title: Therapeutical Administration of Peptide Pep19-2.5 and Ibuprofen Reduces Inflammation and Prevents Lethal Sepsis.
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.
authors.affiliation: Clinical & Experimental Pathology, Research Center Borstel, Leibniz-Center for Medicine and Bioscience, Borstel, Germany; Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Großhansdorf, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Heinbockel
authors.affiliation: Clinical & Experimental Pathology, Research Center Borstel, Leibniz-Center for Medicine and Bioscience, Borstel, Germany; Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Großhansdorf, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Marwitz
authors.affiliation: Department of Microbiology and Parasitology, University of Navarra, Pamplona, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Barcena Varela
authors.affiliation: Department of Microbiology and Parasitology, University of Navarra, Pamplona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Ferrer-Espada
authors.affiliation: Microbial Interface Biology, Research Center Borstel, Leibniz-Center for Medicine and Bioscience, Borstel, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Reiling
authors.affiliation: Clinical & Experimental Pathology, Research Center Borstel, Leibniz-Center for Medicine and Bioscience, Borstel, Germany; Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Großhansdorf, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Goldmann
authors.affiliation: Biophysics, Research Center Borstel, Leibniz-Center for Medicine and Bioscience, Borstel, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gutsmann
authors.affiliation: Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Mier
authors.affiliation: Department of Intensive Care, University Hospital Aachen, Aachen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schürholz
authors.affiliation: Medical Clinic III, University of Schleswig-Holstein, Lübeck, Germany; Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Großhansdorf, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Drömann
authors.affiliation: Microbial Interface Biology, Research Center Borstel, Leibniz-Center for Medicine and Bioscience, Borstel, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Brandenburg
authors.affiliation: Department of Microbiology and Parasitology, University of Navarra, Pamplona, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Martinez de Tejada
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D015232:Dinoprostone / Q000276:immunology; D004357:Drug Synergism; D019446:Endotoxemia / Q000188:drug therapy / Q000276:immunology; D005260:Female; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology / Q000627:therapeutic use*; D007113:Immunity, Innate / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology; D059467:Transcriptome / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D000890:Anti-Infective Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D008070:Lipopolysaccharides; D010455:Peptides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D015232:Dinoprostone; D007052:Ibuprofen