WISP1: A novel regulator of idiopathic pulmonary fibrosis amenable to therapeutic intervention

Idiopathic pulmonary fibrosis (IPF) is a devastating disease, characterized by severe loss of respiratory function due to enhanced extracellular matrix (ECM) deposition and (myo)fibroblast proliferation. Repetitive epithelial injuries with impaired alveolar wound healing represent a trigger mechanism for development of fibrosis, but molecular mechanisms linking alveolar epithelial cell (AEC) repair with development of fibrosis are poorly understood. Using whole genome microarrays, we report altered gene expression profiles of AEC derived from mice with lung fibrosis. In particular, we demonstrate that WISP1 (CCN4/Wnt-inducible signalling protein) RNA and protein expression is highly upregulated in experimental lung fibrosis and lungs of IPF patients. WISP1 protein expression localized to hyperplastic AEC in vitro and in vivo. WISP1 treatment of primary AEC resulted in increased AEC proliferation, mediated by enhanced phosphorylation, but not expression, of protein kinase B (PKB/Akt). WISP1 induced epithelial-to-mesenchymal transition (EMT) and the expression of the profibrotic markers Spp1, Pai1, and Mmp7 in primary AEC, as assessed by qRT-PCR and immunhistochemistry. Depletion of WISP1 (using neutralizing antibodies) in vivo resulted in marked attenuation of bleomycin-induced lung fibrosis and improved survival in vivo, as assessed by histological analysis, flat-panel volumetric computed tomography, lung function, and collagen abundance (Sircoll assay). WISP1 depletion also reduced profibrotic marker gene expression, collagen deposition, and EMT. In sum, our study uncovered WISP1 as a novel regulator of profibrotic pathomechansims in hyperplastic AEC in vitro and in vivo, and presents WISP1 as a potential tool for therapeutic intervention in pulmonary fibrosis.