title: Increased plasma levels of endozepines, endogenous ligands of benzodiazepine receptors, during systemic inflammation: a prospective observational study.
abstract: BACKGROUND
  Recent work has shown that benzodiazepines interact with the immune system and exhibit anti-inflammatory effects. By using in vitro models, researchers in several studies have shown that the peptidergic endogenous ligands of benzodiazepine receptors, named endozepines, are involved in the immune response. All endozepines identified so far derive from diazepam-binding inhibitor (DBI), which generates several biologically active fragments. The aim of the present study was to measure plasma levels of DBI-like immunoreactivity (DBI-LI) in a rat model of sepsis and in patients with systemic inflammation from septic or non-septic origin.
  
  
  METHODS
  Cecal ligation and puncture (CLP) or sham surgery was performed in rats. Blood samples were taken from animals, patients hospitalized for digestive surgery with inflammatory diseases, and healthy volunteers. Measurements of plasma DBI-related peptides were carried out by radioimmunoassay in animal and human samples.
  
  
  RESULTS
  In the rats, CLP provoked an increase of plasma DBI-LI (+37%) 6 hours postsurgery. In humans, DBI-LI levels were significantly higher in the systemic inflammation group than in the healthy volunteer group (48.6 (32.7 to 77.7) pg/ml versus 11.1 (5.9 to 35.3) pg/ml, P <  .001). We found a positive correlation between endozepine levels and Acute Physiology and Chronic Health Evaluation II score (r s = 0.33 (0.026 to 0.58), P < 0.05) and tumor necrosis factor α levels (r s = 0.43 (0.14 to 0.65), P < 0.01). The area under the receiver operating characteristic curve for endozepines was 0.842 (95% CI (0.717 to 0.966), P < 0.0001) for discriminating patients with inflammation from healthy volunteers.
  
