Idiopathic pulmonary fibrosis (IPF) is a severe interstitial lung disease that causes destruction of the lungs architecture by accumulation of scar tissue. The prognosis of IPF is poor and currently the benefit of pharmaceutical treatment is very limited. The pathogenetic mechanisms underlying initiation and progression of the disease are still not completely elucidated and are subject of current investigations.An aberrant activation of the WNT/beta-catenin signaling pathway in the lung tissue of IPF patients has recently been reported and an inhibition of this signal transduction cascade was demonstrated to be able to attenuate bleomycin induced pulmonary fibrosis in mice.The present study focused on Dickkopf (DKK) proteins, potent modulators of the WNT/beta-catenin pathway. An antifibrotic effect of these proteins via inhibition of WNT/beta-catenin signaling has already been demonstrated in mouse models of other fibrosing diseases. However, the role of DKK proteins in IPF had not been addressed before. Therefore the aim of the present study was to investigate and to compare the expression and localization of DKK proteins and their receptors low density lipoprotein receptor-related protein (LRP) and Kremen (KRM) in the unaffected adult human lung and in IPF.By quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot analysis, DKK proteins as well as their LRP and KRM receptors were found expressed in unaffected donor and in IPF lung tissues, with a significantly enhanced expression of DKK1, DKK4 and KRM1 in the fibrotic lungs.Immunohistochemistry identified the bronchial epithelium of donors and IPF patients as well as hyperplastic alveolar epithelial cells of IPF patients as major sources for DKK proteins and their receptors in the lung tissue. A pronounced and distinct accumulation of DKK1 was observed in basal bronchial epithelial cells, one of the cell populations considered as epithelial progenitors.Additionally, an enhanced DKK1 protein content was detected in bronchoalveolar lavage fluids of IPF patients by an enzyme-linked immunosorbent assay (ELISA).Analysis of the human bronchial epithelial cell line BEAS-2B by qRT-PCR demonstrated that besides the DKK receptors, other key components of the WNT/beta-catenin signaling cascade can be expressed by human bronchial epithelial cells as well.Taken together, these data indicate an autocrine or paracrine mode of action for DKK at the bronchial epithelium.In summary, DKK proteins and their receptors are largely located in the lung epithelium and their expression is altered in IPF. Since an impairment of epithelial functions is a key feature of IPF, DKK proteins may be of interest for the understanding of IPF pathogenesis and for treatment strategies of this fatal lung disease.
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