Abstract
BackgroundIdiopathic pulmonary fibrosis (IPF) is a fatal lung disease, characterized by distorted lung architecture and loss of respiratory function. Alveolar epithelial cell injury and hyperplasia, enhanced extracellular matrix deposition, and (myo)fibroblast activation are features of IPF. Wnt/β-catenin signaling has been shown to determine epithelial cell fate during development. As aberrant reactivation of developmental signaling pathways has been suggested to contribute to IPF pathogenesis, we hypothesized that Wnt/β-catenin signaling is activated in epithelial cells in IPF. Thus, we quantified and localized the expression and activity of the Wnt/β-catenin pathway in IPF.Methodology/Principal FindingsThe expression of Wnt1, 3a, 7b, and 10b, the Wnt receptors Fzd1-4, Lrp5-6, as well as the intracellular signal transducers Gsk-3β, β-catenin, Tcf1, 3, 4, and Lef1 was analyzed in IPF and transplant donor lungs by quantitative real-time (q)RT-PCR. Wnt1, 7b and 10b, Fzd2 and 3, β-catenin, and Lef1 expression was significantly increased in IPF. Immunohistochemical analysis localized Wnt1, Wnt3a, β-catenin, and Gsk-3β expression largely to alveolar and bronchial epithelium. This was confirmed by qRT-PCR of primary alveolar epithelial type II (ATII) cells, demonstrating a significant increase of Wnt signaling in ATII cells derived from IPF patients. In addition, Western blot analysis of phospho-Gsk-3β, phospho-Lrp6, and β-catenin, and qRT-PCR of the Wnt target genes cyclin D1, Mmp 7, or Fibronectin 1 demonstrated increased functional Wnt/β-catenin signaling in IPF compared with controls. Functional in vitro studies further revealed that Wnt ligands induced lung epithelial cell proliferation and (myo)fibroblast activation and collagen synthesis.Conclusions/SignificanceOur study demonstrates that the Wnt/β-catenin pathway is expressed and operative in adult lung epithelium. Increased Wnt/β-catenin signaling may be involved in epithelial cell injury and hyperplasia, as well as impaired epithelial-mesenchymal cross-talk in IPF. Thus, modification of Wnt signaling may represent a therapeutic option in IPF.
Highlights
Pulmonary fibrosis can result from a variety of causes, including lung injury, environmental particle and toxin inhalation, chemotherapy, systemic autoimmune diseases, or as an idiopathic entity in form of idiopathic interstitial pneumonias (IIP) [1,2,3,4]
Fibroblast foci occur in subepithelial layers, close to areas of alveolar epithelial cell injury and repair, suggesting that impaired epithelial-mesenchymal crosstalk contributes to the pathobiology of Idiopathic pulmonary fibrosis (IPF) [8,9]
We observed significantly increased mRNA levels of the receptor Fzd3 and the intracellular signaling molecules glycogen synthase kinase (Gsk)-3b, b-catenin, and Lef1 in IPF alveolar epithelial type II (ATII) cells (Figure 6b and 6c, respectively)
Summary
Pulmonary fibrosis can result from a variety of causes, including lung injury, environmental particle and toxin inhalation, chemotherapy, systemic autoimmune diseases, or as an idiopathic entity in form of idiopathic interstitial pneumonias (IIP) [1,2,3,4]. Distortion of the normal lung architecture in IPF is evident by temporo-spatially heterogeneous histology, including areas of normal parenchyma, mild interstitial inflammation due to mononuclear infiltrates, septal fibrosis with subepithelial fibroblast foci, and honeycombing [6,7]. Fibroblast foci occur in subepithelial layers, close to areas of alveolar epithelial cell injury and repair, suggesting that impaired epithelial-mesenchymal crosstalk contributes to the pathobiology of IPF [8,9]. It is well accepted that repetitive injury and subsequent repair of alveolar epithelial type II (ATII) cells, in the presence or absence of local inflammation, represent a key pathogenic mechanism in IPF, which leads to aberrant growth factor activation and perpetuation of fibrotic transformation [10]. We quantified and localized the expression and activity of the Wnt/b-catenin pathway in IPF
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