Abstract
IntroductionRecent 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.MethodsCecal 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.ResultsIn 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 < 0.001). We found a positive correlation between endozepine levels and Acute Physiology and Chronic Health Evaluation II score (rs = 0.33 (0.026 to 0.58), P < 0.05) and tumor necrosis factor α levels (rs = 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.ConclusionsEndozepines might be involved in the inflammatory response in patients with systemic inflammation.
Highlights
Recent work has shown that benzodiazepines interact with the immune system and exhibit anti-inflammatory effects
In the rats, Cecal ligation and puncture (CLP) provoked an increase of plasma diazepam-binding inhibitor (DBI)-LI (+37%) 6 hours postsurgery
DBI-like immunoreactivity (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 < 0.001)
Summary
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. The results of studies performed in animal models and humans suggest that prolonged treatment with benzodiazepines could increase mortality related to sepsis [2,3]. In contrast to CBR, peripheral-type benzodiazepine receptors, renamed translocator protein (TSPO), are mitochondrial receptors coupled to an anion channel, mostly—but —located in peripheral tissues [6] They likely bind the same benzodiazepine ligands, potentiation of the activity of Clavier et al Critical Care (2014) 18:633. The prevention of immunosuppressive effects of benzodiazepines by a specific TSPO antagonist suggests that the anti-inflammatory effect of benzodiazepines is, at least in part, relayed by these receptors and that endogenous ligands of TSPO may play a role in inflammatory pathophysiological processes [17]
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