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  • br Acknowledgment S A was


    Acknowledgment S.A was supported by V Plan Propio US-AccesoUSE-14793-G.
    Introduction Neutrophils are innate immune MLN4924 of primary importance for protecting against infections by microorganisms [1,2] through various antimicrobial abilities, including microorganism phagocytosis and antimicrobial agent secretion [1]. Furthermore, a specific mechanism of neutrophils is the release of extracellular traps to ensnare and kill microorganisms [3,4]. These neutrophil extracellular traps (NETs) are composed of net-like chromatin fibers with attached antimicrobial proteins such as histones, elastase, cathepsin G, proteinase 3, lactoferrin, myeloperoxidase, and calprotectin and cytoplasmic proteins [3,5]. All of these factors can inhibit or kill pathogens by disrupting virulence factors or the integrity of the pathogen\'s cell membrane [6]. In addition to their antimicrobial properties, NETs appear to trap microorganisms to prevent them from spreading, and NETs maintain a high concentration of antimicrobial agents at the infection site to degrade virulence factors and pathogens [3]. The induction of NET production in neutrophils by phorbol myristate acetate (PMA) is a well-characterized NETosis model. PMA is an activator of protein kinase C (PKC) that can trigger NET formation though a reactive oxygen species (ROS)-dependent pathway [7,8]. Inhibition of NADPH oxidase with diphenyleneiodonium (DPI) notably decreases PMA-induced NET formation [9], and phosphorylation of p38 MAPK and ERK1/2 has been demonstrated to be involved in the underlying mechanism. However, it remains unclear whether MAPK and ROS are upstream of the signaling pathway [10,11]. Intravenous anesthetics are extensively used for general anesthesia and sedation. They have also been shown to have immunomodulatory effects, such as inhibiting phagocytic function, chemotaxis, cytokine secretion and ROS generation [[12], [13], [14], [15]]. Propofol and midazolam are commonly used for sedation in the intensive care unit (ICU) [16]; the most common cause of ICU admission is sepsis, and increased NET formation during sepsis is critical for host survival [17,18]. As mentioned above, NETs are a unique means by which neutrophils control infections [3,4], although it remains unknown whether intravenous anesthetics have effects on NET formation. Thus, we compared the effects of four intravenous anesthetics (propofol lipid emulsion, thiamylal sodium, midazolam, and ketamine) on NET formation and analyzed the signaling pathway involved in the modulation of NET formation by these anesthetics.
    Materials and methods
    Discussion NETs are net-like chromatin fibers that have been identified as an alternative mechanism for trapping and killing microorganisms [3,5]. PMA can stimulate NET formation through the ROS-dependent pathway [7,8], and NADPH oxidase activity and MPO-derived ROS are involved in NET release [9]. However, there are inconsistent results regarding the signaling pathway involved in PMA-induced NET formation [10,11], and whether intravenous anesthetics (propofol, thiamylal sodium, midazolam, and ketamine) are able to inhibit NET formation has not yet been investigated. In the present study, we found propofol to be the most effective among four intravenous anesthetics at inhibiting PMA-induced NET formation and total ROS production. The inhibition of NET formation caused by propofol was mediated by two independent mechanisms: decreases in p-ERK and HOCl levels. Previous studies have demonstrated the anti-inflammatory effects of intravenous anesthetics, including the inhibition of phagocytosis, chemotaxis, cytokine secretion and ROS generation in phagocytes [[12], [13], [14], [15]]. The current results provide evidence that the inhibitory effects of four intravenous anesthetics on PMA-induced NET formation and the decrease in NET release mediated by thiamylal sodium depend on an individual\'s neutrophil diversity. Moreover, compared with the other anesthetics tested, propofol was best at inhibiting NET formation (Fig. 2B and C). Propofol is widely used in surgery and sedation in ICUs. Visvabharathy et al. reported that even brief exposure to propofol is sufficient to significantly increase the susceptibility of mice to Listeria monocytogenes and bloodstream MRSA infections, although ketamine or pentobarbital exposure did not enhance susceptibility to systemic infection by L. monocytogenes in mice [22,23]. In addition, propofol exposure increases neutrophilic infiltrates in the kidneys as well as bacterial dissemination throughout kidney tissue [23]. These results indicate that it is worth further investigating in an in vivo model whether propofol also interferes with the NET formation related to bacterial killing.