PAF‐mediated Ca2+ influx in human neutrophils occurs via store‐operated mechanisms
PAF‐mediated Ca2+ influx in human neutrophils occurs via store‐operated mechanisms
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DOI：
10.1189/jlb.69.1.63
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发表时间：
2001-01
影响因子：
5.5
通讯作者：
C. Hauser;Z. Fekete;John M. Adams;M. Garced;D. Livingston;E. Deitch
中科院分区：
文献类型：
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作者：
C. Hauser;Z. Fekete;John M. Adams;M. Garced;D. Livingston;E. Deitch
许多炎症介质激活中性粒细胞（PMN）部分通过增加胞浆钙浓度（[Ca 2 +]i）。因此，调节PMN [Ca 2 +]i可能有助于调节休克或脓毒症后的炎症。然而，传统的钙通道阻滞剂的血流动力学效应可能危及不稳定的患者。现在已知钙池操纵的钙内流（SOCI）有助于“非兴奋”细胞中的Ca 2+通量。因此，我们研究了SOCI在人PMN对促炎配体PAF反应中的作用。PMN [Ca ~（2+）]i测定采用荧光分光光度法。我们研究了PAF对Mn 2+进入和Ca 2+流出毒胡萝卜素（Tg）处理的细胞的影响。在存在和不存在阻滞剂SKF-96365（SKF）、TMB-8和2-APB的情况下评估了内流。PAF [Ca ~（2+）]i动员的一半是通过钙内流进行的。钙内流动力学是SOCI的典型特征，而不是受体介导的钙内流（RMCE）。SKF对[Ca 2 +]i有多种非特异性作用。TMB-8和2-APB对钙库排空的抑制作用阻断了所有钙内流，表明内流具有钙库耗竭依赖性。PAF对钙外流无直接影响。当SOCI最大时，PAF对钙通道流量没有进一步影响。PAF诱导的钙信号高度依赖于SOCI，而不依赖于RMCE。SOCI特异性阻断可能调节PMN介导的炎症，并在休克和脓毒症中保护心血管功能。
Many inflammatory mediators activate neutrophils (PMN) partly by increasing cytosolic calcium concentration ([Ca2+]i). Modulation of PMN [Ca2+]i might therefore be useful in regulating inflammation after shock or sepsis. The hemodynamic effects of traditional Ca2+ channel blockade, however, could endanger unstable patients. Store‐operated calcium influx (SOCI) is known now to contribute to Ca2+ flux in “nonexcitable” cells. Therefore, we studied the role of SOCI in human PMN responses to the proinflammatory ligand PAF. PMN [Ca2+]i was studied by spectrofluorometry with and without external calcium. We studied the effects of PAF on Mn2+ entry into and on Ca2+ efflux from thapsigargin (Tg)‐treated cells. Influx was assessed in the presence and absence of the blockers SKF‐96365 (SKF), TMB‐8, and 2‐APB. Half of PAF [Ca2+]i mobilization occurs via calcium influx. The kinetics of calcium entry were typical of SOCI rather than receptor‐mediated calcium entry (RMCE). SKF had multiple nonspecific effects on [Ca2+]i. Inhibition of store emptying by TMB‐8 and 2‐APB blocked all calcium entry, demonstrating influx was store depletion‐dependent. PAF has no direct effect on calcium efflux. Where SOCI is maximal, PAF has no further effect on calcium‐channel traffic. PAF‐induced calcium signals are highly dependent on SOCI and independent of RMCE. SOCI‐specific blockade might modulate PMN‐mediated inflammation and spare cardiovascular function in shock and sepsis.