature about the impact of hypoxia on lung epithelial cells defined 0.21 as normoxia. 13,41,[44][45][46][47] Hence, our current data are comparable with those in the established literature. In addition, our study did not aim to investigate the exact mechanism by which HIF-1a regulates innate immune mechanisms in bronchial epithelial cells.…”

Submersion and Hypoxia Inhibit Ciliated Cell Differentiation in a Notch-Dependent Manner

“…The observation that hypoxia reduces ciliated cell differentiation in NHBE cells in vitro by potentiating Notch signaling suggests that hypoxia may also influence differentiation of other epithelial cell types in the adult airway. Consistent with this idea, hypoxia was shown to increase the number of MUC5AC-positive cells during NHBE cell differentiation in vitro (48). In addition, regions of hypoxia have been observed in the airways of patients with respiratory diseases, such as cystic fibrosis and chronic obstructive pulmonary disease (48,49), diseases that also exhibit goblet cell hyperplasia, mucus hypersecretion (5,50), and reduced numbers of ciliated cells (8,10).…”

“…Consistent with this idea, hypoxia was shown to increase the number of MUC5AC-positive cells during NHBE cell differentiation in vitro (48). In addition, regions of hypoxia have been observed in the airways of patients with respiratory diseases, such as cystic fibrosis and chronic obstructive pulmonary disease (48,49), diseases that also exhibit goblet cell hyperplasia, mucus hypersecretion (5,50), and reduced numbers of ciliated cells (8,10). Thus, the interplay between oxygen concentration and Notch signaling may contribute to alterations in the cellular composition of the airway epithelium observed in respiratory disease, and suggests a new potential therapeutic target.…”

Novel Therapies to Inhibit Mucus Synthesis and Secretion in Airway Hypersecretory Diseases

“…HIF-1 is also activated by IL-13 and responds to inflammation; it could therefore partially contribute to mucin overproduction in inflammatory diseases such as asthma and COPD [2]. Cigarette smoke increases HIF-1 production and activity in human bronchial epithelial cells, and other HIF-1 signalling pathways, encouraging goblet cell hyperplasia [33,34]. …”

“…4) [34]. The importance of MARCKS in mucin secretion was demonstrated when a lipidated peptide was introduced into human bronchial epithelial cells in vitro to interfere with MARCKS function; mucin secretion was significantly reduced [36].…”