Plasma ATP is required for neutrophil activation in a mouse sepsis model.
Plasma ATP is required for neutrophil activation in a mouse sepsis model.
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小鼠败血症模型中嗜中性粒细胞激活需要血浆ATP。
DOI：
10.1097/shk.0000000000000180
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发表时间：
2014-08
期刊：
影响因子：
--
通讯作者：
Junger WG
中科院分区：
文献类型：
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作者：
Sumi Y;Woehrle T;Chen Y;Bao Y;Li X;Yao Y;Inoue Y;Tanaka H;Junger WG
我们之前的研究表明，多形核中性粒细胞（PMN）的激活需要细胞释放三磷酸腺苷（ATP）并进行自分泌嘌呤能信号传导。在此，我们通过盲肠结扎穿孔（CLP）小鼠模型，研究脓毒症是否会影响这一嘌呤能信号传导过程，进而改变脓毒症发生后PMN的反应。利用高效液相色谱法，我们发现，CLP术后最初8小时内，血浆中的ATP、二磷酸腺苷（ADP）和一磷酸腺苷（AMP）浓度升高达6倍，峰值水平显著高于未进行CLP的假手术对照动物。假手术动物在术后4小时白细胞和PMN计数显著增加，而脓毒症动物的这些血细胞计数却有所下降。与假手术组和未处理的对照组动物相比，脓毒症动物PMN细胞表面的CD11b表达显著升高。这些研究结果表明，脓毒症发生后PMN激活增加，且PMN从循环系统中被隔离。血浆ATP水平与CD11b表达相关，这表明血浆中升高的ATP浓度有助于PMN的激活。我们发现，用ATP受体拮抗剂苏拉明治疗脓毒症小鼠可降低CD11b的表达，这表明血浆ATP通过刺激PMN的P2受体促进PMN激活。PMN激活增加可保护宿主免受入侵微生物的侵害。然而，PMN激活增加也可能因促进继发性器官损伤而产生不利影响。我们得出结论，以P2受体为药物靶点可能有助于调节脓毒症中PMN的反应。
Our previous work has shown that polymorphonuclear neutrophils (PMN) require cellular ATP release and autocrine purinergic signaling for their activation. Here we studied in a mouse model of cecal ligation and puncture (CLP) whether sepsis affects this purinergic signaling process and thereby alters PMN responses after sepsis. Using high performance liquid chromatography, we found that plasma ATP, ADP, and AMP concentrations increased up to 6 fold during the first 8 h after CLP, reaching top levels that were significantly higher than those in sham control animals without CLP. While leukocyte and PMN counts in sham animals increased significantly after 4 h, these blood cell counts decreased in sepsis animals. CD11b expression on the cell surface of PMN of septic animals was significantly higher compared to sham and untreated control animals. These findings suggest increased PMN activation and sequestration of PMN from the circulation after sepsis. Plasma ATP levels correlated with CD11b expression, suggesting that increased ATP concentrations in plasma contribute to PMN activation. We found that treatment of septic mice with the ATP receptor antagonist suramin diminished CD11b expression, indicating that plasma ATP contributs to PMN activation by stimulating P2 receptors of PMN. Increased PMN activation can protect the host from invading microorganisms. However, increased PMN activation can also be detrimental by promoting secondary organ damage. We conclude that pharmacological targeting of P2 receptors may allow modulation of PMN responses in sepsis.