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Activation of the WNT/β-catenin pathway attenuates experimental emphysema

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Abstract
Rationale: Chronic obstructive pulmonary disease (COPD) is a devastating disease, for which no causal therapy is available. Objectives: To characterize WNT/beta-catenin signaling in COPD in humans and elucidate its potential role as a preventive and therapeutic target in experimental emphysema in mice. Methods: The expression, localization, and activity of WNT/beta-catenin signaling was assessed in 12 COPD and 12 transplant donor samples using quantitative reverse transcriptase polymerase chain reaction, immunohistochemistry, and Western blotting. The role of WNT/beta-catenin signaling was assessed in elastase- and cigarette smoke induced emphysema and therapeutic modulation thereof in elastase-induced emphysema in TOPGAL reporter and wild-type mice in vivo. Measurements and Main Results: No differences in the mRNA expression profile of the main WNT/beta-catenin signaling components were observed comparing COPD and donor lung homogenates. Immunohistochemical analysis revealed reduced numbers of nuclear beta-catenin positive alveolar epithelial cells in COPD. Similarly, WNT/beta-catenin signaling was down-regulated in both experimental emphysema models. Preventive and therapeutic, WNT/beta-catenin activation by lithium chloride attenuated experimental emphysema, as assessed by decreased airspace enlargement, improved lung function, reduced collagen content, and elevated expression of alveolar epithelial cell markers. Conclusions: Decreased WNT/beta-catenin signaling is involved in parenchymal tissue destruction and impaired repair capacity in emphysema. These data indicate a crucial role of WNT/beta-catenin signaling in lung repair mechanisms in vivo, and highlight WNT/beta-catenin activation as a future therapeutic approach for emphysema.
Keywords
REPAIR, MECHANISMS, FIBROSIS, NATURAL-HISTORY, BETA-CATENIN, LUNG-CANCER, STEM-CELLS, WNT SIGNALING PATHWAY, OBSTRUCTIVE PULMONARY-DISEASE, lung development, WNT, emphysema, DEATH, chronic obstructive pulmonary disease

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Citation

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Chicago
Kneidinger, Nikolaus, Ali Oender Yildirim, Lens Callegari, Shinji Takenaka, Maria Magdalena Stein, Rio Dumitrascu, Alexander Bohla, et al. 2011. “Activation of the WNT/β-catenin Pathway Attenuates Experimental Emphysema.” American Journal of Respiratory and Critical Care Medicine 183 (6): 723–733.
APA
Kneidinger, N., Yildirim, A. O., Callegari, L., Takenaka, S., Stein, M. M., Dumitrascu, R., Bohla, A., et al. (2011). Activation of the WNT/β-catenin pathway attenuates experimental emphysema. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 183(6), 723–733.
Vancouver
1.
Kneidinger N, Yildirim AO, Callegari L, Takenaka S, Stein MM, Dumitrascu R, et al. Activation of the WNT/β-catenin pathway attenuates experimental emphysema. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE. 2011;183(6):723–33.
MLA
Kneidinger, Nikolaus, Ali Oender Yildirim, Lens Callegari, et al. “Activation of the WNT/β-catenin Pathway Attenuates Experimental Emphysema.” AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 183.6 (2011): 723–733. Print.
@article{1852890,
  abstract     = {Rationale: Chronic obstructive pulmonary disease (COPD) is a devastating disease, for which no causal therapy is available. Objectives: To characterize WNT/beta-catenin signaling in COPD in humans and elucidate its potential role as a preventive and therapeutic target in experimental emphysema in mice. Methods: The expression, localization, and activity of WNT/beta-catenin signaling was assessed in 12 COPD and 12 transplant donor samples using quantitative reverse transcriptase polymerase chain reaction, immunohistochemistry, and Western blotting. The role of WNT/beta-catenin signaling was assessed in elastase- and cigarette smoke induced emphysema and therapeutic modulation thereof in elastase-induced emphysema in TOPGAL reporter and wild-type mice in vivo. Measurements and Main Results: No differences in the mRNA expression profile of the main WNT/beta-catenin signaling components were observed comparing COPD and donor lung homogenates. Immunohistochemical analysis revealed reduced numbers of nuclear beta-catenin positive alveolar epithelial cells in COPD. Similarly, WNT/beta-catenin signaling was down-regulated in both experimental emphysema models. Preventive and therapeutic, WNT/beta-catenin activation by lithium chloride attenuated experimental emphysema, as assessed by decreased airspace enlargement, improved lung function, reduced collagen content, and elevated expression of alveolar epithelial cell markers. Conclusions: Decreased WNT/beta-catenin signaling is involved in parenchymal tissue destruction and impaired repair capacity in emphysema. These data indicate a crucial role of WNT/beta-catenin signaling in lung repair mechanisms in vivo, and highlight WNT/beta-catenin activation as a future therapeutic approach for emphysema.},
  author       = {Kneidinger, Nikolaus and Yildirim, Ali Oender and Callegari, Lens and Takenaka, Shinji and Stein, Maria Magdalena and Dumitrascu, Rio and Bohla, Alexander and Bracke, Ken and Morty, Rory E and Brusselle, Guy and Schermuly, Ralph Theo and Eickelberg, Oliver and Konigshoff, Melanie},
  issn         = {1073-449X},
  journal      = {AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE},
  keywords     = {REPAIR,MECHANISMS,FIBROSIS,NATURAL-HISTORY,BETA-CATENIN,LUNG-CANCER,STEM-CELLS,WNT SIGNALING PATHWAY,OBSTRUCTIVE PULMONARY-DISEASE,lung development,WNT,emphysema,DEATH,chronic obstructive pulmonary disease},
  language     = {eng},
  number       = {6},
  pages        = {723--733},
  title        = {Activation of the WNT/β-catenin pathway attenuates experimental emphysema},
  url          = {http://dx.doi.org/10.1164/rccm.200910-1560OC},
  volume       = {183},
  year         = {2011},
}

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