Human airway smooth muscle cells secrete amphiregulin via bradykinin/COX-2/PGE2, inducing COX-2, CXCL8, and VEGF expression in airway epithelial cells
Human airway smooth muscle cells secrete amphiregulin via bradykinin/COX-2/PGE2, inducing COX-2, CXCL8, and VEGF expression in airway epithelial cells
复制标题
DOI：
10.1152/ajplung.00390.2014
复制
发表时间：
2015-08-01
影响因子：
4.9
通讯作者：
Knox, Alan J.
中科院分区：
文献类型：
--
作者：
Deacon, Karl;Knox, Alan J.
人气道平滑肌细胞（HASMC）通过增加平滑肌质量和升高的细胞因子/趋化因子输出而促进哮喘病理生理学。HASMC和气道上皮细胞如何相互作用以调节慢性气道炎症和重塑，目前还知之甚少。双调蛋白是表皮生长因子受体（EGFR）激动剂家族的成员，具有细胞生长和促炎作用，并在哮喘患者的肺中表达增加。我们发现缓激肽（BK）刺激HASMC增加双调蛋白分泌的机制依赖于BK诱导的考克斯-2表达，增加PGE（2）输出，以及刺激HASMC EP 2和EP 4受体。BK处理的HASMC的条件培养基诱导CXCL 8、VEGF和考克斯-2 mRNA和蛋白在气道上皮细胞中的积累，这被抗双调蛋白抗体和双调蛋白siRNA阻断，表明HASMC衍生的双调蛋白对气道上皮细胞的旁分泌作用。与此一致，重组双调蛋白诱导气道上皮细胞中的CXCL 8、VEGF和考克斯-2。最后，我们发现双调蛋白刺激的气道上皮细胞的条件培养基诱导HASMC中双调蛋白的表达，并且这依赖于气道上皮细胞考克斯-2的活性。我们的研究提供了HASMC和上皮细胞之间相互作用的动态轴的证据，该轴放大了CXCL 8、VEGF、考克斯-2和双调蛋白的产生。
Human airway smooth muscle cells (HASMC) contribute to asthma pathophysiology through an increased smooth muscle mass and elevated cytokine/chemokine output. Little is known about how HASMC and the airway epithelium interact to regulate chronic airway inflammation and remodeling. Amphiregulin is a member of the family of epidermal growth factor receptor (EGFR) agonists with cell growth and proinflammatory roles and increased expression in the lungs of asthma patients. Here we show that bradykinin (BK) stimulation of HASMC increases amphiregulin secretion in a mechanism dependent on BK-induced COX-2 expression, increased PGE(2) output, and the stimulation of HASMC EP2 and EP4 receptors. Conditioned medium from BK treated HASMC induced CXCL8, VEGF, and COX-2 mRNA and protein accumulation in airway epithelial cells, which were blocked by anti-amphiregulin antibodies and amphiregulin siRNA, suggesting a paracrine effect of HASMC-derived amphiregulin on airway epithelial cells. Consistent with this, recombinant amphiregulin induced CXCL8, VEGF, and COX-2 in airway epithelial cells. Finally, we found that conditioned media from amphiregulin-stimulated airway epithelial cells induced amphiregulin expression in HASMC and that this was dependent on airway epithelial cell COX-2 activity. Our study provides evidence of a dynamic axis of interaction between HASMC and epithelial cells that amplifies CXCL8, VEGF, COX-2, and amphiregulin production.