A2B adenosine receptor blockade enhances macrophage-mediated bacterial phagocytosis and improves polymicrobial sepsis survival in mice.
A2B adenosine receptor blockade enhances macrophage-mediated bacterial phagocytosis and improves polymicrobial sepsis survival in mice.
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DOI：
10.4049/jimmunol.1001567
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发表时间：
2011-02-15
期刊：
影响因子：
--
通讯作者：
Sitkovsky M
中科院分区：
文献类型：
--
作者：
Belikoff BG;Hatfield S;Georgiev P;Ohta A;Lukashev D;Buras JA;Remick DG;Sitkovsky M
必须改进抗菌治疗策略以降低脓毒症患者的高死亡率。在急性炎症的非感染性模型中，细胞外富含腺苷的微环境中A2 B腺苷受体（A2 BR）的激活导致免疫抑制。我们研究了A2 BR在盲肠结扎穿孔（CLP）脓毒症模型中的抗菌反应。A2 BR的拮抗作用显著增加了远交（ICR/CD-1）小鼠CLP后的存活率，增强了细菌吞噬作用，并降低了IL-6和MIP-2（CXC趋化因子）水平。在A2 BR基因敲除小鼠中CLP诱导的脓毒症反应期间，与野生型小鼠相比，除了更好的存活率和降低的血浆IL-6水平外，血流动力学参数得到改善。A2 BR缺乏导致腹膜细菌显著减少4-log。这些改善的机制是由于增强的巨噬细胞吞噬活性而不增加中性粒细胞对细菌的吞噬作用。在离体LPS刺激后，与野生型小鼠相比，来自A2 BR敲除小鼠的脓毒症巨噬细胞的IL-6和TNF-α分泌增加。通过使用血浆生物标志物来研究A2 BR阻断的治疗性干预，以指导对预测死亡的那些小鼠的治疗。即使在脓毒症发作后32小时，A2 BR的药理学阻断也使预测死亡的小鼠的存活率增加了65%。因此，即使用A2 BR拮抗剂的晚期治疗也显著改善了小鼠（ICR/CD-1）的存活率，否则根据血浆IL-6水平确定小鼠死亡。我们的发现增强细菌清除和宿主存活表明，A2 BR的拮抗作用提供了一个治疗靶点，以改善巨噬细胞功能，在后期治疗方案，提高脓毒症生存。
Antimicrobial treatment strategies must improve to reduce the high mortality rates in septic patients. In noninfectious models of acute inflammation, activation of A2B adenosine receptors (A2BR) in extracellular adenosine-rich microenvironments causes immunosuppression. We examined A2BR in antibacterial responses in the cecal ligation and puncture (CLP) model of sepsis. Antagonism of A2BR significantly increased survival, enhanced bacterial phagocytosis, and decreased IL-6 and MIP-2 (a CXC chemokine) levels after CLP in outbred (ICR/CD-1) mice. During the CLP-induced septic response in A2BR knockout mice, hemodynamic parameters were improved compared with wild-type mice in addition to better survival and decreased plasma IL-6 levels. A2BR deficiency resulted in a dramatic 4-log reduction in peritoneal bacteria. The mechanism of these improvements was due to enhanced macrophage phagocytic activity without augmenting neutrophil phagocytosis of bacteria. Following ex vivo LPS stimulation, septic macrophages from A2BR knockout mice had increased IL-6 and TNF-α secretion compared with wild-type mice. A therapeutic intervention with A2BR blockade was studied by using a plasma biomarker to direct therapy to those mice predicted to die. Pharmacological blockade of A2BR even 32 h after the onset of sepsis increased survival by 65% in those mice predicted to die. Thus, even the late treatment with an A2BR antagonist significantly improved survival of mice (ICR/CD-1) that were otherwise determined to die according to plasma IL-6 levels. Our findings of enhanced bacterial clearance and host survival suggest that antagonism of A2BRs offers a therapeutic target to improve macrophage function in a late treatment protocol that improves sepsis survival.
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DOI：
10.1016/j.bbrc.2008.07.059
发表时间：
2008-10-24
影响因子：
3.1
作者：
Hilaire, Cynthia St.;Koupenova, Milka;Carroll, Shannon H.;Smith, Barbara D.;Ravid, Katya
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DOI：
10.1073/pnas.0809422106
发表时间：
2009-04-14
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
20.3
作者：
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影响因子：
3.1
作者：
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4.8
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