Document Detail

In vivo toll-like receptor 4 antagonism restores cardiac function during endotoxemia.
MedLine Citation:
PMID:  22089127     Owner:  NLM     Status:  In-Data-Review    
ABSTRACT: Severe sepsis and septic shock are often accompanied by acute cardiovascular depression. Lipopolysaccharide (LPS) signaling via Toll-like receptor 4 (TLR4) can induce septic organ dysfunction. The aim of this study was to elucidate the in vivo impact of pharmacological TLR4 antagonism on LPS-induced cardiovascular depression using eritoran tetrasodium (E5564). To simulate sepsis, C3H/HeN mice were challenged i.p. with 2 mg/kg body weight LPS. With the intent to antagonize the LPS effects, eritoran was administered i.v. (4 mg/kg body weight). Physical activity, peripheral blood pressure, and heart frequency were recorded before and after LPS and eritoran injection. In addition, intracardiac hemodynamic parameters were analyzed with a pressure conductance catheter. After 2 and 6 h of LPS stimulation ± eritoran treatment, the hearts and aortae were harvested, and TLR as well as inflammatory mediator expression was measured using reverse transcription-quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. Lipopolysaccharide significantly decreased arterial blood pressure over time. Administration of eritoran partially prevented the LPS-dependent reduction in blood pressure and preserved cardiac function. In addition, LPS increased the expression of CD14 and TLR2 in cardiac and aortic tissue. In aortic tissue, eritoran attenuated this increase, whereas no significant reduction was observed in the heart. Furthermore, cardiac and aortic inducible nitric oxide synthetase mRNA levels were significantly increased 6 h after LPS application. This effect was reduced in the presence of eritoran. In summary, the beneficial influence of eritoran on cardiovascular function in vivo seems to rely mainly on reduction of LPS-induced inducible nitric oxide synthetase expression as well as on attenuated cytokine expression in the vascular wall.
Stefan Ehrentraut; Ralph Lohner; Markus Schwederski; Heidi Ehrentraut; Olaf Boehm; Svenja Noga; Pia Langhoff; Georg Baumgarten; Rainer Meyer; Pascal Knuefermann
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Shock (Augusta, Ga.)     Volume:  36     ISSN:  1540-0514     ISO Abbreviation:  Shock     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-11-17     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9421564     Medline TA:  Shock     Country:  United States    
Other Details:
Languages:  eng     Pagination:  613-20     Citation Subset:  IM    
*Department of Anaesthesiology and Intensive Care Medicine, University Hospital Bonn, and †Institute of Physiology II, University of Bonn, Bonn, Germany.
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