| Critical role of CFTR-dependent lipid rafts in cigarette smoke-induced lung epithelial injury. | |
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MedLine Citation:
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PMID: 21378025 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Apoptosis of lung epithelial and endothelial cells by exposure to cigarette smoke (CS) severely damages the lung tissue, leading to the pathogenesis of emphysema, but the underlying mechanisms are poorly understood. We have recently established a direct correlation between decreased lipid raft CFTR expression and emphysema progression through increased ceramide accumulation. In the present work, we investigated the role of membrane CFTR in regulating apoptosis and autophagy responses to CS exposure. We report a constitutive and CS-induced increase in the number of TUNEL-positive apoptotic cells in Cftr(-/-) murine lungs compared with Cftr(+/+) murine lungs that also correlated with a concurrent increase in the expression of ceramide, NF-κB, CD95/Fas, lipid raft proteins, and zonula occludens (ZO)-1/2 (P < 0.001). We also verified that stable wild-type CFTR expression in CFBE41o(-) cells controls constitutively elevated caspase-3/7 activity (-1.6-fold, P < 0.001). Our data suggest that membrane CFTR regulates ceramide-enriched lipid raft signaling platforms required for the induction of Fas-mediated apoptotic signaling. In addition, lack of membrane CFTR also modulates autophagy, as demonstrated by the significant increase in constitutive (P < 0.001) and CSE-induced (P < 0.005) perinuclear accumulation of green fluorescent protein-microtubule-associated protein 1 light chain-3 (LC3) in the absence of membrane CFTR (CFBE41o(-) cells). The significant constitutive and CS-induced increase (P < 0.05) in p62 and LC3β expression in CFTR-deficient cells and mice corroborates these findings and suggest a defective autophagy response in the absence of membrane CFTR. Our data demonstrate the critical role of membrane-localized CFTR in regulating apoptotic and autophagic responses in CS-induced lung injury that may be involved in the pathogenesis of severe emphysema. |
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Authors:
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Manish Bodas; Taehong Min; Neeraj Vij |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-03-04 |
Journal Detail:
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Title: American journal of physiology. Lung cellular and molecular physiology Volume: 300 ISSN: 1522-1504 ISO Abbreviation: Am. J. Physiol. Lung Cell Mol. Physiol. Publication Date: 2011 Jun |
Date Detail:
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Created Date: 2011-06-03 Completed Date: 2011-08-11 Revised Date: 2011-09-26 |
Medline Journal Info:
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Nlm Unique ID: 100901229 Medline TA: Am J Physiol Lung Cell Mol Physiol Country: United States |
Other Details:
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Languages: eng Pagination: L811-20 Citation Subset: IM |
Affiliation:
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Department of Pediatric Respiratory Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis Autophagy Blotting, Western Caspase 3 / metabolism Caspase 7 / metabolism Cells, Cultured Ceramides / metabolism Cystic Fibrosis Transmembrane Conductance Regulator / metabolism* Fas Ligand Protein / metabolism Flow Cytometry Green Fluorescent Proteins / metabolism Humans In Situ Nick-End Labeling Lung Injury / etiology*, metabolism, pathology Membrane Microdomains / metabolism* Membrane Proteins / metabolism Mice Mice, Inbred CFTR Mice, Knockout NF-kappa B / metabolism Phosphoproteins / metabolism Smoking / adverse effects* |
| Grant Support | |
ID/Acronym/Agency:
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R03 HL096931-01/HL/NHLBI NIH HHS; R03 HL096931-02/HL/NHLBI NIH HHS; RHL-096931//PHS HHS; RR-025005/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Ceramides; 0/Fas Ligand Protein; 0/Membrane Proteins; 0/NF-kappa B; 0/Phosphoproteins; 0/enhanced green fluorescent protein; 0/zonula occludens-1 protein; 0/zonula occludens-2 protein; 126880-72-6/Cystic Fibrosis Transmembrane Conductance Regulator; 147336-22-9/Green Fluorescent Proteins; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 7 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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