analysis of the mechanism for aspirin modulation of IgE-dependent mast cell activation

阿司匹林引起免疫副作用，这些副作用统称为阿司匹林不耐受。阿司匹林不耐受是一种疾病，可引起荨麻疹、哮喘和过敏反应。阿司匹林不耐受的一个关键临床特征是肥大细胞中LTC4、LTD4和LTE4的过量产生，它们都是由花生四烯酸酯依次合成的。这些半胱氨酸LTs （cys-LTs）是有效的促炎介质，引起平滑肌收缩和血管通透性增加。最近，我们发现阿司匹林和水杨酸盐上调肥大细胞中ige介导的Ca2+反应和LTC4分泌（Togo等人，2009；Suzuki等人，2010；Suzuki等人，2010）。然而，引人注目的是，这两种药物抑制而不是促进Ca2+通道的激活，Ca2+通道是Ca2+内流和LTC4分泌的主要途径。相反，它们促进了非soc的激活。在本研究中，我们试图确定阿司匹林敏感Ca2+通道的分子实体，并阐明阿司匹林激活它们的分子机制。我们的数据表明，阿司匹林和水杨酸盐通过激活Cav1.2 l型Ca2+通道（LTCC）促进分泌反应，并表明这两种药物通过线粒体活性氧（ROS）的产生和去极化发挥作用。

Aspirin induces immunological side effects, which are collectively referred to as aspirin intolerance. Aspirin intolerance is a disorder that induces urticaria, asthma and anaphylaxis in response to oral administration of the drug. One key clinical feature of aspirin intolerance is overproduction of LTC4, LTD4 and LTE4 in mast cells, which are all sequentially synthesized from arachidonate. These cysteinyl LTs (cys-LTs) are potent proinflammatory mediators and cause smooth muscle contraction and increased vascular permeability. Recently, we showed that aspirin and salicylates upregulate IgE-mediated Ca2+ responses and LTC4 secretion in mast cells (Togo et al., 2009; Suzuki et al., 2010; Suzuki et al., 2010). Strikingly, however both drugs inhibited rather than facilitated the activation of store-operated Ca2+ channels, the major pathway for Ca2+ influx and LTC4 secretion. Instead, they facilitated the activation of a non-SOCC. In the present study, we attempted to identify the molecular entity of the aspirin-sensitive Ca2+ channels and clarify the molecular mechanisms underlying their activation by aspirin. Our data show that aspirin and salicylates facilitate secretion responses through Cav1.2 L-type Ca2+ channel (LTCC) activation and suggest that both drugs exert the effects via mitochondrial reactive oxygen species (ROS) production and depolarization.