Department of Biomedical Engineering, 2420 Engineering Hall, University of California, Irvine, CA 92697-2715, USA.
Am J Respir Cell Mol Biol. 2013 Mar;48(3):299-305. doi: 10.1165/rcmb.2012-0174OC. Epub 2012 Dec 6.
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.
上皮细胞损伤和气道高反应性是哮喘的显著特征。我们之前已经证明，通过钙（Ca（2+））依赖性平滑肌缩短，激光消融单个上皮细胞会立即引起全球气道收缩。该反应由受伤的单个上皮细胞释放的可溶性介质介导；然而，尚未鉴定出可溶性介质和信号转导机制。在这项研究中，我们研究了导致 L 型电压依赖性钙（Ca（2+））通道（VGCC）介导的 Ca（2+）内流的上皮衍生可溶性介质的性质和相关信号通路。我们发现，抑制腺苷 A1 受体（或用腺苷脱氨酶去除腺苷）、环氧化酶（COX）-2 或前列腺素 E 受体 3（EP3）受体、表皮生长因子受体（EGFR）或血小板衍生生长因子受体（PDGFR）均可显著阻止平滑肌细胞中的 Ca（2+）振荡和局部上皮损伤引起的气道收缩。在存在和不存在选择性受体拮抗剂的情况下使用选择性激动剂激活受体，我们发现腺苷激活了信号通路 A1R→EGFR/PDGFR→COX-2→EP3→VGCCs→钙诱导的钙释放，导致气道平滑肌细胞中的细胞内 Ca（2+）振荡和气道收缩。
