Com Gulnur, Clancy J P
University of Arkansas Medical Sciences, Arkansas Children's Hospital, Little Rock, AR 72202-3591, USA.
Handb Exp Pharmacol. 2009(193):363-81. doi: 10.1007/978-3-540-89615-9_12.
Adenosine (Ado) regulates diverse cellular functions in the lung through its local production, release, metabolism, and subsequent stimulation of G-protein-coupled P1 purinergic receptors. The A(2B) adenosine receptor (A(2B)AR) is the predominant P1 purinergic receptor isoform expressed in surface airway epithelia, and Ado is an important regulator of airway surface liquid (ASL) volume through its activation of the cystic fibrosis transmembrane conductance regulator (CFTR). Through a delicate balance between sodium (Na(+)) absorption and chloride (Cl(-)) secretion, the ASL volume is optimized to promote ciliary activity and mucociliary clearance, effectively removing inhaled particulates. When CFTR is dysfunctional, the Ado/A(2B)AR regulatory system fails to optimize the ASL volume, leading to its depletion and interruption of mucociliary clearance. In cystic fibrosis (CF), loss of CFTR function and resultant mucus stasis leaves the lower airways susceptible to mucus obstruction, chronic bacterial infection, relentless inflammation, and eventually panbronchiectasis. Adenosine triphosphate (ATP) also regulates transepithelial Cl(-) conductance, but through a separate system that relies on stimulation of P2Y(2) purinergic receptors, mobilization of intracellular calcium, and activation of calcium-activated chloride channels (CaCCs). These pathways remain functional in CF, and may serve a protective role in the disease. In this chapter, we will review our current understanding of how Ado and related nucleotides regulate CFTR and Cl(-) conductance in the human airway, including the regulation of additional intracellular and extracellular signaling pathways that provide important links between ion transport and inflammation relevant to the disease.
腺苷（Ado）通过其在局部的产生、释放、代谢以及随后对G蛋白偶联P1嘌呤能受体的刺激来调节肺内多种细胞功能。A2B腺苷受体（A2BAR）是气道表面上皮中表达的主要P1嘌呤能受体亚型，Ado通过激活囊性纤维化跨膜传导调节因子（CFTR），是气道表面液体（ASL）量的重要调节因子。通过钠（Na+）吸收和氯（Cl-）分泌之间的微妙平衡，ASL量得以优化，以促进纤毛活动和黏液纤毛清除，有效清除吸入的颗粒物。当CFTR功能失调时，Ado/A2BAR调节系统无法优化ASL量，导致其减少以及黏液纤毛清除中断。在囊性纤维化（CF）中，CFTR功能丧失及由此导致的黏液淤滞使下呼吸道易受黏液阻塞、慢性细菌感染、持续性炎症影响，最终导致全支气管扩张。三磷酸腺苷（ATP）也调节跨上皮Cl-传导，但通过一个独立的系统，该系统依赖于对P2Y2嘌呤能受体的刺激、细胞内钙的动员以及钙激活氯通道（CaCCs）的激活。这些途径在CF中仍发挥作用，可能在该疾病中起到保护作用。在本章中，我们将综述目前对Ado和相关核苷酸如何调节人类气道中CFTR和Cl-传导的理解，包括对其他细胞内和细胞外信号通路的调节，这些信号通路在与该疾病相关的离子转运和炎症之间提供了重要联系。
