Document Detail


The hydroxylase inhibitor dimethyloxallyl glycine attenuates endotoxic shock via alternative activation of macrophages and IL-10 production by B1 cells.
MedLine Citation:
PMID:  21844787     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Localized tissue hypoxia is a feature of infection and inflammation, resulting in the upregulation of the transcription factors hypoxia-inducible factor 1α and nuclear factor κB (NF-κB) via inhibition of oxygen sensing hydroxylase enzymes. Previous studies have demonstrated a beneficial role for the hydroxylase inhibitor dimethyloxallyl glycine (DMOG) in inflammatory conditions, including experimental colitis, by regulating the activity of hypoxia-inducible factor 1 and NF-κB. We have demonstrated in vivo that pretreatment with DMOG attenuates systemic LPS-induced activation of the NF-κB pathway. Furthermore, mice treated with DMOG had significantly increased survival in LPS-induced shock. Conversely, in models of polymicrobial sepsis, DMOG exacerbates disease severity. Dimethyloxallyl glycine treatment of mice promotes M2 polarization in macrophages within the peritoneal cavity, resulting in the downregulation of proinflammatory cytokines such as TNF-α. In addition, in vivo DMOG treatment upregulates IL-10 expression, specifically in the peritoneal B1 cell population. This study demonstrates cell type-specific roles for hydroxylase inhibition in vivo and provides insight into the mechanism underlying the protection conveyed by DMOG in models of endotoxic shock.
Authors:
Emily Hams; Sean P Saunders; Eoin P Cummins; Aisling O'Connor; Murtaza T Tambuwala; William M Gallagher; Annette Byrne; Antonio Campos-Torres; Paul M Moynagh; Christian Jobin; Cormac T Taylor; Padraic G Fallon
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Shock (Augusta, Ga.)     Volume:  36     ISSN:  1540-0514     ISO Abbreviation:  Shock     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-08-16     Completed Date:  2012-02-02     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  9421564     Medline TA:  Shock     Country:  United States    
Other Details:
Languages:  eng     Pagination:  295-302     Citation Subset:  IM    
Affiliation:
Institute of Molecular Medicine, Trinity College, Dublin, Ireland.
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MeSH Terms
Descriptor/Qualifier:
Amino Acids, Dicarboxylic / therapeutic use*
Animals
Flow Cytometry
Immunoblotting
Interleukin-10 / metabolism
Lipopolysaccharides / toxicity
Macrophages / drug effects*,  metabolism*
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mixed Function Oxygenases / antagonists & inhibitors
NF-kappa B / metabolism
Polymerase Chain Reaction
Receptors, Interleukin-10 / blood
Sepsis / drug therapy
Shock, Septic / chemically induced,  drug therapy*
Grant Support
ID/Acronym/Agency:
R01 DK047700-07/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Amino Acids, Dicarboxylic; 0/Lipopolysaccharides; 0/NF-kappa B; 0/Receptors, Interleukin-10; 130068-27-8/Interleukin-10; 5262-39-5/oxalylglycine; EC 1.-/Mixed Function Oxygenases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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