Functional Wnt signaling is increased in idiopathic pulmonary fibrosis.

<h4>Background</h4>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 fea...

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Autores principales:	Melanie Königshoff, Nisha Balsara, Eva-Maria Pfaff, Monika Kramer, Izabella Chrobak, Werner Seeger, Oliver Eickelberg
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2008
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1b1e0f42b743467f9b13ad1574ed014a
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spelling	oai:doaj.org-article:1b1e0f42b743467f9b13ad1574ed014a2021-11-25T06:12:29ZFunctional Wnt signaling is increased in idiopathic pulmonary fibrosis.1932-620310.1371/journal.pone.0002142https://doaj.org/article/1b1e0f42b743467f9b13ad1574ed014a2008-05-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18478089/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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.Melanie KönigshoffNisha BalsaraEva-Maria PfaffMonika KramerIzabella ChrobakWerner SeegerOliver EickelbergPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 3, Iss 5, p e2142 (2008)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Melanie Königshoff Nisha Balsara Eva-Maria Pfaff Monika Kramer Izabella Chrobak Werner Seeger Oliver Eickelberg Functional Wnt signaling is increased in idiopathic pulmonary fibrosis.
description	<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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.
format	article
author	Melanie Königshoff Nisha Balsara Eva-Maria Pfaff Monika Kramer Izabella Chrobak Werner Seeger Oliver Eickelberg
author_facet	Melanie Königshoff Nisha Balsara Eva-Maria Pfaff Monika Kramer Izabella Chrobak Werner Seeger Oliver Eickelberg
author_sort	Melanie Königshoff
title	Functional Wnt signaling is increased in idiopathic pulmonary fibrosis.
title_short	Functional Wnt signaling is increased in idiopathic pulmonary fibrosis.
title_full	Functional Wnt signaling is increased in idiopathic pulmonary fibrosis.
title_fullStr	Functional Wnt signaling is increased in idiopathic pulmonary fibrosis.
title_full_unstemmed	Functional Wnt signaling is increased in idiopathic pulmonary fibrosis.
title_sort	functional wnt signaling is increased in idiopathic pulmonary fibrosis.
publisher	Public Library of Science (PLoS)
publishDate	2008
url	https://doaj.org/article/1b1e0f42b743467f9b13ad1574ed014a
work_keys_str_mv	AT melaniekonigshoff functionalwntsignalingisincreasedinidiopathicpulmonaryfibrosis AT nishabalsara functionalwntsignalingisincreasedinidiopathicpulmonaryfibrosis AT evamariapfaff functionalwntsignalingisincreasedinidiopathicpulmonaryfibrosis AT monikakramer functionalwntsignalingisincreasedinidiopathicpulmonaryfibrosis AT izabellachrobak functionalwntsignalingisincreasedinidiopathicpulmonaryfibrosis AT wernerseeger functionalwntsignalingisincreasedinidiopathicpulmonaryfibrosis AT olivereickelberg functionalwntsignalingisincreasedinidiopathicpulmonaryfibrosis
_version_	1718414028660801536

Functional Wnt signaling is increased in idiopathic pulmonary fibrosis.

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