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

长效β2激动剂引起气道粘液分泌过多和气道清除功能障碍的分子机制

• 批准号: 23591127
• 负责人: TAMAOKI Jun
• 金额: $ 3.24万
• 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: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2013
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23591127/
• 关键词: 気道クリアランス; 粘液線毛輸送; 気道上皮細胞; 線毛運動; β2受容体; 気道上皮; 細胞増殖; 粘液分泌; 喘息; β２刺激薬; リモデリング; 上皮成長因子受容体; ERKカスケード; チロシンリン酸化

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.

用长效β-2激动剂沙美特罗刺激小鼠气管上皮细胞，以浓度依赖的方式增加DNA和蛋白质的合成，这种作用在特定的β-2受体拮抗剂存在时被取消。沙美特罗还可诱导气管上皮细胞EGFR的磷酸化和上调MUC5AC的表达，这种作用可被EGFR酪氨酸激酶抑制剂和H-RAS的显性负性突变体显著抑制，提示RAS-ERK信号转导通路可能参与沙美特罗诱导的细胞反应。此外，沙美特罗还增加了小鼠呼吸道从隆突到口咽的粘液纤毛转运速率。用光电方法测定的气管上皮细胞纤毛搏动频率随沙美特罗的增加而增加。这些发现表明，用长效β-2激动剂模拟呼吸道上皮细胞可以改善呼吸道清除。

项目成果

Diagnosis, evaluation and monitoring of asthma.

哮喘的诊断、评估和监测。

• DOI: 10.2332/allergolint.12-ed-0483
• 发表时间: 2012
• 期刊: Allergology International
• 影响因子: 6.8
• 作者: J. Tamaoki;H. Saito
• 通讯作者: H. Saito

鼻炎合併喘息の病態と治療：one airway, one diseaseの観点から

哮喘并发鼻炎的病理及治疗：从一种气道、一种疾病的角度

• 发表时间: 2013
• 作者: Arimura K;Aoshiba K;Tsuji T;Tamaoki J;Tamaoki J;Tamaoki J;玉置淳;玉置淳
• 通讯作者: 玉置淳

Effect of tiotropium on mucus hypersecretion and their impact and nasal mucociliary clearance in patients with COPD

噻托溴铵对 COPD 患者粘液过度分泌及其影响和鼻粘液纤毛清除能力的影响

• 作者: Tagaya E;Tamaoki J;Kirishi S;Isono K;Nagaoka M;Kimura N;Kondo M;Nagai A
• 通讯作者: Nagai A

風邪症候群と関連疾患:気管・気管支炎,肺炎.ENT臨床フロンティアシリーズ

寒证及相关疾病：气管/支气管炎、肺炎。耳鼻喉科临床前沿系列

• 发表时间: 2013
• 作者: Kondo M;Nakata J;Arai N;Tagaya E;Takeyama K;Tamaoki J (ed;Tamaoki J);玉置淳,八木理充,落合克律 (小林俊光,高橋晴雄,浦野正美編)
• 通讯作者: 玉置淳,八木理充,落合克律 (小林俊光,高橋晴雄,浦野正美編)

シンポジウム:呼吸器感染症における炎症制御:気道過分泌および粘液線毛輸送の調節

研讨会：呼吸道感染的炎症控制：气道分泌过多和粘液纤毛运输的调节

• 发表时间: 2014
• 作者: Kondo M;Nakata J;Arai N;Izumo T;Takeyama K;Tamaoki J;Nagai A;玉置淳;玉置淳;玉置淳;玉置淳;玉置淳
• 通讯作者: 玉置淳