The effects of dexmedetomidine on human neutrophil apoptosis

Kishikawa, Hiroaki; Kobayashi, Katsuya; Takemori, Ken; Okabe, Tadashi; Ito, Kenyu; Sakamoto, Atsuhiro

doi:10.2220/biomedres.29.189

Cited by 26 publications

(29 citation statements)

References 21 publications

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“…Different a2-adrenoceptor agonists have been associated with the induction of apoptosis in a variety of cell types (42,43), including neutrophils (44). Similar concentrations of peripheral blood neutrophils were found in xylazine-treated and control animals (data not shown).…”

Section: A2-adrenoceptormentioning

confidence: 53%

“…Their presence has also been suggested, similarly by indirect evidence, in human neutrophils (35). Given the absence of a biological response to a2-adrenoceptor agonists, however, a number of studies were unable to find any evidence supporting the presence of these receptors in neutrophils (9,36,44,59). Our study demonstrates that resting human neutrophils, in a manner similar to HUVECs, constitutively express transcripts of all three a2-adrenoceptor subtypes, although only the a2A subtype was detectable at the protein level.…”

Section: Discussionmentioning

confidence: 96%

“…Treatment of these animals with the a2-adrenergic antagonist RX821002 prevented the anti-inflammatory action of both a2-agonists. Hypothermia (40) and neutrophil apoptosis (44) are two in vivo effects that have been attributed to a2-agonists, both of which might have contributed to the observed decrease in neutrophil transmigration (41). Controlling a2-agonist-induced hypothermia by an external heat source, however, did not significantly interfere with the anti-inflammatory action of xylazine.…”

Section: Discussionmentioning

confidence: 99%

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Prevention of Neutrophil Extravasation by α2-Adrenoceptor–Mediated Endothelial Stabilization

Herrera-García

Domínguez-Luis

Arce-Franco

et al. 2014

The Journal of Immunology

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Adrenergic receptors are expressed on the surface of inflammation-mediating cells, but their potential role in the regulation of the inflammatory response is still poorly understood. The objectives of this work were to study the effects of α2-adrenergic agonists on the inflammatory response in vivo and to determine their mechanism of action. In two mouse models of inflammation, zymosan air pouch and thioglycolate-induced peritonitis models, the i.m. treatment with xylazine or UK14304, two α2-adrenergic agonists, reduced neutrophil migration by 60%. The α2-adrenergic antagonist RX821002 abrogated this effect. In flow cytometry experiments, the basal surface expression of L-selectin and CD11b was modified neither in murine nor in human neutrophils upon α2-agonist treatment. Similar experiments in HUVEC showed that UK14304 prevented the activation-dependent upregulation of ICAM-1. In contrast, UK14304 augmented electrical resistance and reduced macromolecular transport through a confluent HUVEC monolayer. In flow chamber experiments, under postcapillary venule-like flow conditions, the pretreatment of HUVECs, but not neutrophils, with α2-agonists decreased transendothelial migration, without affecting neutrophil rolling. Interestingly, α2-agonists prevented the TNF-α–mediated decrease in expression of the adherens junctional molecules, VE-cadherin, β-catenin, and plakoglobin, and reduced the ICAM-1–mediated phosphorylation of VE-cadherin by immunofluorescence and confocal analysis and Western blot analysis, respectively. These findings indicate that α2-adrenoceptors trigger signals that protect the integrity of endothelial adherens junctions during the inflammatory response, thus pointing at the vascular endothelium as a therapeutic target for the management of inflammatory processes in humans.

