Department of Pulmonary Medicine, University Hospital, Freiburg, Germany.
J Immunol. 2010 Jul 1;185(1):688-97. doi: 10.4049/jimmunol.0904042. Epub 2010 Jun 2.
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.
细胞外 ATP 作为一种“危险信号”，通过与嘌呤能受体结合可诱导炎症。慢性阻塞性肺疾病是最常见的与吸烟吸入相关的炎症性疾病之一，但潜在机制尚不完全清楚。在本研究中，我们表明，在吸烟引起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。ATP 中和或非特异性 P2R 阻断显著减少了吸烟引起的肺炎症和肺气肿。我们检测到在吸烟引起的肺炎症动物的中性粒细胞（例如，P2Y2R）、巨噬细胞和肺组织中嘌呤能受体亚型的上调。通过使用 P2Y(2)R 缺陷型 ((-/-)) 动物，我们表明 ATP 通过 P2Y(2)R 诱导血液中性粒细胞向肺部募集。此外，P2Y(2)R 缺陷型动物在急性吸烟暴露后肺部炎症减少。一系列具有 P2Y(2)R(-/-) 和野生型嵌合体动物的实验表明，造血细胞上的 P2Y(2)R 表达在观察到的效应中起关键作用。我们首次证明，内源性 ATP 通过激活嘌呤能受体亚型（如 P2Y(2)R），促进吸烟引起的肺炎症，然后发展为肺气肿。
