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Reduced frizzled receptor 4 expression prevents WNT/b-catenin-driven alveolar lung repair in chronic obstructive pulmonary disease

Skronska-Wasek, Wioletta; Mutze, Kathrin; Baarsma, Hoeke A.; Bracke, Ken R.; Alsafadi, Hani N.; Lehmann, Mareike; Costa, Ana Rita; Stornaiuolo, Mariano; Novellino, Ettore and Brusselle, Guy, et al. (2017) In American Journal of Respiratory and Critical Care Medicine 196(2). p.172-185
Abstract

Rationale: Chronic obstructive pulmonary disease (COPD), in particular emphysema, is characterized by loss of parenchymal alveolar tissue and impaired tissue repair. Wingless and INT-1 (WNT)/b-catenin signaling is reduced in COPD; however, the mechanisms thereof, specifically the role of the frizzled (FZD) family of WNT receptors, remain unexplored. Objectives: To identify and functionally characterize specific FZD receptors that control downstream WNT signaling in impaired lung repair in COPD. Methods: FZD expression was analyzed in lung homogenates and alveolar epithelial type II (ATII) cells of never-smokers, smokers, patients with COPD, and two experimental COPD models by quantitative reverse transcriptase-polymerase chain reaction,... (More)

Rationale: Chronic obstructive pulmonary disease (COPD), in particular emphysema, is characterized by loss of parenchymal alveolar tissue and impaired tissue repair. Wingless and INT-1 (WNT)/b-catenin signaling is reduced in COPD; however, the mechanisms thereof, specifically the role of the frizzled (FZD) family of WNT receptors, remain unexplored. Objectives: To identify and functionally characterize specific FZD receptors that control downstream WNT signaling in impaired lung repair in COPD. Methods: FZD expression was analyzed in lung homogenates and alveolar epithelial type II (ATII) cells of never-smokers, smokers, patients with COPD, and two experimental COPD models by quantitative reverse transcriptase-polymerase chain reaction, immunoblotting, and immunofluorescence. The functional effects of cigarette smoke on FZD4, WNT/b-catenin signaling, and elastogenic components were investigated in primary ATII cells in vitro and in three-dimensional lung tissue cultures ex vivo. Gain- and loss-of-function approaches were applied to determinethe effects of FZD4 signaling on alveolar epithelial cell wound healing and repair, as well as on expression of elastogenic components. Measurements and Main Results: FZD4 expression was reduced in human and experimental COPD lung tissues as well as in primary human ATII cells from patients with COPD. Cigarette smoke exposure down-regulated FZD4 expression in vitro and in vivo, along with reduced WNT/b-catenin activity. Inhibition of FZD4 decreased WNT/b-catenin-driven epithelial cell proliferation and wound closure, and it interfered with ATII-to-ATI cell transdifferentiation and organoid formation, which were augmented by FZD4 overexpression. Moreover, FZD4 restoration by overexpression or pharmacological induction led to induction of WNT/b-catenin signaling and expression of elastogenic components in threedimensional lung tissue cultures ex vivo. Conclusions: Reduced FZD4 expression in COPD contributes to impaired alveolar repair capacity.

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type
Contribution to journal
publication status
published
keywords
Cigarette smoke, Emphysema, Frizzled 4 receptor, Regeneration, Smoking
in
American Journal of Respiratory and Critical Care Medicine
volume
196
issue
2
pages
14 pages
publisher
Am Thoracic Soc
external identifiers
  • scopus:85025168120
ISSN
1073-449X
DOI
10.1164/rccm.201605-0904OC
language
English
LU publication?
no
id
604d1428-4e80-458a-a92c-bdbc90665997
date added to LUP
2017-08-15 14:34:32
date last changed
2017-08-24 15:20:08
@article{604d1428-4e80-458a-a92c-bdbc90665997,
  abstract     = {<p>Rationale: Chronic obstructive pulmonary disease (COPD), in particular emphysema, is characterized by loss of parenchymal alveolar tissue and impaired tissue repair. Wingless and INT-1 (WNT)/b-catenin signaling is reduced in COPD; however, the mechanisms thereof, specifically the role of the frizzled (FZD) family of WNT receptors, remain unexplored. Objectives: To identify and functionally characterize specific FZD receptors that control downstream WNT signaling in impaired lung repair in COPD. Methods: FZD expression was analyzed in lung homogenates and alveolar epithelial type II (ATII) cells of never-smokers, smokers, patients with COPD, and two experimental COPD models by quantitative reverse transcriptase-polymerase chain reaction, immunoblotting, and immunofluorescence. The functional effects of cigarette smoke on FZD4, WNT/b-catenin signaling, and elastogenic components were investigated in primary ATII cells in vitro and in three-dimensional lung tissue cultures ex vivo. Gain- and loss-of-function approaches were applied to determinethe effects of FZD4 signaling on alveolar epithelial cell wound healing and repair, as well as on expression of elastogenic components. Measurements and Main Results: FZD4 expression was reduced in human and experimental COPD lung tissues as well as in primary human ATII cells from patients with COPD. Cigarette smoke exposure down-regulated FZD4 expression in vitro and in vivo, along with reduced WNT/b-catenin activity. Inhibition of FZD4 decreased WNT/b-catenin-driven epithelial cell proliferation and wound closure, and it interfered with ATII-to-ATI cell transdifferentiation and organoid formation, which were augmented by FZD4 overexpression. Moreover, FZD4 restoration by overexpression or pharmacological induction led to induction of WNT/b-catenin signaling and expression of elastogenic components in threedimensional lung tissue cultures ex vivo. Conclusions: Reduced FZD4 expression in COPD contributes to impaired alveolar repair capacity.</p>},
  author       = {Skronska-Wasek, Wioletta and Mutze, Kathrin and Baarsma, Hoeke A. and Bracke, Ken R. and Alsafadi, Hani N. and Lehmann, Mareike and Costa, Ana Rita and Stornaiuolo, Mariano and Novellino, Ettore and Brusselle, Guy and Wagner, Darcy E. and Yildirim, Ali O and Königshoff, Melanie},
  issn         = {1073-449X},
  keyword      = {Cigarette smoke,Emphysema,Frizzled 4 receptor,Regeneration,Smoking},
  language     = {eng},
  month        = {07},
  number       = {2},
  pages        = {172--185},
  publisher    = {Am Thoracic Soc},
  series       = {American Journal of Respiratory and Critical Care Medicine},
  title        = {Reduced frizzled receptor 4 expression prevents WNT/b-catenin-driven alveolar lung repair in chronic obstructive pulmonary disease},
  url          = {http://dx.doi.org/10.1164/rccm.201605-0904OC},
  volume       = {196},
  year         = {2017},
}