期刊
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
卷 183, 期 6, 页码 723-733出版社
AMER THORACIC SOC
DOI: 10.1164/rccm.200910-1560OC
关键词
chronic obstructive pulmonary disease; emphysema; WNT; lung development
资金
- German Research Foundation (DFG) Excellence Cluster Cardiopulmonary System (ECCPS)
- School of Medicine, Justus-Liebig-University Giessen, Giessen, Germany
- Helmholtz Research Center of Environmental Health, Munich, Germany
- AstraZeneca
- GlaxoSmithKline
- Novartis
- UCB
- Boehringer Ingelheim
- Pfizer
- Solvay
- Ergonex
- Actelion
- Bayer-Schering
- Gilead
- Roche
- Bayer
- Ergonex Pharma
- Helmholtz Society
- German Research Foundation
- European Union
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.
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