  
  CONCLUSIONS
  Endozepines might be involved in the inflammatory response in patients with systemic inflammation.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), U982, Place Emile Blondel, 76130, Mont-Saint-Aignan, France. thomas.clavier@chu-rouen.fr.|Normandy University, Institute for Research and Innovation in Biomedicine (IRIB), Place Emile Blondel, 76130, Mont-Saint-Aignan, France. thomas.clavier@chu-rouen.fr.|Rouen University, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Place Emile Blondel, 76130, Mont-Saint-Aignan, France. thomas.clavier@chu-rouen.fr.|Department of Anesthesiology and Critical Care, Rouen University Hospital, Rue de Germont, 76000, Rouen, France. thomas.clavier@chu-rouen.fr.
authors.forename: Thomas
authors.initials: T
authors.lastname: Clavier
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), U982, Place Emile Blondel, 76130, Mont-Saint-Aignan, France. marie-christine.tonon@univ-rouen.fr.|Normandy University, Institute for Research and Innovation in Biomedicine (IRIB), Place Emile Blondel, 76130, Mont-Saint-Aignan, France. marie-christine.tonon@univ-rouen.fr.|Rouen University, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Place Emile Blondel, 76130, Mont-Saint-Aignan, France. marie-christine.tonon@univ-rouen.fr.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Tonon
authors.affiliation: Department of Anesthesiology and Critical Care, Rouen University Hospital, Rue de Germont, 76000, Rouen, France. anne.foutel@chu-rouen.fr.
authors.forename: Anne
authors.initials: A
authors.lastname: Foutel
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), U982, Place Emile Blondel, 76130, Mont-Saint-Aignan, France. emmanuel.besnier@chu-rouen.fr.|Normandy University, Institute for Research and Innovation in Biomedicine (IRIB), Place Emile Blondel, 76130, Mont-Saint-Aignan, France. emmanuel.besnier@chu-rouen.fr.|Rouen University, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Place Emile Blondel, 76130, Mont-Saint-Aignan, France. emmanuel.besnier@chu-rouen.fr.|Department of Anesthesiology and Critical Care, Rouen University Hospital, Rue de Germont, 76000, Rouen, France. emmanuel.besnier@chu-rouen.fr.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Besnier
authors.affiliation: Department of Anesthesiology and Critical Care, Rouen University Hospital, Rue de Germont, 76000, Rouen, France. antoine.lefevre-scelles@chu-rouen.fr.
authors.forename: Antoine
authors.initials: A
authors.lastname: Lefevre-Scelles
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), U982, Place Emile Blondel, 76130, Mont-Saint-Aignan, France. fabrice.morin@univ-rouen.fr.|Normandy University, Institute for Research and Innovation in Biomedicine (IRIB), Place Emile Blondel, 76130, Mont-Saint-Aignan, France. fabrice.morin@univ-rouen.fr.|Rouen University, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Place Emile Blondel, 76130, Mont-Saint-Aignan, France. fabrice.morin@univ-rouen.fr.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Morin
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), U982, Place Emile Blondel, 76130, Mont-Saint-Aignan, France. pierrick.gandolfo@univ-rouen.fr.|Normandy University, Institute for Research and Innovation in Biomedicine (IRIB), Place Emile Blondel, 76130, Mont-Saint-Aignan, France. pierrick.gandolfo@univ-rouen.fr.|Rouen University, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Place Emile Blondel, 76130, Mont-Saint-Aignan, France. pierrick.gandolfo@univ-rouen.fr.
authors.forename: Pierrick
authors.initials: P
authors.lastname: Gandolfo
authors.affiliation: Department of Digestive Surgery, Rouen University Hospital, Rue de Germont, 76000, Rouen, France. jean-jacques.tuech@chu-rouen.fr.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Tuech
authors.affiliation: Department of Medical Biochemistry, Institute of Clinical Biology, Rouen University Hospital, 76000, Rouen, France. muriel.quillard@chu-rouen.fr.
authors.forename: Muriel
authors.initials: M
authors.lastname: Quillard
authors.affiliation: Department of Anesthesiology and Critical Care, Rouen University Hospital, Rue de Germont, 76000, Rouen, France. benoit.veber@chu-rouen.fr.
authors.forename: Benoit
authors.initials: B
authors.lastname: Veber
authors.affiliation: Department of Anesthesiology and Critical Care, Rouen University Hospital, Rue de Germont, 76000, Rouen, France. bertrand.dureuil@chu-rouen.fr.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Dureuil
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), U982, Place Emile Blondel, 76130, Mont-Saint-Aignan, France. helene.castel@univ-rouen.fr.|Normandy University, Institute for Research and Innovation in Biomedicine (IRIB), Place Emile Blondel, 76130, Mont-Saint-Aignan, France. helene.castel@univ-rouen.fr.|Rouen University, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Place Emile Blondel, 76130, Mont-Saint-Aignan, France. helene.castel@univ-rouen.fr.
authors.forename: Hélène
authors.initials: H
authors.lastname: Castel
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), U982, Place Emile Blondel, 76130, Mont-Saint-Aignan, France. vincent.compere@chu-rouen.fr.|Normandy University, Institute for Research and Innovation in Biomedicine (IRIB), Place Emile Blondel, 76130, Mont-Saint-Aignan, France. vincent.compere@chu-rouen.fr.|Rouen University, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Place Emile Blondel, 76130, Mont-Saint-Aignan, France. vincent.compere@chu-rouen.fr.|Department of Anesthesiology and Critical Care, Rouen University Hospital, Rue de Germont, 76000, Rouen, France. vincent.compere@chu-rouen.fr.
authors.forename: Vincent
authors.initials: V
authors.lastname: Compère
mesh_terms: D000328:Adult; D000818:Animals; D026261:Diazepam Binding Inhibitor / Q000097:blood*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000175:diagnosis; D018836:Inflammation Mediators / Q000097:blood*; D008024:Ligands; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000097:blood*; D013045:Species Specificity; D018746:Systemic Inflammatory Response Syndrome / Q000097:blood* / Q000175:diagnosis
chemical_list: D026261:Diazepam Binding Inhibitor; D018836:Inflammation Mediators; D008024:Ligands; D011963:Receptors, GABA-A