Identifier to cite or link to this item: http://hdl.handle.net/20.500.13003/13725
Sustained CTL activation by murine pulmonary epithelial cells promotes the development of COPD-like disease
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DOI: 10.1172/JCI34462
ISSN: 0021-9738
eISSN: 1558-8238
WOS ID: 000263941000025
Scopus EID: 2-s2.0-65649102628
PMID: 19197141
Embase PUI: L354950164
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Borchers, Michael T.; Wesselkamper, Scott C.; Curull, Victor; Ramirez-Sarmiento, Alba; Sanchez-Font, Albert; Garcia-Aymerich, Judith; Coronell, Carios; Lloreta, Josep; Agusti, Alvar G.; Gea, Joaquim; Howington, John A.; Reed, Michael F.; Starnes, Sandra L.; Harris, Nathaniel L.; Vitucci, Mark; Eppert, Bryan L.; Motz, Gregory T.; Fogel, Kevin; McGraw, Dennis W.; Tichelaar, Jay W.; Orozco-Levi, MauricioPublication date
2009-03Document type
research articleCitation
Borchers Michael T., Wesselkamper Scott C., Curull Victor, Ramirez-Sarmiento Alba, Sanchez-Font Albert, Garcia-Aymerich Judith, et al. Sustained CTL activation by murine pulmonary epithelial cells promotes the development of COPD-like disease. J Clin Invest. 2009 Mar;119(3):636-649. Epub 2009 Feb 9.Abstract
Chronic obstructive pulmonary disease (COPD) is a lethal progressive lung disease culminating in permanent airway obstruction and alveolar enlargement. Previous studies suggest CTL involvement in COPD progression; however, their precise role remains unknown. Here, we investigated whether the CTL activation receptor NK cell group 2D (NKG2D) contributes to the development of COPD. Using primary murine lung epithelium isolated from mice chronically exposed to cigarette smoke and cultured epithelial cells exposed to cigarette smoke extract in vitro, we demonstrated induced expression of the NKG2D ligand retinoic acid early transcript 1 (RAET1) as well as NKG2D-mediated cytotoxicity. Furthermore, a genetic model of inducible RAET1 expression on mouse pulmonary epithelial cells yielded a severe emphysematous phenotype characterized by epithelial apoptosis and increased CTL activation, which was reversed by blocking NKG2D activation. We also assessed whether NKG2D ligand expression corresponded with pulmonary disease in human patients by staining airway and peripheral lung tissues from never smokers, smokers with normal lung function, and current and former smokers with COPD. NKG2D ligand expression was independent of NKG2D receptor expression in COPD patients, demonstrating that ligand expression is the limiting factor in CTL activation. These results demonstrate that aberrant, persistent NKG2D ligand expression in the pulmonary epithelium contributes to the development of COPD pathologies.
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https://dx.doi.org/10.1172/JCI34462MeSH
EmphysemaPulmonary Disease, Chronic Obstructive
Smoke
Gene Expression Regulation
Smoking
Respiratory Mucosa
Lymphocyte Activation
Membrane Proteins
Disease Models, Animal
Killer Cells, Natural
Lung
Animals
CD8-Positive T-Lymphocytes
NK Cell Lectin-Like Receptor Subfamily K
Mice
DeCS
Linfocitos T CD8-positivosAnimales
Mucosa Respiratoria
Células Asesinas Naturales
Pulmón
Activación de Linfocitos
Proteínas de la Membrana
Modelos Animales de Enfermedad
Regulación de la Expresión Génica
Subfamilia K de Receptores Similares a Lectina de Células NK
Humo
Fumar
Enfermedad Pulmonar Obstructiva Crónica
Enfisema
Ratones