Abstract
Sepsis is still a major cause of death and many efforts have been made to improve the physical condition of sepsis patients and to reduce the high mortality rate associated with this disease. While achievements were implemented in the intensive care treatment, all attempts within the field of novel therapeutics have failed. As a consequence new medications and improved patient stratification as well as a thoughtful management of the support therapies are urgently needed. In this study, we investigated the simultaneous administration of ibuprofen as a commonly used nonsteroidal anti-inflammatory drug (NSAID) and Pep19-2.5 (Aspidasept), a newly developed antimicrobial peptide. Here, we show a synergistic therapeutic effect of combined Pep19-2.5-ibuprofen treatment in an endotoxemia mouse model of sepsis. In vivo protection correlates with a reduction in plasma levels of both tumor necrosis factor α and prostaglandin E, as a likely consequence of Pep19-2.5 and ibuprofen-dependent blockade of TLR4 and COX pro-inflammatory cascades, respectively. This finding is further characterised and confirmed in a transcriptome analysis of LPS-stimulated human monocytes. The transcriptome analyses showed that Pep19-2.5 and ibuprofen exerted a synergistic global effect both on the number of regulated genes as well as on associated gene ontology and pathway expression. Overall, ibuprofen potentiated the anti-inflammatory activity of Pep19-2.5 both in vivo and in vitro, suggesting that NSAIDs could be useful to supplement future anti-sepsis therapies.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Anti-Infective Agents / chemistry
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Anti-Infective Agents / pharmacology
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Anti-Infective Agents / therapeutic use*
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
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Dinoprostone / immunology
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Drug Synergism
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Endotoxemia / drug therapy
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Endotoxemia / immunology
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Female
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Humans
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Ibuprofen / pharmacology
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Ibuprofen / therapeutic use*
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Immunity, Innate / drug effects
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Inflammation / drug therapy*
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Inflammation / immunology
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Lipopolysaccharides / immunology
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Mice
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Mice, Inbred BALB C
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Molecular Sequence Data
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Monocytes / drug effects
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Monocytes / immunology
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Monocytes / metabolism
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Peptides / chemistry
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Peptides / pharmacology
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Peptides / therapeutic use*
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Sepsis / drug therapy*
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Sepsis / immunology
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Toll-Like Receptor 4 / immunology
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Transcriptome / drug effects
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Tumor Necrosis Factor-alpha / immunology
Substances
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Anti-Infective Agents
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Anti-Inflammatory Agents, Non-Steroidal
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Lipopolysaccharides
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Peptides
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Tlr4 protein, mouse
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Toll-Like Receptor 4
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Tumor Necrosis Factor-alpha
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Dinoprostone
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Ibuprofen
Grants and funding
Research at the laboratories of the authors is supported by the Else-Kröner-Fresenius Stiftung (project 2011_A140), and the Deutsche Forschungsgemeinschaft (DFG, project DR797/3-1 611672). G.M.T. was also funded by a grant from Proyectos de Investigación Universidad de Navarra (PIUNA-P2011-17), Spain. S.B.V. and R.F.E. were recipients of doctoral fellowships from "Asociación de Amigos de la Universidad de Navarra" and from Gobierno Vasco, Spain, respectively. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.