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Original article
Ectopic respiratory epithelial cell differentiation in bronchiolised distal airspaces in idiopathic pulmonary fibrosis
  1. Laurent Plantier1,
  2. Bruno Crestani2,3,
  3. Susan E Wert1,
  4. Monique Dehoux3,4,
  5. Barbara Zweytick5,
  6. Andreas Guenther6,7,
  7. Jeffrey A Whitsett1
  1. 1Section of Neonatology, Perinatal and Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  2. 2Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Service de Pneumologie A, Paris, France
  3. 3Inserm U 700, Université Paris Diderot-Paris 7, UFR de Médecine-site Bichat, Paris, France
  4. 4Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Service de Biochimie A, Paris, France
  5. 5Department of Thoracic Surgery, Vienna General Hospital, Vienna, Austria
  6. 6University of Giessen Lung Centre, Department of Internal Medicine, Giessen, Germany
  7. 7Lung Clinic Waldhof-Elgershausen, Greifenstein, Germany
  1. Correspondence to Jeffrey A Whitsett, Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Perinatal Institute, MLC7029, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA; jeff.whitsett{at}


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.

Conclusion 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.

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  • See Editorial, p 647

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  • Funding This work was supported by a travel grant from the Société de Pneumologie de Langue Française (LP), the National Institutes of Health HL095580 and HL090156, the Cystic Fibrosis Foundation RDP Center and the European Commission (FP7 grant agreement #202224, European IPF Network). Other Funders: NIH.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Justus-Liebig University of Giessen.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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