Hypertonic saline enhances neutrophil elastase release through activation of P2 and A3 receptors
Hypertonic saline enhances neutrophil elastase release through activation of P2 and A3 receptors
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DOI：
10.1152/ajpcell.00216.2005
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发表时间：
2006-04-01
影响因子：
5.5
通讯作者：
Junger, WG
中科院分区：
文献类型：
--
作者：
Chen, Y;Hashiguchi, N;Junger, WG
高渗盐水(HS)可抑制中性粒细胞(PMN)的激活，从而防止宿主组织损伤和相关的创伤后并发症，因此有望成为治疗创伤患者的一种新型复苏液。然而，根据细胞激活的情况，HS会增加PMN脱颗粒，这可能会加剧创伤受害者的组织损伤。HS增加脱颗粒的细胞机制尚不清楚。在本研究中，我们测试了HS诱导的中性粒细胞释放ATP以及通过P1和/或P2受体的反馈是否参与了HS促进脱颗粒的作用。我们发现，在用甲酰肽(FMLP)或佛波酯(PMA)激活PMN后加入HS，可促进弹性蛋白酶的释放以及ERK和p38MAPK的激活。P2核苷酸和A3腺苷受体激动剂可模拟HS的这些增强作用，而A3受体拮抗剂或用apyrase去除细胞外ATP则减弱HS的反应。A1腺苷受体拮抗剂可增强HS的增强作用，A1受体激动剂则抑制弹性蛋白酶的释放。这些数据表明，HS通过释放ATP和通过P2和A3受体进行正反馈来上调脱颗粒。我们认为这些反馈机制可以作为调整HS复苏临床效果的潜在药理学靶点。
Hypertonic saline ( HS) holds promise as a novel resuscitation fluid for the treatment of trauma patients because HS inhibits polymorphonuclear neutrophil ( PMN) activation and thereby prevents host tissue damage and associated posttraumatic complications. However, depending on conditions of cell activation, HS can increase PMN degranulation, which could exacerbate tissue damage in trauma victims. The cellular mechanism by which HS increases degranulation is unknown. In the present study, we tested whether HS-induced ATP release from PMN and feedback via P1 and/or P2 receptors may be involved in the enhancement of degranulation by HS. We found that HS enhances elastase release and ERK and p38 MAPK activation when HS is added after activation of PMN with formyl peptide ( fMLP) or phorbol ester ( PMA). Agonists of P2 nucleotide and A3 adenosine receptors mimicked these enhancing effects of HS, whereas antagonists of A3 receptors or removal of extracellular ATP with apyrase diminished the response to HS. A1 adenosine receptor antagonists increased the enhancing effect of HS, whereas A1 receptor agonists inhibited elastase release. These data suggest that HS upregulates degranulation via ATP release and positive feedback through P2 and A3 receptors. We propose that these feedback mechanisms can serve as potential pharmacological targets to fine-tune the clinical effectiveness of HS resuscitation.