Department of Respiratory Diseases, West China School of Medicine and West China Hospital, Sichuan University, Chengdu, 610041, China.
Department of Respiratory Diseases, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.
Sci Rep. 2017 Jan 4;7:39905. doi: 10.1038/srep39905.
Mechanisms underlying β-adrenoreceptor (βAR) inverse agonist mediated bronchoprotectiveness remain unknown. We incubated ICI118,551, formoterol, budesonide, and formoterol plus budesonide, as well as ICI118,551 or pindolol plus formoterol, ICI118,551 plus forskolin, SQ22,536 or H89 plus formoterol in ASMCs to detect expressions of MR, PLCβ and IP. The level of MR in the presence of 10 mmol/L ICI118,551 were significantly decreased at 12 h, 24 h and 48 h (P < 0.05), and at 24 h were significantly reduced in ICI118,551 with concentration of 10mmol/L, 10mmol/L, 10mmol/L, and 10mmol/L (P < 0.05). The level of IP in 10mmol/L ICI118,551 was significantly diminished at 24 h (P < 0.01), except for that at 1 h, neither was in the level of PLCβ. A concentration of 10mmol/L ICI118,551 at 24 h showed a significant reduction of MR level compared to formoterol (P < 0.01), budesonide (P < 0.01), and formoterol + budesonide (P < 0.05), but significant reduction of PLCβ and IP was only found between 10mmol/L ICI118,551 and formoterol at 24 h, but not in the comparison of budesonide or formoterol + budesonide. Pindolol and H89 could not inhibit the formoterol-induced expression of MR (P > 0.05), but SQ22,536 significantly antagonized the formoterol-induced MR expression (P < 0.05). In conclusions, βAR inverse agonist, ICI118,551, exerts similar bronchoprotective effects to corticosteroids via decreasing the expression of MR and inhibiting the production of IP.
β-肾上腺素能受体（βAR）反向激动剂介导的支气管保护作用的机制尚不清楚。我们孵育了 ICI118551、福莫特罗、布地奈德以及福莫特罗加布地奈德，还有 ICI118551 或心得安加福莫特罗、ICI118551 加 forskolin、SQ22536 或 H89 加福莫特罗，以检测 MR、PLCβ 和 IP 的表达。在 10mmol/L ICI118551 存在的情况下，MR 的水平在 12 小时、24 小时和 48 小时时显著降低（P<0.05），并且在浓度为 10mmol/L、10mmol/L、10mmol/L 和 10mmol/L 的 ICI118551 中，24 小时时的水平显著降低（P<0.05）。在 10mmol/L ICI118551 中，IP 的水平在 24 小时时显著降低（P<0.01），除了在 1 小时时，PLCβ 的水平没有变化。在 24 小时时，浓度为 10mmol/L 的 ICI118551 与福莫特罗（P<0.01）、布地奈德（P<0.01）和福莫特罗加布地奈德（P<0.05）相比，MR 水平显著降低，但仅在 24 小时时发现 ICI118551 与福莫特罗之间的 PLCβ 和 IP 水平显著降低，而在布地奈德或福莫特罗加布地奈德之间则没有发现。心得安和 H89 不能抑制福莫特罗诱导的 MR 表达（P>0.05），但 SQ22536 显著拮抗福莫特罗诱导的 MR 表达（P<0.05）。总之，βAR 反向激动剂 ICI118551 通过降低 MR 的表达和抑制 IP 的产生，发挥与皮质类固醇相似的支气管保护作用。
