Leukotriene E4-induced pulmonary inflammation is mediated by the P2Y12 receptor.
Leukotriene E4-induced pulmonary inflammation is mediated by the P2Y12 receptor.
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DOI：
10.1084/jem.20091240
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发表时间：
2009-10-26
期刊：
影响因子：
--
通讯作者：
Boyce JA
中科院分区：
文献类型：
--
作者：
Paruchuri S;Tashimo H;Feng C;Maekawa A;Xing W;Jiang Y;Kanaoka Y;Conley P;Boyce JA
在包含半胱氨酰白三烯（LT; LTC 4、LTD 4和LTE 4）的有效脂质炎症介质中，只有LTE 4在体内是稳定和丰富的。尽管LTE 4在cys-LT的1型和2型受体（CysLT 1 R和CysLT 2 R）上显示出可忽略的活性，但它是哮喘患者粘膜嗜酸性粒细胞增多和气道高反应性的强有力诱导剂。我们发现，腺苷二磷酸（ADP）反应性嘌呤能（P2 Y12）受体是LTE 4介导的肺部炎症所必需的。P2 Y12受体表达允许中国仓鼠卵巢细胞中LTE 4诱导的细胞外信号调节激酶活化，并允许人肥大细胞系LAD 2细胞产生趋化因子和前列腺素D2。P2 Y12受体表达的LAD 2细胞之间的竞争所需的放射性标记的ADP和未标记的LTE 4，但不直接结合的LTE 4，表明P2 Y12复合物与另一种受体识别LTE 4。致敏小鼠气道给予LTE 4可增强嗜酸性粒细胞增多、杯状细胞化生和白细胞介素-13的表达，以响应低剂量雾化变应原。这些反应在缺乏CysLT 1 R和CysLT 2 R的小鼠中持续存在，但在缺乏P2 Y12受体的小鼠中不存在。LTE 4对气道中P2 Y12的影响被血小板耗竭所消除。因此，P2 Y12受体是稳定丰富的介质LTE 4的促炎作用所必需的，并且是哮喘的新的潜在治疗靶点。
Of the potent lipid inflammatory mediators comprising the cysteinyl leukotrienes (LTs; LTC4, LTD4, and LTE4), only LTE4 is stable and abundant in vivo. Although LTE4 shows negligible activity at the type 1 and 2 receptors for cys-LTs (CysLT1R and CysLT2R), it is a powerful inducer of mucosal eosinophilia and airway hyperresponsiveness in humans with asthma. We show that the adenosine diphosphate (ADP)–reactive purinergic (P2Y12) receptor is required for LTE4-mediated pulmonary inflammation. P2Y12 receptor expression permits LTE4 -induced activation of extracellular signal-regulated kinase in Chinese hamster ovary cells and permits chemokine and prostaglandin D2 production by LAD2 cells, a human mast cell line. P2Y12 receptor expression by LAD2 cells is required for competition between radiolabeled ADP and unlabeled LTE4 but not for direct binding of LTE4, suggesting that P2Y12 complexes with another receptor to recognize LTE4. Administration of LTE4 to the airways of sensitized mice potentiates eosinophilia, goblet cell metaplasia, and expression of interleukin-13 in response to low-dose aerosolized allergen. These responses persist in mice lacking both CysLT1R and CysLT2R but not in mice lacking P2Y12 receptors. The effects of LTE4 on P2Y12 in the airway were abrogated by platelet depletion. Thus, the P2Y12 receptor is required for proinflammatory actions of the stable abundant mediator LTE4 and is a novel potential therapeutic target for asthma.
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DOI：
10.1164/ajrccm/146.6.1506
发表时间：
1992-12-01
期刊：
AMERICAN REVIEW OF RESPIRATORY DISEASE
影响因子：
--
作者：
CHRISTIE, PE;HAWKSWORTH, R;LEE, TH
通讯作者：
LEE, TH
影响因子：
4.4
作者：
Feng, CL;Mery, AG;Boyce, JA
通讯作者：
Boyce, JA
影响因子：
20.3
作者：
Jin, JG;Quinton, TM;Kunapuli, SP
通讯作者：
Kunapuli, SP
DOI：
10.1164/ajrccm.157.4.9707089
发表时间：
1998-04-01
影响因子：
24.7
作者：
Dahlén, B;Nizankowska, E;Dahlén, SE
通讯作者：
Dahlén, SE
DOI：
10.1164/ajrccm/140.6.1745
发表时间：
1989-12-01
期刊：
AMERICAN REVIEW OF RESPIRATORY DISEASE
影响因子：
--
作者：
JEFFERY, PK;WARDLAW, AJ;KAY, AB
通讯作者：
KAY, AB