Document Detail

Activation of the heat shock response attenuates the interleukin 1β-mediated inhibition of the amiloride-sensitive alveolar epithelial ion transport.
MedLine Citation:
PMID:  23324889     Owner:  NLM     Status:  MEDLINE    
Acute lung injury (ALI) is a clinical syndrome characterized by hypoxia, which is caused by the breakdown of the alveolar capillary barrier. Interleukin 1β (IL-1β), a cytokine released within the airspace in ALI, downregulates the α subunit of the epithelial sodium channel (αENaC) transcription and protein expression via p38 MAP kinase-dependent signaling. Although induction of the heat shock response can restore alveolar fluid clearance compromised by IL-1β following the onset of severe hemorrhagic shock in rats, the mechanisms are not fully understood. In this study, we report that the induction of the heat shock response prevents IL-1β-dependent inhibition of αENaC mRNA expression and subsequent channel function. Heat shock results in IRAK1 detergent insolubility and a disruption of Hsp90 binding to IRAK1. Likewise, TAK1, another client protein of Hsp90 and signaling component of the IL-1β pathway, is also detergent insoluble after heat shock. Twenty-four hours after heat shock, both IRAK1 and TAK1 are again detergent soluble, which correlates with the IL-1β-dependent p38 activation. Remarkably, IL-1β-dependent p38 activation 24 h after heat shock did not result in an inhibition of αENaC mRNA expression and channel function. Further analysis demonstrates prolonged preservation of αENaC expression by the activation of the heat shock response that involves inducible Hsp70. Inhibition of Hsp70 at 24 h after heat shock results in p38-dependent IL-1β inhibition of αENaC mRNA expression, whereas overexpression of Hsp70 attenuates the p38-dependent IL-1β inhibition of αENaC mRNA expression. These studies demonstrate new mechanisms by which the induction of the heat shock response protects the barrier function of the alveolar epithelium in ALI.
Marybeth Howard; Jérémie Roux; Karen E Iles; Byron Miyazawa; Sarah Christiaans; Naseem Anjum; Dale A Dickinson; Arnaud Goolaerts; Michael A Matthay; Jean Francois Pittet
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Shock (Augusta, Ga.)     Volume:  39     ISSN:  1540-0514     ISO Abbreviation:  Shock     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-17     Completed Date:  2013-06-07     Revised Date:  2014-02-04    
Medline Journal Info:
Nlm Unique ID:  9421564     Medline TA:  Shock     Country:  United States    
Other Details:
Languages:  eng     Pagination:  189-96     Citation Subset:  IM    
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MeSH Terms
Acute Lung Injury / prevention & control*
Amiloride / pharmacology*
Benzoquinones / pharmacology
Cytoskeletal Proteins / pharmacology
DNA-Binding Proteins / pharmacology
Epithelial Sodium Channel Blockers / pharmacology*
Epithelial Sodium Channels / drug effects
HSP70 Heat-Shock Proteins / metabolism
Heat-Shock Response / physiology*
Interleukin-1 Receptor-Associated Kinases / metabolism
Interleukin-1beta / physiology*
LIM Domain Proteins / pharmacology
Lactams, Macrocyclic / pharmacology
MAP Kinase Kinase Kinases / metabolism
MAP Kinase Signaling System / physiology
Pulmonary Alveoli / metabolism*
RNA, Messenger / metabolism
Respiratory Mucosa / metabolism
Grant Support
Reg. No./Substance:
0/Benzoquinones; 0/Cytoskeletal Proteins; 0/DNA-Binding Proteins; 0/Epithelial Sodium Channel Blockers; 0/Epithelial Sodium Channels; 0/HSP70 Heat-Shock Proteins; 0/Interleukin-1beta; 0/LIM Domain Proteins; 0/Lactams, Macrocyclic; 0/RNA, Messenger; 0/Tgfb1i1 protein, rat; 4GY0AVT3L4/tanespimycin; 7DZO8EB0Z3/Amiloride; EC Receptor-Associated Kinases; EC Kinase Kinase Kinases; EC kinase kinase kinase 7

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