Signal transduction in beta2 receptor-mediated remodeling in airway mucosa

为了确定β2-激动剂是否影响体内气道上皮细胞增殖，如果是，其作用机制是什么，我们检查了沙丁胺醇对小鼠气道形态的影响。SPF-SD大鼠使用“流通式”鼻吸入室以0.2-20μg的每日剂量给予雾化沙丁胺醇长达6周。观察气管黏膜形态、BrdU标记上皮细胞和支气管反应性。暴露于沙丁胺醇以剂量和时间依赖性方式增加气管上皮层厚度和BrdU阳性上皮细胞数量，EGFR抑制剂AG 1478抑制了这种作用。在体外培养的气道上皮细胞研究中，与沙丁胺醇孵育刺激蛋白质和DNA合成，并诱导磷酸化EGFR及其mRNA的表达。这些作用被HB-EGF和金属蛋白酶的特异性抑制剂降低。提示β2受体激动剂通过EGFR依赖性途径刺激气道上皮细胞增殖，导致气道壁增厚，并参与金属蛋白酶的释放和HB-EGF的后续加工。

To determine whether β2-agonist affects airway epithelial cell proliferation in vivo and, if so, what the mechanism of action is, we examined the effect of salbutamol on the morphology of murine airways. SPF-SD rats were given aerosolized salbutamol using "flow-through" nose-only inhalation chambers at daily doses of 0.2-20μg for up to 6 weeks. Morphology of tracheal mucosa, labeling of epithelial cells with BrdU, and bronchial responsiveness were assessed. Exposure to salbutamol increased the thickness of tracheal epithelial layer and the number of BrdU-positive epithelial cells in a dose-and time-dependent manner, an effect that was inhibited by the EGFR inhibitor AG1478. In in vitro study with cultured airway epithelial cells, incubation with salbutamol stimulated protein and DNA syntheses and induced the expression of phosphorylated EGFR and its mRNA. These effects were reduced by specific inhibitors of HB-EGF and metalloproteinase. These results suggest that β2-agonist stimulates proliferation of airway epithelial cells and produces airway wall thickening via EGFR-dependent pathway, involving the release of metalloproteinase and the subsequent processing of HB-EGF.