Wnt-inducible protein (WISP-1) is a key regulator of alveolar epithelial cell hyperplasia in pulmonary fibrosis
Fibrotic lung disease is characterized by distorted lung architecture and severe loss of respiratory function secondary to alveolar epithelial cell (AEC) hyperplasia, enhanced extracellular matrix (ECM) deposition and fibroblast proliferation. Repetitive epithelial injuries with impaired alveolar wo...
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European Respiratory Society
2006-12-01
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doaj-5f655deb6c9f4f8d87d90c6156f519602020-11-25T02:02:38ZengEuropean Respiratory SocietyEuropean Respiratory Review0905-91801600-06172006-12-0115101180181Wnt-inducible protein (WISP-1) is a key regulator of alveolar epithelial cell hyperplasia in pulmonary fibrosisMelanie KönigshoffJochen WilhelmAndreas JahnOana AmarieKamila KitowskaAnke WilhelmRainer. M. BohleWerner SeegerFrank RoseLudger FinkAndreas GuentherOliver EickelbergFibrotic lung disease is characterized by distorted lung architecture and severe loss of respiratory function secondary to alveolar epithelial cell (AEC) hyperplasia, enhanced extracellular matrix (ECM) deposition and fibroblast proliferation. Repetitive epithelial injuries with impaired alveolar wound healing and altered AEC gene expression represent a trigger mechanism for development of fibrosis. To reveal gene regulatory networks in lung fibrosis, we compared gene expression profiles of freshly isolated AEC obtained from mice 14 days after saline or bleomycin (BM) instillation using whole genome microarray analysis. Several genes of the Wnt signaling pathway, in particular WISP-1, a member of the CCN family, were highly regulated. WISP-1 protein expression was demonstrated in proliferating AEC in BM-treated lungs by immunofluorescence. When analyzing all six CCN family members, WISP-1 was upregulated the most 14 days after BM challenge, as analyzed by qRT-PCR. To elucidate WISP-1 function, cultured primary mouse AEC were stimulated with WISP-1 and demonstrated a 230% increase in proliferation, analyzed by 3H-thymidine incorporation. This was mediated through enhanced phosphorylation, but not expression of protein kinase B (PKB/Akt), as detected by immunoblot. Finally, increased expression of WISP-1 was detected in lung homogenates and isolated AEC from IPF patients, using qRT-PCR. Immunohistochemical analysis of WISP-1 and Ki67 verified the existence of hyperplastic and proliferative AEC expressing WISP-1 in vivo. Our study thus identifies WISP-1 as a novel regulator of AEC injury and repair, and suggests that WISP-1 is a key mediator in pulmonary fibrosis. http://err.ersjournals.com/cgi/content/full/15/101/180 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Melanie Königshoff Jochen Wilhelm Andreas Jahn Oana Amarie Kamila Kitowska Anke Wilhelm Rainer. M. Bohle Werner Seeger Frank Rose Ludger Fink Andreas Guenther Oliver Eickelberg |
spellingShingle |
Melanie Königshoff Jochen Wilhelm Andreas Jahn Oana Amarie Kamila Kitowska Anke Wilhelm Rainer. M. Bohle Werner Seeger Frank Rose Ludger Fink Andreas Guenther Oliver Eickelberg Wnt-inducible protein (WISP-1) is a key regulator of alveolar epithelial cell hyperplasia in pulmonary fibrosis European Respiratory Review |
author_facet |
Melanie Königshoff Jochen Wilhelm Andreas Jahn Oana Amarie Kamila Kitowska Anke Wilhelm Rainer. M. Bohle Werner Seeger Frank Rose Ludger Fink Andreas Guenther Oliver Eickelberg |
author_sort |
Melanie Königshoff |
title |
Wnt-inducible protein (WISP-1) is a key regulator of alveolar epithelial cell hyperplasia in pulmonary fibrosis |
title_short |
Wnt-inducible protein (WISP-1) is a key regulator of alveolar epithelial cell hyperplasia in pulmonary fibrosis |
title_full |
Wnt-inducible protein (WISP-1) is a key regulator of alveolar epithelial cell hyperplasia in pulmonary fibrosis |
title_fullStr |
Wnt-inducible protein (WISP-1) is a key regulator of alveolar epithelial cell hyperplasia in pulmonary fibrosis |
title_full_unstemmed |
Wnt-inducible protein (WISP-1) is a key regulator of alveolar epithelial cell hyperplasia in pulmonary fibrosis |
title_sort |
wnt-inducible protein (wisp-1) is a key regulator of alveolar epithelial cell hyperplasia in pulmonary fibrosis |
publisher |
European Respiratory Society |
series |
European Respiratory Review |
issn |
0905-9180 1600-0617 |
publishDate |
2006-12-01 |
description |
Fibrotic lung disease is characterized by distorted lung architecture and severe loss of respiratory function secondary to alveolar epithelial cell (AEC) hyperplasia, enhanced extracellular matrix (ECM) deposition and fibroblast proliferation. Repetitive epithelial injuries with impaired alveolar wound healing and altered AEC gene expression represent a trigger mechanism for development of fibrosis. To reveal gene regulatory networks in lung fibrosis, we compared gene expression profiles of freshly isolated AEC obtained from mice 14 days after saline or bleomycin (BM) instillation using whole genome microarray analysis. Several genes of the Wnt signaling pathway, in particular WISP-1, a member of the CCN family, were highly regulated. WISP-1 protein expression was demonstrated in proliferating AEC in BM-treated lungs by immunofluorescence. When analyzing all six CCN family members, WISP-1 was upregulated the most 14 days after BM challenge, as analyzed by qRT-PCR. To elucidate WISP-1 function, cultured primary mouse AEC were stimulated with WISP-1 and demonstrated a 230% increase in proliferation, analyzed by 3H-thymidine incorporation. This was mediated through enhanced phosphorylation, but not expression of protein kinase B (PKB/Akt), as detected by immunoblot. Finally, increased expression of WISP-1 was detected in lung homogenates and isolated AEC from IPF patients, using qRT-PCR. Immunohistochemical analysis of WISP-1 and Ki67 verified the existence of hyperplastic and proliferative AEC expressing WISP-1 in vivo. Our study thus identifies WISP-1 as a novel regulator of AEC injury and repair, and suggests that WISP-1 is a key mediator in pulmonary fibrosis. |
url |
http://err.ersjournals.com/cgi/content/full/15/101/180 |
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