Ectopic respiratory epithelial cell differentiation in bronchiolised distal airspaces in idiopathic pulmonary fibrosis

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 NRG1 alpha and NRG1 beta. 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). NRG1 alpha and NRG1 beta 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. NRG1 alpha 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. NRG1 alpha 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. NRG1 alpha may contribute to bronchiolisation of the distal lung seen in IPF.