Adenosine Receptor Adora2b Plays a Mechanistic Role in the Protective Effect of the Volatile Anesthetic Sevoflurane during Liver Ischemia/Reperfusion
Adenosine Receptor Adora2b Plays a Mechanistic Role in the Protective Effect of the Volatile Anesthetic Sevoflurane during Liver Ischemia/Reperfusion
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DOI：
10.1097/aln.0000000000001234
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发表时间：
2016-09-01
期刊：
影响因子：
8.8
通讯作者：
Straub, Andreas
中科院分区：
文献类型：
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作者：
Granja, Tiago F.;Koehler, David;Straub, Andreas
背景：肝脏缺血/再灌注（IR）损伤的特点是肝组织损伤和炎症反应。这伴随着血小板-中性粒细胞缀合物（PNC）的形成和血管隔离。通过 Adora2b 腺苷受体发出的信号可以提供肝脏保护。挥发性麻醉剂可能与腺苷受体相互作用。本研究探讨了挥发性麻醉剂七氟醚在肝脏 IR 期间的潜在抗炎作用。方法：使用人血和野生型、Adora2a(-/-) 和 Adora2b(-/-) 小鼠的肝脏 IR 模型进行离体实验。使用流式细胞术、发光法和免疫荧光分析七氟醚对血小板活化、PNC 形成和隔离、细胞因子释放和肝损伤（丙氨酸转氨酶释放）的影响。使用免疫组织化学和实时聚合酶链反应分析肝组织中的腺苷受体表达。结果：离体实验表明七氟醚抑制血小板和白细胞活化（n = 5）。在肝脏 IR 期间，七氟醚 (2 Vol%) 使野生型小鼠的 PNC 形成减少 2.4 倍 (P < 0.05)，但在 Adora2b(-/-) 小鼠中则不然 (n >= 5)。在野生型小鼠中，七氟烷使 PNC 隔离减少 1.9 倍 (P < 0.05)，丙氨酸转氨酶释放减少 3.5 倍 (P < 0.05)，但在 Adora2b(-/-) 小鼠中则不然 (n = 5)。在 Adora2a(-/-) 小鼠中，七氟烷还抑制 PNC 形成和细胞因子释放。七氟醚减少野生型肝组织中的细胞因子释放 (n >= 3) 并增加 Adora2b 转录和表达 (n = 4)。结论：我们的实验强调了七氟醚在肝脏 IR 过程中的抗炎和组织保护特性，并揭示了 Adora2b 在七氟醚相关效应中的机制作用。有针对性地使用七氟醚不仅作为麻醉剂，而且还可以预防红外线损伤，是治疗危重患者的一种有前景的方法。
Background: Liver ischemia/reperfusion (IR) injury is characterized by hepatic tissue damage and an inflammatory response. This is accompanied by the formation and vascular sequestration of platelet-neutrophil conjugates (PNCs). Signaling through Adora2b adenosine receptors can provide liver protection. Volatile anesthetics may interact with adenosine receptors. This study investigates potential antiinflammatory effects of the volatile anesthetic sevoflurane during liver IR.Methods: Experiments were performed ex vivo with human blood and in a liver IR model with wild-type, Adora2a(-/-), and Adora2b(-/-) mice. The effect of sevoflurane on platelet activation, PNC formation and sequestration, cytokine release, and liver damage (alanine aminotransferase release) was analyzed using flow cytometry, luminometry, and immunofluorescence. Adenosine receptor expression in liver tissue was analyzed using immunohistochemistry and real-time polymerase chain reaction.Results: Ex vivo experiments indicate that sevoflurane inhibits platelet and leukocyte activation (n = 5). During liver IR, sevoflurane (2 Vol%) decreased PNC formation 2.4-fold in wild-type (P < 0.05) but not in Adora2b(-/-) mice (n >= 5). Sevoflurane reduced PNC sequestration 1.9-fold (P < 0.05) and alanine aminotransferase release 3.5-fold (P < 0.05) in wild-type but not in Adora2b(-/-) mice (n = 5). In Adora2a(-/-) mice, sevoflurane also inhibited PNC formation and cytokine release. Sevoflurane diminished cytokine release (n >= 3) and increased Adora2b transcription and expression in liver tissue of wild-types (n = 4).Conclusions: Our experiments highlight antiinflammatory and tissue-protective properties of sevoflurane during liver IR and reveal a mechanistic role of Adora2b in sevoflurane-associated effects. The targeted use of sevoflurane not only as an anesthetic but also to prevent IR damage is a promising approach in the treatment of critically ill patients.