挥发性麻醉剂通过干扰 CXCR2 信号转导减少中性粒细胞炎症反应。

Volatile anaesthetics reduce neutrophil inflammatory response by interfering with CXC receptor-2 signalling.

机构信息

Institute of Anaesthesiology, University Hospital Zurich, Zürich, Switzerland Institute of Physiology, Zurich Center of Integrative Human Physiology, University of Zurich, Zürich, Switzerland.

Institute of Anaesthesiology, University Hospital Zurich, Zürich, Switzerland Institute of Physiology, Zurich Center of Integrative Human Physiology, University of Zurich, Zürich, Switzerland Department of Anesthesiology, University of Illinois Hospital & Health Sciences Center, Chicago, IL, USA.

出版信息

Br J Anaesth. 2015 Jan;114(1):143-9. doi: 10.1093/bja/aeu189. Epub 2014 Jul 2.

DOI:10.1093/bja/aeu189

PMID:24989774

Abstract

BACKGROUND

Growing evidence suggests a protective effect of volatile anaesthetics in ischaemia-reperfusion (I/R)-injury, and the accumulation of neutrophils is a crucial event. Pro-inflammatory cytokines carrying the C-X-C-motif including interleukin-8 (IL-8) and CXC-ligand 1 (CXCL1) activate CXC receptor-1 (CXCR1; stimulated by IL-8), CXC receptor-2 (CXCR2; stimulated by IL-8 and CXCL1), or both to induce CD11b-dependent neutrophil transmigration. Inhibition of CXCR1, CXCR2, or both reduces I/R-injury by preventing neutrophil accumulation. We hypothesized that interference with CXCR1/CXCR2 signalling contributes to the well-established beneficial effect of volatile anaesthetics in I/R-injury.

METHODS

Isolated human neutrophils were stimulated with IL-8 or CXCL1 and exposed to volatile anaesthetics (sevoflurane/desflurane). Neutrophil migration was assessed using an adapted Boyden chamber. Expression of CD11b, CXCR1, and CXCR2 was measured by flow cytometry. Blocking antibodies against CXCR1/CXCR2/CD11b and phorbol myristate acetate were used to investigate specific pathways.

RESULTS

Volatile anaesthetics reduced CD11b-dependent neutrophil transmigration induced by IL-8 by >30% and CD11b expression by 18 and 27% with sevoflurane/desflurane, respectively. This effect was independent of CXCR1/CXCR2 expression and CXCR1/CXCR2 endocytosis. Inhibition of CXCR1 signalling did not affect downregulation of CD11b with volatile anaesthetics. Blocking of CXCR2-signalling neutralized effects by volatile anaesthetics on CD11b expression. Specific stimulation of CXCR2 with CXCL1 was sufficient to induce upregulation of CD11b, which was impaired with volatile anaesthetics. No effect of volatile anaesthetics was observed with direct stimulation of protein kinase C located downstream of CXCR1/CXCR2.

CONCLUSION

Volatile anaesthetics attenuate neutrophil inflammatory responses elicited by CXC cytokines through interference with CXCR2 signalling. This might contribute to the beneficial effect of volatile anaesthetics in I/R-injury.

摘要

背景

越来越多的证据表明挥发性麻醉剂对缺血再灌注（I/R）损伤具有保护作用，而中性粒细胞的积累是一个关键事件。含有 C-X-C 基序的促炎细胞因子，包括白细胞介素-8（IL-8）和 CXC 配体 1（CXCL1），激活 CXC 受体-1（CXCR1；受 IL-8 刺激）、CXC 受体-2（CXCR2；受 IL-8 和 CXCL1 刺激）或两者，以诱导 CD11b 依赖性中性粒细胞迁移。抑制 CXCR1、CXCR2 或两者都可以通过阻止中性粒细胞积聚来减少 I/R 损伤。我们假设，干扰 CXCR1/CXCR2 信号传导有助于挥发性麻醉剂在 I/R 损伤中确立的有益作用。

方法

用白细胞介素-8 或 CXCL1 刺激分离的人中性粒细胞，并暴露于挥发性麻醉剂（七氟醚/地氟醚）。使用改良的 Boyden 室评估中性粒细胞迁移。通过流式细胞术测量 CD11b、CXCR1 和 CXCR2 的表达。使用针对 CXCR1/CXCR2/CD11b 的阻断抗体和佛波醇肉豆蔻酸乙酯来研究特定途径。

结果

挥发性麻醉剂分别使七氟醚/地氟醚降低由 IL-8 诱导的 CD11b 依赖性中性粒细胞迁移超过 30%，并使 CD11b 表达降低 18%和 27%。这种效应与 CXCR1/CXCR2 表达和 CXCR1/CXCR2 内吞作用无关。抑制 CXCR1 信号传导不影响挥发性麻醉剂对 CD11b 下调的作用。抑制 CXCR2 信号传导可中和挥发性麻醉剂对 CD11b 表达的作用。用 CXCL1 特异性刺激 CXCR2 足以诱导 CD11b 的上调，而挥发性麻醉剂则会损害这种上调。在直接刺激位于 CXCR1/CXCR2 下游的蛋白激酶 C 时，未观察到挥发性麻醉剂的作用。