Inhibition of sepsis-induced inflammatory response by β1-adrenergic antagonists.
BACKGROUND
Although previous studies have described potential benefits of nonselective β-adrenergic antagonist therapy in sepsis, there is a paucity of data on the use of β1-selective antagonists (B1AA). The purposes of this study were to describe the effects of B1AA on survival in septic animals and to explore for molecular mechanisms of potential treatment benefit.


METHODS
C57BL/6 male mice received intraperitoneal injection of lipopolysaccharide. Continuous infusion of a B1AA (esmolol) or an equal volume of saline (control) was initiated at 4 hours after injection. Kaplan-Meier survival analysis at 120 hours was used to explore for mortality differences. A subgroup of animals was sacrificed for microarray expression analysis. Top candidate genes were validated in vitro and in silico. Expression of our candidate genes in a human microarray database (GSE28750) was explored.


RESULTS
B1AA infusion resulted in increased survival (p = 0.001) at 120 hours. Mean survival difference was 23.6 hours (p = 0.002). Hazard ratio for mortality with B1AA is 0.43 (95% confidence interval, 0.26-0.72). Immunologic disease (p = 0.0003-0.036) and cell death/survival (p = 0.0001-0.042) were significantly associated with improved survival in septic mice treated with B1AA. Further analysis of the gene structure revealed that eight genes shared common promoter activating sequence for NFKB and/or BRCA1 motifs. Analysis of a human sepsis database identified the up-regulation of CAMP (p = 0.032) and TNFSF10 (p = 0.001) genes in septic patients compared with healthy controls.


CONCLUSIONS
Continuous infusion of a B1AA initiated after septic insult improves survival at 5 days in a murine model. Benefits may be caused by modulation of gene expression in immunologic pathways leading to an increase in CAMP and TNFSF10 expression. This observed effect may be explained by the activation of NFKB and BRCA1 genes involved in immune response and cell repair pathways. Our findings support further investigation of the use of B1AA in the treatment of sepsis.
From the Division of Trauma, Critical Care & Emergency Surgery, Department of Surgery, University of Arizona, Tucson, Arizona.
Irada
I
Ibrahim-Zada
Peter
P
Rhee
Christopher T
CT
Gomez
John
J
Weller
Randall S
RS
Friese
D058671:Adrenergic beta-1 Receptor Antagonists / Q000008:administration & dosage*; D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D053208:Kaplan-Meier Estimate; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D008967:Molecular Biology; D052002:NF-kappa B p50 Subunit / Q000235:genetics; D011412:Propanolamines / Q000008:administration & dosage*; D012313:RNA / Q000235:genetics; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012016:Reference Values; D018805:Sepsis / Q000188:drug therapy* / Q000401:mortality; D016019:Survival Analysis; D018746:Systemic Inflammatory Response Syndrome / Q000235:genetics / Q000401:mortality / Q000517:prevention & control*
D058671:Adrenergic beta-1 Receptor Antagonists; D019313:BRCA1 Protein; D008070:Lipopolysaccharides; D052002:NF-kappa B p50 Subunit; D011412:Propanolamines; C073701:Nfkb1 protein, mouse; D012313:RNA; C036604:esmolol