| Defective organellar acidification as a cause of cystic fibrosis lung disease: reexamination of a recurring hypothesis. | |
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MedLine Citation:
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PMID: 19329540 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The cellular mechanisms by which loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel produce cystic fibrosis (CF) lung disease remain uncertain. Defective organellar function has been proposed as an important determinant in the pathogenesis of CF lung disease. According to one hypothesis, reduced CFTR chloride conductance in organelles in CF impairs their acidification by preventing chloride entry into the organelle lumen, which is needed to balance the positive charge produced by proton entry. According to a different hypothesis, CFTR mutation hyperacidifies organelles by an indirect mechanism involving unregulated sodium efflux through epithelial sodium channels. There are reports of defective Golgi, endosomal and lysosomal acidification in CF epithelial cells, defective phagolysosomal acidification in CF alveolar macrophages, and organellar hyperacidification in CF respiratory epithelial cells. The common theme relating too high or low organellar pH to cellular dysfunction and CF pathogenesis is impaired functioning of organellar enzymes, such as those involved in ceramide metabolism and protein processing in epithelial cells and antimicrobial activity in alveolar macrophages. We review here the evidence for defective organellar acidification in CF. Significant technical and conceptual concerns are discussed regarding the validity of data showing too high/low organellar pH in CF cells, and rigorous measurements of organellar pH in CF cells are reviewed that fail to support defective organellar acidification in CF. Indeed, there is an expanding body of evidence supporting the involvement of non-CFTR chloride channels in organellar acidification. We conclude that biologically significant involvement of CFTR in organellar acidification is unlikely. |
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Authors:
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Peter M Haggie; A S Verkman |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Review Date: 2009-03-27 |
Journal Detail:
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Title: American journal of physiology. Lung cellular and molecular physiology Volume: 296 ISSN: 1040-0605 ISO Abbreviation: Am. J. Physiol. Lung Cell Mol. Physiol. Publication Date: 2009 Jun |
Date Detail:
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Created Date: 2009-05-29 Completed Date: 2009-07-16 Revised Date: 2010-09-23 |
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: L859-67 Citation Subset: IM |
Affiliation:
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1246 Health Sciences East Tower, Box 0521, Univ. of California, San Francisco, San Francisco, CA 94143-0521, USA. peter.haggie@ucsf.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acid-Base Equilibrium
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physiology Acids / metabolism* Animals Cystic Fibrosis* / etiology, metabolism, pathology Humans Lung / metabolism*, pathology Organelles / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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DK-35124/DK/NIDDK NIH HHS; DK-72517/DK/NIDDK NIH HHS; DK-81355/DK/NIDDK NIH HHS; EB-00415/EB/NIBIB NIH HHS; EY-13574/EY/NEI NIH HHS; HL-59198/HL/NHLBI NIH HHS; HL-73856/HL/NHLBI NIH HHS; R01 HL073856-08/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Acids |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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