Microarray analysis reveals NFIB as a potential target of the matricellular protein WISP1 in alveolar epithelial cells in idiopathic pulmonary fibrosis

Rationale: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease, characterized by loss of respiratory function. Alveolar epithelial cell (AEC) hyperplasia, distorted epithelial-mesenchymal crosstalk, and enhanced extracellular matrix deposition by (myo)fibroblasts are key features of IPF. Previously, we identified the matricellular protein WISP1 as a profibrotic regulator in hyperplastic AEC in IPF and potential target for therapeutic intervention. Here, we sought to identify signal molecules involved in WISP1 function.

Methods and Results: A whole genome microarray analysis was performed in human primary AEC stimulated for different time points with WISP1 (8 or 24h). The microarray analysis revealed 179 and 229 genes to be significantly regulated by WISP1 after 8h and 24h, respectively. Among these, the nuclear factor (NF) IB protein, a member of the NFI family of transcription factors known to control cellular differentiation, was identified and confirmed by quantitative real-time (qRT)-PCR. NFIB was highly regulated on both the mRNA and protein level in IPF as analysed by qRT-PCR and Western Blot analysis. Immunohistochemical analysis demonstrated that NFIB was expressed largely in alveolar epithelial type II cells in lung tissue from donor and IPF patients.

Conclusion: Taken together, our microarray analysis of WISP1-stimulated primary AEC revealed novel genes, which may be mediators of WISP1-dependent regulation of AEC proliferation and motility. The dysregulation of NFIB in IPF indicates that this candidate protein may contribute to the development of IPF.