Document Detail


Inhibition of guanylyl cyclase restores neutrophil migration and maintains bactericidal activity increasing survival in sepsis.
MedLine Citation:
PMID:  20823697     Owner:  NLM     Status:  In-Process    
Abstract/OtherAbstract:
Sepsis results from an overwhelming response to infection and is a major contributor to death in intensive care units worldwide. In recent years, we and others have shown that neutrophil functionality is impaired in sepsis. This correlates with sepsis severity and contributes to aggravation of sepsis by precluding bacterial clearance. Nitric oxide (NO) is a major contributor to the impairment of neutrophil function in sepsis. However, attempts to inhibit NO synthesis in sepsis resulted in increased death despite restoring neutrophil migration. This could be in part attributed to a reduction of the NO-dependent microbicidal activity of neutrophils. In sepsis, the beneficial effects resulting from the inhibition of soluble guanylyl cyclase (sGC), a downstream target of NO, have long been appreciated but poorly understood. However, the effects of sGC inhibition on neutrophil function in sepsis have never been addressed. In the present study, we show that TLR activation in human neutrophils leads to decreased chemotaxis, which correlated with chemotactic receptor internalization and increased G protein-coupled receptor kinase 2 expression, in a process involving the NO-sGC-protein kinase G axis. We also demonstrate that inhibition of sGC activity increased survival in a murine model of sepsis, which was paralleled by restored neutrophil migratory function and increased bacterial clearance. Finally, the beneficial effect of sGC inhibition could also be demonstrated in mice treated after the onset of sepsis. Our results suggest that the beneficial effects of sGC inhibition in sepsis could be at least in part attributed to a recovery of neutrophil functionality.
Authors:
Heitor A Paula-Neto; José C Alves-Filho; Fabricio O Souto; Fernando Spiller; Rafael S Amêndola; Andressa Freitas; Fernando Q Cunha; Christina Barja-Fidalgo
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Shock (Augusta, Ga.)     Volume:  35     ISSN:  1540-0514     ISO Abbreviation:  Shock     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2010-12-16     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9421564     Medline TA:  Shock     Country:  United States    
Other Details:
Languages:  eng     Pagination:  17-27     Citation Subset:  IM    
Affiliation:
Laboratório de Farmacologia Bioquímica e Celular, Departamento de Farmacologia, Instituto de Biologia Roberto Alcântara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brasil.
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