Pneumologie 2010; 64 - A45
DOI: 10.1055/s-0029-1247942

Dickkopf proteins influence lung epithelial cell proliferation in idiopathic pulmonary fibrosis

EM Pfaff 1, S Becker 1, A Guenther 1, O Eickelberg 2, M Königshoff 2
  • 1Department of Medicine, University of Gießen Lung Center, University of Gießen, Gießen, Germany
  • 2Comprehensive Pneumology Center, Ludwig-Maximilians-University, Asklepios Hospital, and Helmholtz Zentrum München, Institute of Lung Biology and Disease (iLBD), Neuherberg/Munich, Germany

Rationale: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with unknown pathogenesis. The WNT/β-catenin pathway has recently been reported to be operative in epithelial cells in IPF. Dickkopf (DKK) proteins are known to regulate WNT signaling via interaction with Kremen (KRM) receptors, yet their expression and role in the adult lung and in IPF has not been addressed. Methods: We analyzed the expression, localization, and function of DKK and KRM proteins in IPF lungs using western blotting, quantitative RT-PCR, immunohistochemistry, ELISA, and functional in vitro studies. Results: Enhanced expression of DKK1 and 4 and KRM1 was detected in lung homogenates of IPF patients compared with transplant donors. Immunohistochemistry revealed that DKK1 was predominantly localized in basal bronchial epithelial cells. Furthermore, prominent expression of all proteins was observed in hyperplastic alveolar epithelial cells in IPF. Quantification of DKK1 protein in bronchoalveolar lavage fluids corroborated enhanced epithelial secretion of DKK1 in IPF. Finally, functional studies using human bronchial and alveolar epithelial cells demonstrated that WNT-induced epithelial cell proliferation is regulated by DKK1 in a dose-dependent fashion. Conclusion: In sum, DKK proteins are expressed in the lung epithelium in IPF. DKK proteins influence epithelial cell proliferation and may therefore be suitable therapeutic targets for IPF.