title: Adenosine A(1) and prostaglandin E receptor 3 receptors mediate global airway contraction after local epithelial injury.
abstract: Epithelial injury and airway hyperresponsiveness are prominent features of asthma. We have previously demonstrated that laser ablation of single epithelial cells immediately induces global airway constriction through Ca(2+)-dependent smooth muscle shortening. The response is mediated by soluble mediators released from wounded single epithelial cells; however, the soluble mediators and signaling mechanisms have not been identified. In this study, we investigated the nature of the epithelial-derived soluble mediators and the associated signaling pathways that lead to the L-type voltage-dependent Ca(2+) channel (VGCC)-mediated Ca(2+) influx. We found that inhibition of adenosine A1 receptors (or removal of adenosine with adenosine deaminase), cyclooxygenase (COX)-2 or prostaglandin E receptor 3 (EP3) receptors, epidermal growth factor receptor (EGFR), or platelet-derived growth factor receptor (PDGFR) all significantly blocked Ca(2+) oscillations in smooth muscle cells and airway contraction induced by local epithelial injury. Using selective agonists to activate the receptors in the presence and absence of selective receptor antagonists, we found that adenosine activated the signaling pathway A1R→EGFR/PDGFR→COX-2→EP3→VGCCs→calcium-induced calcium release, leading to intracellular Ca(2+) oscillations in airway smooth muscle cells and airway constriction.
authors.affiliation: Department of Biomedical Engineering, 2420 Engineering Hall, University of California, Irvine, CA 92697-2715, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.forename: Martha B
authors.initials: MB
authors.lastname: Alvarez-Elizondo
authors.forename: Elliot
authors.initials: E
authors.lastname: Botvinick
authors.forename: Steven C
authors.initials: SC
authors.lastname: George
mesh_terms: D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000187:drug effects / Q000293:injuries / Q000378:metabolism*; D012137:Respiratory System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014947:Wounds and Injuries / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D020746:Calcium Channels, L-Type; D052246:Cyclooxygenase 2 Inhibitors; D043682:Receptor, Adenosine A1; D058308:Receptors, Prostaglandin E, EP3 Subtype; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; C483803:Egfr protein, rat; D066246:ErbB Receptors; D017479:Receptors, Platelet-Derived Growth Factor; D002118:Calcium