Functional Wnt Signaling Is Increased in Idiopathic Pulmonary Fibrosis

BACKGROUND: Idiopathic 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/beta-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/beta-catenin signaling is activated in epithelial cells in IPF. Thus, we quantified and localized the expression and activity of the Wnt/beta-catenin pathway in IPF. METHODOLOGY/PRINCIPAL FINDINGS: The expression of Wnt1, 3a, 7b, and 10b, the Wnt receptors Fzd1-4, Lrp5-6, as well as the intracellular signal transducers Gsk-3beta, beta-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, beta-catenin, and Lef1 expression was significantly increased in IPF. Immunohistochemical analysis localized Wnt1, Wnt3a, beta-catenin, and Gsk-3beta 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-3beta, phospho-Lrp6, and beta-catenin, and qRT-PCR of the Wnt target genes cyclin D1, Mmp 7, or Fibronectin 1 demonstrated increased functional Wnt/beta-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/SIGNIFICANCE: Our study demonstrates that the Wnt/beta-catenin pathway is expressed and operative in adult lung epithelium. Increased Wnt/beta-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

Similarity of rocky intertidal assemblages along the Pacific coast of Japan : effects of spatial scales and geographic distance

Factors and processes affecting community structures operate at various spatial and temporal scales. We analyzed how similarities of rocky intertidal assemblages vary at different spatial scales using a nested, hierarchical sampling design. Intertidal assemblages consisting of algae, sessile animals, and mobile animals were censused on five rock walls at each of five shores chosen within each of six regions along the Pacific coast of Japan, encompassing 1,800 km of coastlines. Based on this sampling design, similarities in assemblages were calculated using both qualitative (presence/absence) and quantitative (percent cover and density) data, and compared at three spatial levels: (1) rock level (the finest spatial scale, encompassing several to hundreds of meters), (2) shore level (the intermediate spatial scale, encompassing several to tens of kilometers), and (3) region level (the broadest spatial scale, encompassing hundreds to thousands of kilometers). Cluster analysis showed that assemblages were categorized into distinct regional groups except for the two southern regions, but they did not separate clearly from each shore. A nested analysis of similarities revealed significant variation in similarities among regions and among shores within each region, with the former showing greater variation. Similarity was negatively correlated with geographic distance at the regional level but not at the shore or the rock levels. At the regional level, similarity decreased more rapidly with distance for mobile animals than sessile organisms. The analyses highlighted the importance of broad-scale abiotic/biotic factors such as oceanic current conditions and biogeographic factors in determining observed patterns in similarity of rocky intertidal assemblages