title: Ectopic respiratory epithelial cell differentiation in bronchiolised distal airspaces in idiopathic pulmonary fibrosis.
abstract: BACKGROUND
  Bronchiolisation of distal airspaces is an unexplained feature of idiopathic pulmonary fibrosis (IPF). The authors sought to identify mechanisms driving the differentiation of mucus cells during the bronchiolisation process.
  
  
  METHODS
  Pathways governing airway mucus cell differentiation include SRY (sex determining region Y)-box 2 (SOX2), Notch, forkhead box A3(FOXA3)/SAM pointed domain containing ETS transcription factor (SPDEF), epidermal growth factor (EGF) and the EGF-related neuregulins NRG1α and NRG1β. Immunostaining for components of those pathways and mucins were performed on lung tissue obtained from patients with IPF (n=20), chronic obstructive pulmonary disease (n=13), idiopathic pulmonary artery hypertension (n=5) and from organ donors (n=6). NRG1α and NRG1β were quantified in bronchoalveolar lavage fluid (BALF) of patients with early IPF (n=20), controls (n=9), and patients with other interstitial pneumonias (n=13).
  
  
  RESULTS
  In IPF, the bronchiolised and enlarged distal airspaces stained for SOX2 are consistent with epithelial differentiation characteristic of conducting airway epithelium. IPF mucus cells expressed MUC5B but low levels of MUC5AC and MUC2, a profile typical of submucosal glands. Singularly, SPDEF, a transcription factor associated with mucus metaplasia, was rarely detected in mucus cells in IPF. The Notch target, HES1, was present in mucus cells from all groups. NRG1α was detected in serous cells within normal submucosal glands and in epithelial cells lining honeycombing areas in IPF, and was not detected in other patients. NRG1α concentrations were elevated in BALF from patients with early IPF.
  
  
  CONCLUSIONS
  Expression of SOX2 and MUC5B and lack of SPDEF in atypically differentiated cells of bronchiolised distal airspaces are consistent with abnormal programming of airway epithelial cells in IPF. NRG1α may contribute to bronchiolisation of the distal lung seen in IPF.
authors.affiliation: Section of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Perinatal Institute, MLC7029, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Plantier
authors.forename: Bruno
authors.initials: B
authors.lastname: Crestani
authors.forename: Susan E
authors.initials: SE
authors.lastname: Wert
authors.forename: Monique
authors.initials: M
authors.lastname: Dehoux
authors.forename: Barbara
authors.initials: B
authors.lastname: Zweytick
authors.forename: Andreas
authors.initials: A
authors.lastname: Guenther
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Whitsett
mesh_terms: D055745:Bronchioles / Q000378:metabolism / Q000473:pathology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002454:Cell Differentiation; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000473:pathology; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology*; D016040:Lung Transplantation; D008565:Membrane Proteins / Q000378:metabolism; D055257:Mucin-5B / Q000378:metabolism; D009077:Mucins / Q000378:metabolism; D020890:Neuregulin-1 / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism / Q000473:pathology; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology*; D055748:SOXB1 Transcription Factors / Q000378:metabolism
chemical_list: C081876:CKAP4 protein, human; C524578:MUC5B protein, human; D008565:Membrane Proteins; D055257:Mucin-5B; D009077:Mucins; D020890:Neuregulin-1; D050783:Proto-Oncogene Proteins c-ets; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C403974:SPDEF protein, human