Signal transduction in beta2 receptor-mediated remodeling in airway mucosa

β2受体介导的气道粘膜重塑中的信号转导

• 批准号: 14570566
• 负责人: TAMAOKI Jun
• 金额: $ 2.5万
• 依托单位: Tokyo Women's Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570566/
• 关键词: Beta2 receptor; Adrenaline; Airway remodeling; Airway epithelium; Cytokine; Epidermal growth factor; Salbutamol; Asthma; β2刺戟薬; β2受容体

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.

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。

项目成果

Tamaoki J: "Remodeling of airway mucosa in patients with asthma."Respiratory Medicine. 2. 307-311 (2002)

Tamaoki J：“哮喘患者气道粘膜的重塑。”呼吸医学。

玉置淳: "気道分泌および粘液線毛輸送能の病態生理"JOHNS. 19. 787-792 (2003)

Jun Tamaki：“气道分泌和粘液纤毛运输的病理生理学”JOHNS 19. 787-792 (2003)。

玉置 淳: "気管支喘息における気道リモデリングをめぐって"呼吸器科. 2. 307-311 (2002)

Jun Tamaki：“关于支气管哮喘的气道重塑”呼吸内科 2. 307-311 (2002)。

Tamaoki J: "Airway mucus secretion and mucin gene."Respiration. 23. 1056-1061 (2003)

Tamaoki J：“气道粘液分泌和粘蛋白基因。”呼吸。

Tamaoki J: "Airway mucosal remodeling : goblet cells and CFTR."Asthma. 15. 68-72 (2002)

Tamaoki J：“气道粘膜重塑：杯状细胞和 CFTR。”哮喘。