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Section: A2-adrenoceptormentioning

confidence: 53%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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Prevention of Neutrophil Extravasation by α2-Adrenoceptor–Mediated Endothelial Stabilization

Herrera-García

Domínguez-Luis

Arce-Franco

et al. 2014

The Journal of Immunology

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“…Underlying mechanisms are associated with the caspase cascade and mitochondrial trifunctional protein loss (58). In a study investigating the effects of clamping across the femoral artery and vein in an epigastric island skin flap model, significant increases in myeloperoxidase (MPO) activity levels and in the flap necrosis area were observed as a result of I/R.…”

Section: Inflammatory Responsementioning

confidence: 99%

Molecular targets and mechanism of action of dexmedetomidine in treatment of ischemia/reperfusion injury (Review)

Cai

Jia

et al. 2014

Molecular Medicine Reports

113

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Abstract. Dexmedetomidine (DEX), a highly specific α 2 -adrenergic agonist, which exhibits anaesthetic-sparing, analgesia and sympatholytic properties. DEX modulates gene expression, channel activation, transmitter release, inflammatory processes and apoptotic and necrotic cell death. It has also been demonstrated to have protective effects in a variety of animal models of ischemia/reperfusion (I/R) injury, including the intestine, myocardial, renal, lung, cerebral and liver. The broad spectrum of biological activities associated with DEX continues to expand, and its diverse effects suggest that it may offer a novel therapeutic approach for the treatment of human diseases with I/R involvement.

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“…Intravenous dexmedetomidine administration showed opioid-sparing effects with reduced inhalational anesthetic requirements (Keniya et al 2011). However, one study reported that dexmedetomidine may also induce apoptosis (Kishikawa et al 2008). The safety of dexmedetomidine use in nerve blocks was reviewed but was determined to be insufficient for the clinical setting (Abdallah & Brull 2013).…”

Section: Introductionmentioning

confidence: 99%

Dexmedetomidine, α₂-adrenoceptor agonist, does not induce apoptosis in the brachial plexus of rats

Han

Kim

et al. 2014

Animal Cells and Systems

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Dexmedetomidine (Precedex) is a selective α 2 -adrenoceptor agonist that shows opioid-sparing effects with reduced inhalational anesthetic requirement. Since the possibility that dexmedetomidine could induce nerve degeneration has not been completely ruled out, we evaluated whether it can induce apoptosis in rats when used in a nerve block. We performed hematoxylin and eosin staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays, immunohistochemistry for caspase-3 and neurofilament, and western blotting for BAX, Bcl-2, and nerve growth factor (NGF) in the brachial plexus of rats. The axillary brachial plexus was carefully exposed and 100 μl (40 µg/kg) dexmedetomidine was administered directly. Rats were sacrificed at 6 h, 12 h, or 24 h after dexmedetomidine administration. In the present study, dexmedetomidine did not exert any effects on histological findings and neurofilament expression. The number of TUNELpositive and caspase-3-positive cells in the brachial plexus did not change following dexmedetomidine administration. The Bcl-2 to BAX ratio temporarily increased and then returned to the control level at 24 h after dexmedetomidine administration. Expression of NGF in the brachial plexus temporarily increased and then returned to the control level 12 h after dexmedetomidine administration. The results of our study demonstrated that dexmedetomidine did not induce apoptosis and degeneration when used in the brachial plexus.

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The effects of dexmedetomidine on human neutrophil apoptosis

Cited by 26 publications

References 21 publications

Prevention of Neutrophil Extravasation by α2-Adrenoceptor–Mediated Endothelial Stabilization

Prevention of Neutrophil Extravasation by α2-Adrenoceptor–Mediated Endothelial Stabilization

Molecular targets and mechanism of action of dexmedetomidine in treatment of ischemia/reperfusion injury (Review)

Dexmedetomidine, α₂-adrenoceptor agonist, does not induce apoptosis in the brachial plexus of rats

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The effects of dexmedetomidine on human neutrophil apoptosis

Cited by 26 publications

References 21 publications

Prevention of Neutrophil Extravasation by α2-Adrenoceptor–Mediated Endothelial Stabilization

Prevention of Neutrophil Extravasation by α2-Adrenoceptor–Mediated Endothelial Stabilization

Molecular targets and mechanism of action of dexmedetomidine in treatment of ischemia/reperfusion injury (Review)

Dexmedetomidine, α2-adrenoceptor agonist, does not induce apoptosis in the brachial plexus of rats

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Dexmedetomidine, α₂-adrenoceptor agonist, does not induce apoptosis in the brachial plexus of rats