Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, North Carolina, USA.
Purinergic Signal. 2006 Jun;2(2):399-408. doi: 10.1007/s11302-006-9001-7. Epub 2006 May 30.
Chronic obstructive lung diseases are characterized by the inability to prevent bacterial infection and a gradual loss of lung function caused by recurrent inflammatory responses. In the past decade, numerous studies have demonstrated the importance of nucleotide-mediated bacterial clearance. Their interaction with P2 receptors on airway epithelia provides a rapid 'on-and-off' signal stimulating mucus secretion, cilia beating activity and surface hydration. On the other hand, abnormally high ATP levels resulting from damaged epithelia and bacterial lysis may cause lung edema and exacerbate inflammatory responses. Airway ATP concentrations are regulated by ecto nucleoside triphosphate diphosphohydrolases (E-NTPDases) which are expressed on the mucosal surface and catalyze the sequential dephosphorylation of nucleoside triphosphates to nucleoside monophosphates (ATP --> ADP --> AMP). The common bacterial product, Pseudomonas aeruginosa lipopolysaccharide (LPS), induces an acute reduction in azide-sensitive E-NTPDase activities, followed by a sustained increase in activity as well as NTPDase 1 and NTPDase 3 expression. Accordingly, chronic lung diseases, including cystic fibrosis (CF) and primary ciliary dyskinesia, are characterized by higher rates of nucleotide elimination, azide-sensitive E-NTPDase activities and expression. This review integrates the biphasic regulation of airway E-NTPDases with the function of purine signaling in lung diseases. During acute insults, a transient reduction in E-NTPDase activities may be beneficial to stimulate ATP-mediated bacterial clearance. In chronic lung diseases, elevating E-NTPDase activities may represent an attempt to prevent P2 receptor desensitization and nucleotide-mediated lung damage.
慢性阻塞性肺疾病的特征是无法预防细菌感染，并且由于反复的炎症反应，肺功能逐渐丧失。在过去的十年中，大量研究表明核苷酸介导的细菌清除的重要性。它们与气道上皮细胞上的 P2 受体相互作用，提供了一个快速的“开-关”信号，刺激黏液分泌、纤毛运动和表面水合作用。另一方面，由于上皮细胞损伤和细菌裂解导致的异常高 ATP 水平可能导致肺水肿并加重炎症反应。气道中的 ATP 浓度受细胞外核苷酸三磷酸二磷酸水解酶（E-NTPDases）的调节，这些酶在黏膜表面表达，催化核苷三磷酸的顺序去磷酸化生成核苷单磷酸（ATP-->ADP-->AMP）。常见的细菌产物铜绿假单胞菌脂多糖（LPS）诱导对叠氮敏感的 E-NTPDase 活性急性降低，随后活性持续增加以及 NTPDase 1 和 NTPDase 3 的表达增加。因此，包括囊性纤维化（CF）和原发性纤毛运动障碍在内的慢性肺部疾病的特征是核苷酸消除率、对叠氮敏感的 E-NTPDase 活性和表达增加。本综述将气道 E-NTPDase 的双相调节与嘌呤信号在肺部疾病中的功能相结合。在急性损伤时，E-NTPDase 活性的短暂降低可能有助于刺激 ATP 介导的细菌清除。在慢性肺部疾病中，提高 E-NTPDase 活性可能代表一种试图防止 P2 受体脱敏和核苷酸介导的肺损伤的尝试。
