Molecular mechanisms of airway mucus hypersecretion and airway clearance dynfunction induced by long-acting beta-2 agonist

用长效β-2受体激动剂沙美特罗刺激小鼠气管上皮细胞，以浓度依赖性方式增加DNA和蛋白质合成，在存在特异性β-2受体拮抗剂的情况下，这种作用被消除。沙美特罗还诱导培养的气管上皮细胞中EGFR磷酸化和MUC 5AC表达上调，并且这些作用被EGFR酪氨酸激酶抑制剂和转染显性负突变体H-Ras显著抑制，表明Ras-ERK级联可能参与沙美特罗诱导的细胞反应。此外，沙美特罗增加了小鼠气道中从隆突向口咽部的粘膜纤毛转运速率。光电法测定的气管上皮细胞纤毛搏动频率对沙美特罗的反应增加。这些发现表明，用长效β-2激动剂模拟气道上皮细胞可改善气道清除率。

Stimulation of mouse tracheal epithelial cells with the long-acting beta-2 agonist salmeterol increased DNA and protein synthesis in a concentration-dependent manner, an effect that was abolished in the presence of a specific beta-2 receptor antagonist. Salmeterol also induced phosphorylation of EGFR and upregulated the expression of MUC5AC in cultured tracheal epithelial cells, and these effects were significantly inhibited by a EGFR tyrosine kinase inhibitor and transfection of dominant negative mutant of H-Ras, indicating that Ras-ERK cascade may be involved in the salmeterol-induced cell responses. Moreover, salmeterol increased mucociliary transport rate from the carina toward oropharynx in the mouse airway. Ciliary beat frequency of tracheal epithelial cells determined by a photoelectric method was increased in response to salmeterol. These findings suggest that simulation of airway epithelial cells with long-acting beta-2 agonist causes an improvement of airway clearance.