Purinergic Receptor Inhibition Prevents the Development of Smoke-Induced Lung Injury and Emphysema
Purinergic Receptor Inhibition Prevents the Development of Smoke-Induced Lung Injury and Emphysema
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DOI：
10.4049/jimmunol.0904042
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发表时间：
2010-07-01
影响因子：
4.4
通讯作者：
Idzko, Marco
中科院分区：
文献类型：
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作者：
Cicko, Sanja;Lucattelli, Monica;Idzko, Marco
细胞外的三磷酸腺苷起着“危险信号”的作用，可以通过与嘌呤能受体结合而引发炎症。慢性阻塞性肺疾病是与香烟烟雾吸入有关的最常见的炎症性疾病之一，但其潜在的机制尚不完全清楚。在这项研究中，我们证明了在烟雾诱导的急性肺炎症和肺气肿的小鼠模型中，内源性肺ATP水平增加。三磷酸腺苷中和或非特异性的P2R阻断可显著减少吸烟引起的肺部炎症和肺气肿。我们检测到烟雾诱导的肺炎症动物的中性粒细胞(例如，P2Y2R)、巨噬细胞和肺组织上的嘌呤能受体亚型上调。通过使用P2Y(2)R缺陷((-/-))动物，我们证明了ATP通过P2Y(2)R诱导血中性粒细胞募集到肺中，而且，在急性烟雾暴露后，P2Y(2)R缺陷动物的肺部炎症减轻。用P2Y(2)R(-/-)和野生型嵌合体动物进行的一系列实验表明，造血细胞上的P2Y(2)R表达在观察到的效应中起着关键作用。我们首次证明，内源性三磷酸腺苷通过激活嘌呤能受体亚型，如P2Y(2)R，在吸烟诱导的肺部炎症和随后的肺气肿发展中起作用。免疫学杂志，2010,185：688-697。
Extracellular ATP acts as a "danger signal" and can induce inflammation by binding to purinergic receptors. Chronic obstructive pulmonary disease is one of the most common inflammatory diseases associated with cigarette smoke inhalation, but the underlying mechanisms are incompletely understood. In this study, we show that endogenous pulmonary ATP levels are increased in a mouse model of smoke-induced acute lung inflammation and emphysema. ATP neutralization or nonspecific P2R-blockade markedly reduced smoke-induced lung inflammation and emphysema. We detected an upregulation the purinergic receptors subtypes on neutrophils (e.g., P2Y2R), macrophages, and lung tissue from animals with smoke-induced lung inflammation. By using P2Y(2)R deficient ((-/-)) animals, we show that ATP induces the recruitment of blood neutrophils to the lungs via P2Y(2)R. Moreover, P2Y(2)R deficient animals had a reduced pulmonary inflammation following acute smoke-exposure. A series of experiments with P2Y(2)R(-/-) and wild type chimera animals revealed that P2Y(2)R expression on hematopoietic cell plays the pivotal role in the observed effect. We demonstrate, for the first time, that endogenous ATP contributes to smoke-induced lung inflammation and then development of emphysema via activation of the purinergic receptor subtypes, such as P2Y(2)R. The Journal of Immunology, 2010, 185: 688-697.