Nucleosides and nucleotides in the lung: role in asthma.

Abstract

Adenine nucleosides and nucleotides have multiple effects as extracellular mediators in every organ system (1) and initiate or modulate cellular responses via cell surface receptors. Current evidence indicates the existence of four receptors for adenosine: A 1 , A 2A , A 2B , and A 3 (2). These G protein–coupled receptors transduce activation or inhibition of adenylate cyclase and phospholipase C. Reasonably selective antagonists are available for some adenosine receptor subtypes. The receptors for adenine nucleotides, such as adenosine triphosphate (ATP), now encompass seven distinct P2X class receptors (P2X 1 through P2X 7 ) (3) and ten P2Y subfamily receptors: P2Y 1 through P2Y 11 (the former P2Y 7 -receptor is no longer included as a subtype) (4). Five of these receptors are mammalian. Despite its structure, uridine triphosphate (UTP) is a potent ligand at several P2Y-receptors. Responses to P2X-receptor stimulation result from activation of nonselective cation channels in the cell membrane. P2Y-receptor activation stimulates signaling mediated via phospholipase C. There is a paucity of specific antagonists for P2Xand P2Y-receptors, and their characteristics have been defined through the use of relative agonist potencies. Additional information about the molecular characteristics of these receptors, their pharmacologic properties, and associated signaling pathways can be found in several recent compendia and reviews (1, 5–8). Nucleosides and nucleotides have several important actions in the lung (9), among which are contractile and relaxant effects on airway smooth muscle, stimulation of mucus and surfactant secretion, and stimulation of ciliarybeating activity. Nucleosides and nucleotides activate or modulate a number of inflammatory cells that are involved in lung disease, including mast cells, neutrophils, macrophages, and eosinophils (1, 10, 11). Two particular aspects of nucleosides and nucleotides have direct applicability to lung disease and its treatment. First, ATP and UTP stimulate with comparable affinity epithelial alternative Cl 2 channels both in normal epithelium and in epithelium from cystic fibrosis (CF) patients, who lack a normally functioning CF-transmembrane conductance regulator Cl 2