Document Detail


Defective organellar acidification as a cause of cystic fibrosis lung disease: reexamination of a recurring hypothesis.
MedLine Citation:
PMID:  19329540     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Peter M Haggie; A S Verkman
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Review     Date:  2009-03-27
Journal Detail:
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:
Created Date:  2009-05-29     Completed Date:  2009-07-16     Revised Date:  2014-09-12    
Medline Journal Info:
Nlm Unique ID:  100901229     Medline TA:  Am J Physiol Lung Cell Mol Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  L859-67     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Acid-Base Equilibrium / physiology
Acids / metabolism*
Animals
Cystic Fibrosis* / etiology,  metabolism,  pathology
Humans
Lung / metabolism*,  pathology
Organelles / metabolism*
Grant Support
ID/Acronym/Agency:
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/HL/NHLBI NIH HHS; R01 HL073856-08/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Acids
Comments/Corrections

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