Adenosine A(1) and Prostaglandin E Receptor 3 Receptors Mediate Global Airway Contraction after Local Epithelial Injury

作者：Zhou Jian; Alvarez Elizondo Martha B; Botvinick Elliot; George Steven C^*

来源：American Journal of Respiratory Cell and Molecular Biology, 2013, 48(3): 299-305.

DOI：10.1165/rcmb.2012-0174OC

• ATP
• epidermal growth factor receptor
• platelet-derived growth factor receptor
• cyclooxygenase-2
• L-type voltage-dependent Ca2+ channels

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 Ca2+-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 Ca2+ channel (VGCC)-mediated Ca2+ influx. We found that inhibition of adenosine A(1) 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 Ca2+ 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 A(1)R -> EGFR/PDGFR -> COX-2 -> EP3 -> VGCCs -> calcium-induced calcium release, leading to intracellular Ca2+ oscillations in airway smooth muscle cells and airway constriction.

• 出版日期2013-3